Cancer treatment methods using antibody-drug conjugates (ADCs) that bind to the 191P4D12 protein

Abstract

To provide a method for preventing or treating cancer in humans. [Solution] The present invention provides a method for treating cancer using an antibody-drug conjugate (ADC) that binds to the 191P4D12 protein. A method for treating urothelial carcinoma using an antibody-drug conjugate (ADC) that binds to 191P4D12 is also provided herein. A method for treating solid tumors using an antibody-drug conjugate (ADC) that binds to 191P4D12 is further provided herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 940,209, filed on 25 November 2019, and U.S. Provisional Patent Application No. 62 / 944,890, filed on 6 December 2019, the disclosures of each of these applications being incorporated herein by reference in their entirety.

[0002] Sequence List This specification is submitted with a computer-readable format (CRF) copy of the sequence listing. The CRF titled "14369-252-228_SEQ_LISTING.txt", created on November 20, 2020, and measuring 39,705 bytes, is incorporated herein by reference in its entirety.

[0003] 1. Field A method for treating cancer using an antibody-drug conjugate (ADC) that binds to the 191P4D12 protein is provided herein. [Background technology]

[0004] 2. Background Cancer is the leading cause of death for people aged 35 to 65 in the United States and the second leading cause of death worldwide. In 2019, it was estimated that there were approximately 1.7 million new cancer cases and approximately 610,000 cancer-related deaths in the United States (National Cancer Institute. 2019. Cancer Stat Facts: Cancer of Any Site. https: / / seer.cancer.gov / statfacts / html / all.html. (Non-patent Literature 1) Accessed June 5, 2019). Globally, it was estimated that there were 18.1 million new cancer cases in 2018, and approximately 9.6 million deaths were due to cancer in that year (World Health Organization. Press Release. Sept 2018. https: / / www.who.int / cancer / PRGlobocanFinal.pdf. (Non-patent Literature 2) Accessed June 5, 2019). Currently, most deaths occur in patients with metastatic cancer. In fact, over the past 20 years, advances in treatment, including surgery, radiation therapy, and adjuvant chemotherapy, have resulted in the cure of most patients with localized cancer. Patients whose cancer manifested as metastatic disease or recurred received little benefit from conventional treatments in terms of overall survival (OS), and were rarely cured.

[0005] Novel therapeutic strategies for advanced and / or metastatic cancers include targeting molecular pathways crucial for cancer cell survival and novel cytotoxic compounds. The benefits of these new drugs are reflected in long-term survival; however, outcomes remain poor for most patients with distant metastases, highlighting the need for new therapies.

[0006] 191P4D12 (also known as Nectin-4) is a type I transmembrane protein and a member of the family of related immunoglobulin-like adhesion molecules involved in cell-cell adhesion. 191P4D12 belongs to the nectin family of adhesion molecules. 191P4D12 consists of an extracellular domain (ECD) containing three Ig-like subdomains, a transmembrane helix, and an intracellular domain (Takai Y et al., Annu Rev Cell Dev Biol 2008;24:309-42 (Non-Patent Literature 3)). Nectins are thought to mediate Ca2+-independent cell-cell adhesion through both homophilic and heterophilic trans interactions at adhesion junctions that can recruit cadherins and regulate cytoskeletal rearrangement (Rikitake & Takai, Cell Mol Life Sci. 2008;65(2):253-63 (Non-Patent Literature 4)). Sequence identity of 191P4D12 to other nectin family members is low, ranging from 25% to 30% in ECD (Reymond N et al, J Biol Chem 2001;43205-15 (Non-Patent Literature 5)). Nectin-promoting adhesion supports several biological processes, including immunomodulation, host-pathogen interaction, and immune evasion (Sakisaka T et al., Current Opinion in Cell Biology 2007;19:593-602 (Non-Patent Literature 6)).

[0007] There is a strong need for further treatment methods for cancer. These include the use of antibodies and antibody-drug conjugates as modes of treatment. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] National Cancer Institute.2019.Cancer Stat Facts:Cancer of Any Site.https: / / seer.cancer.gov / statfacts / html / all.html. [Non-Patent Document 2] World Health Organization.Press Release.Sept 2018.https: / / www.who.int / cancer / PRGlobocanFinal.pdf. [Non-Patent Document 3] Takai Y et al., Annu Rev Cell Dev Biol 2008;24:309-42 [Non-Patent Document 4] Rikitake&Takai,Cell Mol Life Sci.2008;65(2):253-63 [Non-Patent Document 5] Reymond N et al,J Biol Chem 2001;43205-15 [Non-Patent Document 6] Sakisaka T et al.,Current Opinion in Cell Biology 2007;19:593-602 [Overview of the project]

[0009] 3. Overview Appearance 1. A method for preventing or treating cancer in a human subject, comprising the step of administering to the subject a first regimen comprising an effective amount of an antibody-drug conjugate (ADC), The ADC comprises an antibody or antigen-binding fragment conjugated to one or more units of monomethyl auristatin E (MMAE) that binds to 191P4D12, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region containing a complementarity-determining region (CDR) including the amino acid sequence of the CDR of the heavy chain variable region shown in SEQ ID NO:22, and a light chain variable region containing a CDR including the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:23. The subject has urothelial carcinoma, The subject is receiving immune checkpoint inhibitor therapy and chemotherapy. method. Appearance 2. The method according to embodiment 1, wherein the ADC is administered three times within a 28-day cycle. Appearance 3. The method according to embodiment 1 or 2, wherein the ADC is administered on days 1, 8, and 15 of a 28-day cycle. Appearance 4. A method according to any of embodiments 1 to 3, wherein the urothelial carcinoma is locally advanced urothelial carcinoma. Appearance 5. A method according to any of embodiments 1 to 3, wherein the urothelial carcinoma is metastatic urothelial carcinoma. Appearance 6. A method according to any one of embodiments 1 to 5, wherein the immune checkpoint inhibitor therapy is a programmed death receptor 1 (PD-1) inhibitor. Appearance 7. A method according to any one of embodiments 1 to 5, wherein the immune checkpoint inhibitor therapy is a programmed death ligand 1 (PD-L1) inhibitor. Appearance 8. A method in any of embodiments 1 to 7, wherein the chemotherapy is platinum-containing chemotherapy. Appearance 9. The method according to embodiment 8, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in a neoadjuvant setting. Appearance 10. The method according to embodiment 8, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in an adjuvant setting. Appearance 11. A method according to any of embodiments 8 to 10, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in a locally advanced disease setting. Appearance 12. A method in which platinum-containing chemotherapy is platinum-containing chemotherapy in a metastatic setting, as described in any of embodiments 8 to 10. Appearance 13. A method according to any of embodiments 1 to 12, wherein the first regimen includes an ADC dose of approximately 1.25 milligrams / kilogram (mg / kg) of body weight. Appearance 14. The method according to embodiment 13, wherein the subject has a weight of less than 100 kg. Appearance 15. The first regimen comprises an ADC dose of approximately 125 mg to the subject, and the subject has a body weight of 100 kg or more, according to any of embodiments 1 to 12. Appearance 16. (b) A step to determine the target blood glucose level, (c)(b) If the blood glucose level is higher than 250 mg / dL, the administration of the antibody drug conjugate is withheld. Any method of embodiment 1 to 15, further including the above. Appearance 17. (d) A waiting period of time sufficient for blood glucose levels to drop to 250 mg / dL or less. The method of embodiment 16, further comprising: Appearance 18. (e) A step to determine the target blood glucose level, (f) If the blood glucose level in (e) is 250 mg / dL or less, the procedure involves administering a second regimen containing an effective amount of antibody-drug conjugate to the target patient. A method according to embodiment 16 or 17, further including the method according to embodiment 16 or 17. Appearance 19. If the blood glucose level in (b) or (e) exceeds 500 mg / dL, permanently discontinue administration of ADC, according to any of the methods in embodiments 16 to 18. Appearance 20. A method according to any one of embodiments 16 to 19, further comprising the step of repeating (a) to (f). Appearance 21. A method according to any of embodiments 16 to 20, wherein the subject has hyperglycemia. Appearance 22. The method according to embodiment 21, wherein the subject has diabetic ketoacidosis (DKA). Appearance 23. The method according to any of embodiments 16 to 22, wherein the subject further has a higher body mass index and / or a higher baseline A1C. Appearance 24. The method according to any of embodiments 18 to 23, wherein the second regimen is identical to the first regimen. Appearance 25. A method in which blood glucose levels are determined daily, as described in any of embodiments 16 to 24. Appearance 26. A method according to any of embodiments 16 to 24, wherein blood glucose levels are determined every two days, every three days, every four days, every five days, or every six days. Appearance 27. A method according to any of embodiments 16 to 24, wherein blood glucose levels are determined weekly, every other week, once every three weeks, or once every four weeks. Appearance 28. A method according to any of embodiments 16 to 24, wherein blood glucose levels are determined monthly, every two months, or every three months. Appearance 29. (g) A step to determine the target peripheral nerve disorder, If peripheral neuropathy in (h)(g) is grade 2 or higher, the administration of the antibody drug conjugate should be withheld. Any method of embodiment 1 to 28, further including the above. Appearance 30. (i) A waiting period of time sufficient for peripheral neuropathy to decrease to grade 1 or below. The method of embodiment 29, further comprising: Appearance 31. (j) The process of determining the target peripheral nerve disorder, (k) If the peripheral neuropathy (j) is grade 1 or less, a step of administering a second regimen containing an effective dose of ADC to the target, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. A method according to embodiment 29 or 30, further comprising: Appearance 32. If the peripheral neuropathy in (g) or (j) is grade 3 or higher, permanently discontinue administration of ADC, in any of the methods described in aspects 29 to 31. Appearance 33. Any of the methods described in aspects 29 to 32, wherein the peripheral neuropathy is primarily sensory neuropathy. Appearance 34. A method according to any of embodiments 29 to 31 and 33, further comprising the step of repeating (g) to (k). Appearance 35. The method according to any one of embodiments 31 and 33-34, further comprising the step of determining the number of times the conditions for administering a second regimen have been met. Appearance 36. In any of embodiments 31 and 33-35, in which, when the second regimen is administered for the first time, the second regimen is identical to the first regimen. Appearance 37. In (k), if the second regimen has been administered once and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight, according to any of embodiments 31 and 33-36. Appearance 38. In any of embodiments 31 and 33-36, in (k), if the second regimen has been administered once and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject. Appearance 39. In (k), if the second regimen has been administered twice and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight, according to any of embodiments 31 and 33-38. Appearance 40. In (k), if the second regimen has been administered once and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 31 and 33-38. Appearance 41. In (k), if the second regimen has been administered three times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight, according to any of embodiments 31 and 33-40. Appearance 42. In (k), if the second regimen has been administered three times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 31 and 33-40. Appearance 43. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Peripheral neuropathy has returned to grade 1 or lower. In the case of the second regimen, the ADC dose is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more, according to any of embodiments 31 and 33-42. Appearance 44. Peripheral neuropathy is determined daily by any of the methods described in aspects 29 to 43. Appearance 45. Peripheral neuropathy is determined every 2 days, every 3 days, every 4 days, every 5 days, or every 6 days, according to any of the methods in embodiments 29 to 43. Appearance 46. Peripheral neuropathy is determined weekly, every other week, once every three weeks, or once every four weeks, by any of the methods described in aspects 29 to 43. Appearance 47. Peripheral neuropathy is determined monthly, every two months, or every three months, using any of the methods described in aspects 29 to 43. Appearance 48. (l) A step to determine the target skin reaction, If the skin reaction of (m)(l) is grade 3 or higher, the administration of ADC should be withheld. Any method of embodiment 1 to 47, further including the above. Appearance 49. (n) A waiting period sufficient for the skin reaction to decrease to grade 1 or lower. The method of embodiment 48, further including the method of embodiment 48. Appearance 50. (o) A step to determine the target skin reaction, If the skin reaction of (p)(o) is grade 1 or less, the step is to administer a second regimen containing an effective amount of ADC to the subject, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. A method according to embodiment 48 or 49, further including the method according to embodiment 48 or 49. Appearance 51. If the skin reaction of (l) or (o) is grade 4 or higher, permanently discontinue administration of ADC, in any of the methods of aspects 48 to 50. Appearance 52. A method according to any one of embodiments 48 to 51, wherein the skin reaction is selected from the group consisting of maculopapular rash, pruritus, symmetric drug-associated intertriginous flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythematous dysesthesia. Appearance 53. A method according to any of embodiments 48 to 51, wherein a skin reaction of grade 3 or higher is selected from the group consisting of symmetric drug-associated intertriginous and flexural eruption (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar and plantar erythrodysesthesia. Appearance 54. A method according to any of embodiments 48-50 and 52-53, further comprising the step of repeating (l) to (p). Appearance 55. The method according to aspect 54, wherein if a grade 3 skin reaction recurs in (l) or (o), administration of ADC is permanently discontinued. Appearance 56. The method according to any one of embodiments 48-50 and 52-55, further comprising the step of determining the number of times the conditions for administering a second regimen have been met. Appearance 57. In (p), if the second regimen is administered for the first time, the method in any of embodiments 48-50 and 52-56, wherein the second regimen is identical to the first regimen. Appearance 58. In (p), if the second regimen has been administered once or multiple times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of the subject's body weight, according to any of embodiments 48-50 and 52-57. Appearance 59. In (p), if the second regimen has been administered once or multiple times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject, according to any of embodiments 48-50 and 52-57. Appearance 60. In any of embodiments 48-50 and 52-59, in (p), if the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight. Appearance 61. In (p), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 48-50 and 52-59. Appearance 62. In any of embodiments 48-50 and 52-61, if the second regimen has been administered three or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of the subject's body weight. Appearance 63. In (p), if the second regimen has been administered three or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 48-50 and 52-61. Appearance 64. In (p), if the subject has a body weight of less than 100 kg, the second regimen includes an ADC dose of approximately 1.0 mg / kg of the subject's body weight, according to any of embodiments 48-50 and 52-56. Appearance 65. In (p), if the subject has a body weight of 100 kg or more, the second regimen includes an ADC dose of approximately 100 mg for the subject, according to any of embodiments 48-50 and 52-56. Appearance 66. In (p), if the second regimen has been administered once or multiple times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight, according to any of embodiments 48-50, 52-56, and 64-65. Appearance 67. In (p), if the second regimen has been administered once or multiple times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 48-50, 52-56, and 64-65. Appearance 68. In (p), if the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight, according to any of embodiments 48-50, 52-56, and 64-67. Appearance 69. In (p), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 48-50, 52-56, and 64-67. Appearance 70. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Skin reaction has returned to Grade 1 or lower In the case of the second regimen, the ADC dose is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more, according to any of the methods in embodiments 50 and 52-69. Appearance 71. A method according to any of embodiments 48 to 70, wherein the skin reaction is determined daily. Appearance 72. A method according to any of embodiments 48 to 70, wherein the skin reaction is determined once every two days, once every three days, once every four days, or once every five days or once every six days. Appearance 73. A method according to any of embodiments 48 to 70, wherein the skin reaction is determined weekly, every other week, once every three weeks, or once every four weeks. Appearance 74. A method according to any of embodiments 48 to 70, wherein the skin reaction is determined monthly, every two months, or every three months. Appearance 75. (q) A process to determine the non-hematological toxicity of the subject, If the non-hematological toxicity of (s)(q) is grade 3 or higher, the administration of ADC should be withheld. Any method of embodiment 1 to 74, further including the above. Appearance 76. (t) A process that requires waiting for a sufficient period of time for non-hematological toxicity to decrease to grade 1 or below. The method of embodiment 75, further including the method of embodiment 75. Appearance 77. (u) A process to determine the non-hematological toxicity of the subject, (v)(u) If the non-hematological toxicity is grade 1 or less, a step of administering a second regimen containing an effective dose of ADC to the target, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. A method according to embodiment 75 or 76, further comprising: Appearance 78. If the non-hematological toxicity of (q) or (u) is grade 4 or higher, permanently discontinue administration of ADC, in any of embodiments 75 to 77. Appearance 79. A method in which non-hematological toxicity is taste disturbance, as described in any of embodiments 75 to 78. Appearance 80. A method in which the non-hematological toxicity is loss of appetite, as described in any of embodiments 75 to 78. Appearance 81. A method in which the non-hematological toxicity is loss of appetite, as described in any of embodiments 75 to 78. Appearance 82. A method in which non-hematological toxicity is ocular damage, as described in any of embodiments 75 to 78. Appearance 83. The method according to embodiment 79, wherein the ocular disorder is one or more selected from the group consisting of punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision. Appearance 84. A method according to any one of embodiments 75-77 and 79-83, further comprising the step of repeating (q) to (v). Appearance 85. The method according to any one of embodiments 75-77 and 79-84, further comprising the step of determining the number of times the conditions for administering a second regimen have been met. Appearance 86. (v) The method according to any of embodiments 75-77 and 79-85, wherein the second regimen is identical to the first regimen. Appearance 87. In (v), if the second regimen has been administered once or multiple times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight, according to any of embodiments 75-77 and 79-86. Apparatus 88. In (v), if the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject, according to any of embodiments 75-77 and 79-86. Appearance 89. In (v), if the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight, according to any of embodiments 75-77 and 79-88. Appearance 90. In (v), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 75-77 and 79-88. Appearance 91. In (v), if the second regimen has been administered three or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight, according to any of embodiments 75-77 and 79-90. Appearance 92. In (v), if the second regimen has been administered three or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 75-77 and 79-90. Appearance 93. (v) In the case where the subject has a body weight of less than 100 kg, the second regimen includes an ADC dose of approximately 1.0 mg / kg of the subject's body weight, according to any of embodiments 75-77 and 79-85. Appearance 94. (v) In any of embodiments 75-77 and 79-85, if the subject has a body weight of 100 kg or more, the second regimen includes an ADC dose of approximately 100 mg for the subject. Appearance 95. In (v), if the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight, according to any of embodiments 75-77, 79-85, and 93-94. Appearance 96. In (v), if the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 75-77, 79-85, and 93-94. Appearance 97. In (v), if the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight, according to any of embodiments 75-77, 79-85, and 93-96. Appearance 98. In (v), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 75-77, 79-85, and 93-96. Appearance 99. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Non-hematological toxicity has returned to Grade 1 or lower. In the case of the second regimen, the ADC dose is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more, according to any of the methods in embodiments 77 and 79-98. Appearance 100. A method in which non-hematological toxicity is determined daily, as described in any of embodiments 75 to 99. Appearance 101. A method according to any of embodiments 75 to 99, wherein non-hematological toxicity is determined every 2 days, every 3 days, every 4 days, every 5 days, or every 6 days. Appearance 102. A method according to any of embodiments 75 to 99, wherein non-hematological toxicity is determined weekly, bi-weekly, every three weeks, or every four weeks. Appearance 103. Non-hematological toxicity is determined monthly, every two months, or every three months, by any method according to aspects 75 to 99. Appearance 104. (w) A process to determine the blood toxicity of the subject, If the hematological toxicity of (x)(w) is grade 2 or higher, the administration of ADC is withheld. Any method of embodiment 1 to 103, further including the above. Appearance 105. (y) A process that involves waiting for a sufficient period of time for hematological toxicity to decrease to grade 1 or below. The method according to embodiment 104, further including the method according to embodiment 104. Appearance 106. (z) A step to determine the blood toxicity of the subject, If the hematological toxicity of (aa)(z) is grade 1 or less, a step of administering a second regimen containing an effective dose of ADC to the target, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. A method according to embodiment 104 or 105, further comprising: Appearance 107. If the hematological toxicity of (w) or (z) is grade 4 or higher, permanently discontinue administration of ADC, in any of the methods described in embodiments 104 to 106. Appearance 108. A method in which the hematological toxicity is thrombocytopenia, as described in any of embodiments 104 to 107. Appearance 109. A method according to any one of embodiments 104 to 107, wherein the hematological toxicity is selected from the group consisting of anemia, thrombocytopenia, neutropenia, and febrile neutropenia. Appearance 110. A method in any of embodiments 104-106 and 108-109, further comprising the step of repeating (w) to (aa). Appearance 111. The method of either embodiment 106 or embodiment 108-110, wherein if the hematological toxicity of (w) is grade 4 or higher and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight. Appearance 112. In any of embodiments 106 and 108-110, if the hematological toxicity of (w) is grade 4 or higher and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject. Appearance 113. The method of any of embodiments 106 and 108-110, wherein the hematological toxicity of (w) is grade 3 or grade 2. Appearance 114. The method according to any of embodiments 106 and 108-110, wherein the hematological toxicity of (w) is grade 3 thrombocytopenia or grade 2 thrombocytopenia. Appearance 115. The method according to embodiment 113 or 114, further comprising the step of determining the number of times the conditions for administering a second regimen have been met. Appearance 116. In (aa), the method of any of embodiments 113 to 115, wherein the second regimen is identical to the first regimen. Appearance 117. In (aa), if the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight, according to any of embodiments 113 to 116. Appearance 118. In (aa), if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject, according to any of embodiments 113 to 116. Appearance 119. In (aa), if the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of the subject's body weight, according to any of embodiments 113 to 118. Appearance 120. In (aa), if the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg, and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 113 to 118. Appearance 121. In (aa), if the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of the subject's body weight, according to any of embodiments 113 to 120. Appearance 122. In (aa), if the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg, and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 113 to 120. Appearance 123. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Hematological toxicity has returned to Grade 1 or lower. In the case of the second regimen, the ADC dose is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more, according to any method of Embodiment 106 and Embodiments 108-122. Appearance 124. A method in which hematological toxicity is determined daily, as described in any of embodiments 104 to 123. Appearance 125. A method according to any of embodiments 104 to 123, wherein hematological toxicity is determined every 2 days, every 3 days, every 4 days, every 5 days, or every 6 days. Appearance 126. A method according to any of embodiments 104 to 123, wherein hematological toxicity is determined weekly, bi-weekly, every three weeks, or every four weeks. Appearance 127. A method according to any of embodiments 104 to 123, wherein hematological toxicity is determined monthly, every two months, or every three months. Appearance 128. (ab) A process to determine the fatigue of the subject, If fatigue in (ac)(ab) is grade 3 or higher, the administration of ADC is withheld. Any method of embodiment 1 to 127, further including the above. Appearance 129. (ad) A process that involves waiting for a sufficient period of time for fatigue to decrease to Grade 1 or below. The method of embodiment 128, further comprising: Appearance 130. (ae) A process to determine the fatigue of the target, If the fatigue of (af)(ae) is grade 1 or less, a step of administering a second regimen containing an effective amount of ADC to the target, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to embodiment 128 or 129, further comprising: Appearance 131. If fatigue in (ab) or (ae) is grade 4 or higher, permanently discontinue administration of ADC, in any of the methods of aspects 128 to 130. Appearance 132. A method according to any of embodiments 128 to 130, further comprising the step of repeating (ab) to (af). Appearance 133. The method according to any one of embodiments 128-130 and 132, further comprising the step of determining the number of times the conditions for administering a second regimen have been met. Appearance 134. If the fatigue of (ab) is grade 3, the method of any of embodiments 128-130 and 132-133, wherein the second regimen is identical to the first regimen. Appearance 135. In any of embodiments 128-130 and 132-134, if the fatigue of (ab) is grade 3 and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight. Appearance 136. In any of embodiments 128-130 and 132-134, if the fatigue of (ab) is grade 3 and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject. Appearance 137. In (af), if the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of the subject's body weight, according to any of embodiments 128-130 and 132-136. Appearance 138. In (af), if the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg, and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 128-130 and 132-136. Appearance 139. In (af), if the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of the subject's body weight, according to any of embodiments 128-130 and 132-138. Appearance 140. In (af), if the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg, and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 128-130 and 132-138. Appearance 141. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Fatigue has returned to Grade 1 or lower In the case of the second regimen, the ADC dose is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more, according to any method of Embodiment 130 and Embodiments 132-140. Appearance 142. A method in which fatigue is determined on a daily basis, as described in any of embodiments 128 to 141. Appearance 143. A method according to any of embodiments 128 to 141, wherein fatigue is determined once every two days, once every three days, once every four days, once every five days, or once every six days. Appearance 144. The fatigue is determined weekly, every other week, once every three weeks, or once every four weeks, by any of the methods described in embodiments 128 to 141. Appearance 145. The fatigue is determined monthly, every two months, or every three months, according to any of the methods described in embodiments 128 to 141. Appearance 146. (ag) The process of determining the target diarrhea, If diarrhea of ​​(ah)(ag) is grade 3 or higher, the administration of ADC should be withheld. Any method of embodiment 1 to 145, further including the above. Appearance 147. (ai) A waiting period of time sufficient for diarrhea to decrease to grade 1 or below. The method of embodiment 146, further comprising: Appearance 148. (aj) The process of determining the target diarrhea, A step of administering a second regimen containing an effective dose of ADC to a patient whose diarrhea is of grade 1 or less, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to embodiment 146 or 147, further including the method according to embodiment 146 or 147. Appearance 149. If diarrhea of ​​(ag) or (ai) is grade 4 or higher and does not improve to grade 2 or lower within 72 hours with adjunctive treatment, permanently discontinue administration of ADC, in any of the methods described in aspects 146 to 148. Appearance 150. A method in any of embodiments 146 to 148, further comprising the step of repeating (ag) to (ak). Appearance 151. The method according to any one of embodiments 146-148 and 150, further comprising the step of determining the number of times the conditions for administering a second regimen have been met. Appearance 152. The method according to any of embodiments 146-148 and 150-151, wherein in (ak), the second regimen is identical to the first regimen. Appearance 153. In (ak), if the second regimen has been administered once or multiple times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of the subject's body weight, according to any of embodiments 146-148 and 150-152. Appearance 154. In (ak), if the second regimen has been administered once or multiple times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject, according to any of embodiments 146-148 and 150-152. Appearance 155. In (ak), if the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight, according to any of embodiments 146-148 and 150-154. Appearance 156. In (ak), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 146-148 and 150-154. Appearance 157. In (ak), if the second regimen has been administered three or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight, according to any of embodiments 146-148 and 150-156. Appearance 158. In (ak), if the second regimen has been administered three or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 146-148 and 150-156. Appearance 159. In (ak), if the subject has a body weight of less than 100 kg, the second regimen includes an ADC dose of approximately 1.0 mg / kg of the subject's body weight, according to any of embodiments 146-148 and 150-151. Appearance 160. In (ak), if the subject has a body weight of 100 kg or more, the second regimen includes an ADC dose of approximately 100 mg for the subject, according to any of embodiments 146-148 and 150-151. Appearance 161. In (ak), if the second regimen has been administered once or multiple times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight, according to any of embodiments 146-148, 150-151, and 159-160. Appearance 162. In (ak), if the second regimen has been administered once or multiple times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject, according to any of embodiments 146-148, 150-151, and 159-160. Appearance 163. In (ak), if the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight, according to any of embodiments 146-148, 150-151, and 159-162. Appearance 164. In (ak), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject, according to any of embodiments 146-148, 150-151, and 159-162. Appearance 165. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Diarrhea has returned to Grade 1 or lower In the case of the second regimen, the ADC dose is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more, according to any method of Embodiment 148 and Embodiments 150-164. Appearance 166. Diarrhea is determined daily by any of the methods described in aspects 146 to 165. Appearance 167. The method according to any of embodiments 146 to 165, wherein diarrhea is determined to occur once every two days, once every three days, once every four days, or once every five days or once every six days. Appearance 168. The diarrhea is determined to occur weekly, every other week, once every three weeks, or once every four weeks, by any of the methods described in aspects 146 to 165. Appearance 169. The diarrhea is determined to occur monthly, once every two months, or once every three months, by any of the methods described in aspects 146 to 165. Appearance 170. A method according to any one of embodiments 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:9, CDR H2 containing the amino acid sequence of SEQ ID NO:10, CDR H3 containing the amino acid sequence of SEQ ID NO:11; CDR L1 containing the amino acid sequence of SEQ ID NO:12, CDR L2 containing the amino acid sequence of SEQ ID NO:13, and CDR L3 containing the amino acid sequence of SEQ ID NO:14. Appearance 171. A method according to any one of embodiments 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:16, CDR H2 containing the amino acid sequence of SEQ ID NO:17, CDR H3 containing the amino acid sequence of SEQ ID NO:18; CDR L1 containing the amino acid sequence of SEQ ID NO:19, CDR L2 containing the amino acid sequence of SEQ ID NO:20, and CDR L3 containing the amino acid sequence of SEQ ID NO:21. Appearance 172. A method according to any one of embodiments 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR H2 consisting of the amino acid sequence of SEQ ID NO:10, CDR H3 consisting of the amino acid sequence of SEQ ID NO:11; CDR L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:14. Appearance 173. A method according to any one of embodiments 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:16, CDR H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR H3 consisting of the amino acid sequence of SEQ ID NO:18; CDR L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:21. Appearance 174. A method according to any one of embodiments 1 to 173, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:22 and a light chain variable region containing the amino acid sequence of SEQ ID NO:23. Appearance 175. A method according to any one of embodiments 1 to 174, wherein the antibody comprises a heavy chain containing an amino acid sequence in the range from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7, and a light chain containing an amino acid sequence in the range from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8. Appearance 176. A method according to any one of embodiments 1 to 175, wherein the antigen-binding fragment is a Fab, F(ab')2, Fv, or scFv fragment. Appearance 177. A method according to any of embodiments 1 to 176, wherein the antibody is a fully human antibody. Appearance 178. A method for recombinantly producing an antibody or its antigen-binding fragment, as described in any of embodiments 1 to 177. Appearance 179. A method according to any one of embodiments 1 to 178, wherein an antibody or antigen-binding fragment is linked to each unit of monomethyl auristatin E (MMAE) via a linker. Apparatus 180. The method according to embodiment 179, wherein the linker is an enzymatically cleavable linker, and the linker forms a bond with the sulfur atom of the antibody or its antigen-binding fragment. Appearance 181. The method of embodiment 179 or 180, wherein the linker has the formula -Aa-Ww-Yy-, where -A- is an extension unit and a is 0 or 1; -W- is an amino acid unit and w is an integer in the range of 0 to 12; and -Y- is a spacer unit and y is 0, 1, or 2. Appearance 182. The method of embodiment 181, wherein the extension unit has the structure of formula (1) below, the amino acid unit is valinecitrulline, and the spacer unit is a PAB group containing the structure of formula (2) below: TIFF2026048848000002.tif78128. Appearance 183. The method according to embodiment 181 or 182, wherein the extension unit forms a bond with the sulfur atom of the antibody or its antigen-binding fragment, and the spacer unit is linked to the MMAE via a carbamate group. Appearance 184. A method according to any one of embodiments 1 to 183, wherein the antibody is a fully human monoclonal antibody, and the antibody is IgG1. Appearance 185. A method according to any one of embodiments 1 to 184, wherein the ADC contains 1 to 10 units of MMAE per antibody or antigen-binding fragment. Appearance 186. A method according to any one of embodiments 1 to 185, wherein the ADC contains 2 to 8 units of MMAE per antibody or antigen-binding fragment. Appearance 187. A method according to any one of embodiments 1 to 186, wherein the ADC contains 3 to 5 units of MMAE per antibody or antigen-binding fragment. Apparatus 188. A method according to any one of embodiments 1 to 187, wherein the ADC contains 3 to 4 units of MMAE per antibody or antigen-binding fragment. Appearance 189. A method according to any one of embodiments 1 to 188, wherein the ADC contains approximately 4 units of MMAE per antibody or antigen-binding fragment. Appearance 190. The ADC has the following structure: The file TIFF2026048848000003.tif36160 is available, where L- represents an antibody or its antigen-binding fragment, and p is between 1 and 10. Any method of embodiment 1 to 185. Appearance 191. The method of embodiment 190, wherein p is between 2 and 8. Appearance 192. The method of embodiment 190 or 191, wherein p is 3 to 5. Appearance 193. Any of the methods described in embodiments 190 to 192, wherein p is 3 to 4. Appearance 194. Any of the methods described in embodiments 190 to 193, wherein p is approximately 4. Appearance 195. Any of the methods described in embodiments 190 to 193, wherein p is approximately 3.8. Appearance 196. ADC is formulated into a pharmaceutical composition comprising approximately 20 mM L-histidine, approximately 0.02% (w / v) TWEEN-20, approximately 5.5% (w / v) trehalose dihydrate, and hydrochloride, wherein the pH of the pharmaceutical composition is approximately 6.0 at 25°C, according to any of embodiments 1 to 195. Appearance 197. ADC is formulated into a pharmaceutical composition comprising approximately 9 mM histidine, approximately 11 mM histidine hydrochloride monohydrate, approximately 0.02% (w / v) TWEEN-20, and approximately 5.5% (w / v) trehalose dihydrate, wherein the pH of the pharmaceutical composition is approximately 6.0 at 25°C, according to any method of Embodiments 1 to 195. Appearance 198. ADC is formulated at approximately 10 mg / ml in a pharmaceutical composition containing approximately 1.4 mg / ml of histidine, approximately 2.31 mg / ml of histidine hydrochloride monohydrate, approximately 0.2 mg / ml of polysorbate 20 (TWEEN-20), and approximately 55 mg / ml of trehalose dihydrate, wherein the pH of the pharmaceutical composition is approximately 6.0 at 25°C, according to any method of Embodiments 1 to 195. Appearance 199. A method according to any one of embodiments 1 to 195, wherein the ADC is formulated into a vial containing a pharmaceutical composition comprising approximately 20 mg of the ADC, approximately 2.8 mg of histidine, approximately 4.62 mg of histidine hydrochloride monohydrate, approximately 0.4 mg of polysorbate 20 (TWEEN-20), and approximately 110 mg of trehalose dihydrate. Appearance 200. A method according to any one of embodiments 1 to 195, wherein the ADC is formulated into a vial containing a pharmaceutical composition comprising approximately 30 mg of the ADC, approximately 4.2 mg of histidine, approximately 6.93 mg of histidine hydrochloride monohydrate, approximately 0.6 mg of polysorbate 20 (TWEEN-20), and approximately 165 mg of trehalose dihydrate. Appearance 201. A method of administering ADC by intravenous (IV) injection or infusion, as described in any of embodiments 1 to 200. Appearance 202. A method in which an ADC, or an ADC formulated into a pharmaceutical composition, is administered by intravenous (IV) injection or infusion over approximately 30 minutes, in any of embodiments 1 to 201. Appearance 203. A method for treating cancer in a subject, comprising the step of administering a treatment regimen to the subject, wherein the treatment regimen is a. A step of administering one or more doses of an antibody-drug conjugate (ADC) to a target, wherein the one or more doses are administered at a first dose level containing an effective amount of ADC; b. A step of determining whether a subject experiences an adverse reaction in response to the administration of the ADC in (a), wherein the adverse reaction is selected from the group consisting of hyperglycemia, peripheral neuropathy, skin reactions, non-hematological toxicity, and hematological toxicity; c. A step of administering one or more subsequent doses of ADC, each containing an effective amount of ADC, based on the determination in (b), or discontinuing the administration of ADC, i. If it is determined that the subject has not experienced any adverse reactions to the ADC, or that any adverse reactions are below a specified level, administer one or more subsequent doses of the ADC to the subject at the first dose level; ii. If it is determined that the subject has experienced an adverse reaction to the prescribed level or higher of the ADC, the treatment regimen shall be permanently discontinued, or the administration of one or more subsequent doses of the ADC shall be withheld for a period sufficient to allow the adverse reaction to decrease to the desired level, and then the administration of one or more subsequent doses of the ADC shall be at the first dose level or a dose level reduced compared to the first dose level. Process; and d. Optionally, repeat (a) to (c) once or more times, with each repeat of (a) to (c) defining a treatment round, and the first dose level in (a) of each subsequent treatment round is either the first dose level in (a) from the previous round or the reduced dose level in c(ii) from the previous round, and if the subject is found to have recurrent adverse reactions in two consecutive treatment rounds, the process involves reducing one or more subsequent doses of ADC administered in c(ii) compared to the dose administered in (a) during that treatment round, or permanently discontinuing ADC administration. Including, here, i. The subjects are optionally selected from the group of locally advanced or metastatic urothelial carcinoma, have urothelial carcinoma and have been previously treated with immune checkpoint inhibitors and chemotherapeutic agents, the immune checkpoint inhibitor is optionally a programmed death receptor 1 (PD-1) inhibitor or a programmed death ligand 1 (PD-L1) inhibitor, and the immune checkpoint inhibitor is optionally administered in a neoadjuvant or adjuvant setting; and ii. The ADC comprises an antibody or antigen-binding fragment conjugated to 191P4D12 and one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a complementarity-determining region (CDR) comprising a heavy chain variable region CDR shown in SEQ ID NO:22, and a light chain variable region comprising a light chain variable region CDR shown in SEQ ID NO:23. method. Appearance 204. A. The treatment regimen includes (a) to (d); B. The first dose level of the first treatment round is the starting dose level shown in the dose reduction schedule below; and C. The method of embodiment 203, wherein the reduced dose level in c(ii) for each treatment round is reduced to the first dose reduction, second dose reduction, or third dose reduction level shown in the following dose reduction schedule, depending on whether the dose reduction in c(ii) is the first, second, or third dose reduction of the overall treatment round: TIFF2026048848000004.tif67140. Appearance 205. I. The adverse reaction in (b) is hyperglycemia, and the step for determining this includes a step for determining the blood glucose level of the subject; II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the target blood glucose level is 250 mg / dL or less, administer one or more subsequent doses at the first dose level; ii. If the target blood glucose level exceeds 250 mg / dL, administration of one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the blood glucose level to 250 mg / dL or less, and then one or more subsequent doses of ADC should be administered at the first dose level; and iii. If the target blood glucose level exceeds 500 mg / dL, the treatment regimen should be permanently discontinued. The method according to embodiment 203 or 204. Appearance 206. I. The determination of adverse reactions in (b) includes the step of determining whether the subject experiences new or worsening symptoms of peripheral neuropathy; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the patient does not experience symptoms of peripheral neuropathy or has symptoms of peripheral neuropathy of less than grade 2, administer one or more subsequent doses of ADC at the first dose level; ii. If the subject experiences the first onset of Grade 2 peripheral neuropathy symptoms at the first dose level administered in (a), one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the peripheral neuropathy symptoms to Grade 1 or lower, and then one or more subsequent doses of ADC should be resumed at the dose level administered in (a); iii. If the patient has recurrent symptoms of peripheral neuropathy after two consecutive treatment rounds at the same dose level in (a), reduce the dose by one dose level according to the dose reduction schedule; and iv. If the patient experiences symptoms of Grade 3 or higher peripheral neuropathy, permanently discontinue the treatment regimen. The method of embodiment 204. Appearance 207. I. The determination of adverse reactions in (b) includes a step of determining whether the subject experiences a skin reaction; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the subject does not experience a skin reaction or has a skin reaction of less than grade 3, administer one or more subsequent doses of ADC at the first dose level; ii. If the subject experiences a grade 3 skin reaction, one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the skin reaction to grade 1 or lower, and then the administration of one or more subsequent doses of ADC should be resumed at the dose level administered in (a), or reduced by one dose level according to the dose reduction schedule; iii. If the patient experiences a grade 4 skin reaction or has a recurrent grade 3 skin reaction after multiple doses of ADC, permanently discontinue the treatment regimen. The method of embodiment 204. Appearance 208. I. The determination of adverse reactions in (b) includes a step of determining whether the subject has symptoms of non-hematological toxicity; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the patient experiences non-hematological toxicity of less than grade 3, administer one or more subsequent doses of ADC at the first dose level; ii. If the patient experiences a Grade 3 non-hematological toxicity, one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the non-hematological toxicity to Grade 1 or lower, and then administration of one or more subsequent doses of ADC should be resumed at the dose level administered in (a), or reduced by one dose level according to the dose reduction schedule; iii. If the patient experiences grade 4 non-hematological toxicity, permanently discontinue the treatment regimen. The method of embodiment 204. Appearance 209. I. The determination of adverse reactions in (b) includes a step of determining whether the subject has symptoms of hematological toxicity, where hematological toxicity is optionally thrombocytopenia; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the patient experiences hematological toxicity of less than grade 3 and the hematological toxicity is not thrombocytopenia, administer one or more subsequent doses of ADC at the first dose level; ii. If the patient experiences a grade 2 or grade 3 hematological toxicity, and the hematological toxicity is thrombocytopenia, one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the thrombocytopenia to grade 1 or lower, and then the administration of one or more subsequent doses of ADC should be resumed at the dose level administered in (a), or reduced by one dose level according to the dose reduction schedule; iii. If the patient experiences a Grade 4 non-hematological toxicity that is not thrombocytopenia, reduce one or more subsequent doses of the ADC at the dose level administered in (a) by one dose level according to the dose reduction schedule, or permanently discontinue the treatment regimen. The method of embodiment 204. Appearance 210. A method according to any of embodiments 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:9, CDR H2 containing the amino acid sequence of SEQ ID NO:10, CDR H3 containing the amino acid sequence of SEQ ID NO:11; CDR L1 containing the amino acid sequence of SEQ ID NO:12, CDR L2 containing the amino acid sequence of SEQ ID NO:13, and CDR L3 containing the amino acid sequence of SEQ ID NO:14. Appearance 211. A method according to any of embodiments 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:16, CDR H2 containing the amino acid sequence of SEQ ID NO:17, CDR H3 containing the amino acid sequence of SEQ ID NO:18; CDR L1 containing the amino acid sequence of SEQ ID NO:19, CDR L2 containing the amino acid sequence of SEQ ID NO:20, and CDR L3 containing the amino acid sequence of SEQ ID NO:21. Appearance 212. A method according to any one of embodiments 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR H2 consisting of the amino acid sequence of SEQ ID NO:10, CDR H3 consisting of the amino acid sequence of SEQ ID NO:11; CDR L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:14. Appearance 213. A method according to any one of embodiments 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:16, CDR H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR H3 consisting of the amino acid sequence of SEQ ID NO:18; CDR L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:21. Appearance 214. A method according to any one of embodiments 203 to 213, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:22 and a light chain variable region containing the amino acid sequence of SEQ ID NO:23. Appearance 215. The ADC has the following structure: The file TIFF2026048848000005.tif36160 is available, where L- represents an antibody or its antigen-binding fragment, and p is between 1 and 10. Any method of embodiments 203 to 214. Appearance 216. The method of embodiment 215, wherein p is 3 to 5. Appearance 217. The method of embodiment 215 or 216, wherein p is 3 to 4. Appearance 218. Any of the methods in embodiments 215 to 217, wherein p is approximately 4. Appearance 219. Any method of embodiments 215 to 217, wherein p is approximately 3.8. [Brief explanation of the drawing]

[0010] 4. Brief explanation of the drawing [Figure 1A-1] The nucleotide and amino acid sequences of the 191P4D12 protein are shown. [Figure 1A-2] The nucleotide and amino acid sequences of the 191P4D12 protein are shown. [Figure 1B] The nucleotide and amino acid sequences of the heavy chain of Ha22-2(2.4)6.1 are shown. [Figure 1C] The nucleotide and amino acid sequences of the light chain of Ha22-2(2.4)6.1 are shown. [Figure 1D] The amino acid sequence of the heavy chain of Ha22-2(2.4)6.1 is shown. [Figure 1E] The amino acid sequence of the light chain of Ha22-2(2.4)6.1 is shown. [Figure 2]This study demonstrates the efficacy of Ha22-2(2,4)6.1-vcMMAE in human lung cancer xenografts AG-L4 established subcutaneously in SCID mice. The results show that treatment with Ha22-2(2,4)6.1-vcMMAE significantly inhibited the growth of AG-L4 lung cancer xenografts subcutaneously implanted in nude mice compared to both treated and untreated controls. [Figure 3] This study demonstrates the efficacy of Ha22-2(2,4)6.1-vcMMAE in human breast cancer xenografts BT-483 established subcutaneously in SCID mice. The results show that treatment with Ha22-2(2,4)6.1-vcMMAE significantly inhibited the growth of BT-483 breast tumor xenografts subcutaneously implanted in SCID mice compared to treated and untreated control ADCs. [Figure 4-1] Detection of the 191P4D12 protein in cancer patient specimens by IHC. Figures 4A and 4B show breast cancer specimens. Figures 4C and 4D show lung cancer specimens. [Figure 4-2] Detection of the 191P4D12 protein in cancer patient specimens by IHC. Figures 4E and 4F show esophageal cancer specimens. Figures 4G and 4H show head and neck cancer specimens. [Figure 5] Duration of response (DOR) as assessed by blinded independent central review (BICR). [Modes for carrying out the invention]

[0011] 5. Detailed explanation Before further describing this disclosure, it should be understood that this disclosure is not limited to the specific embodiments described herein, and that the terms used herein are intended solely to describe specific embodiments and are not intended to limit them.

[0012] 5.1 Definition The techniques and procedures described or referenced herein include those that are generally well understood and / or commonly adopted by those skilled in the art using conventional methodologies, such as the widely used methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3rd ed. 2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Dubel eds., 2nd ed. 2010).

[0013] Unless otherwise defined herein, technical and scientific terms used in this description have the meanings generally understood by those skilled in the art. For the purpose of interpreting this specification, the following definitions of terms apply, including, wherever singular terms are used, plural forms as well, and vice versa. In the event of any conflict between the definitions of terms provided herein and any documents incorporated herein by reference, the definitions provided below shall prevail.

[0014] The terms “antibody,” “immunoglobulin,” or “Ig” are used interchangeably herein and in their broadest sense, specifically encompassing, for example, monoclonal antibodies (including agonists, antagonists, neutralizing antibodies, full-length or intact monoclonal antibodies), antibody compositions having polyepitope specificity or monoepitope specificity, polyclonal antibodies or monovalent antibodies, multivalent antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies insofar as they exhibit the desired biological activity), single-chain antibodies, and fragments thereof, as described below. Antibodies may be human, humanized, chimeric, and / or affinity-mature antibodies, as well as antibodies from other species, such as mouse and rabbit. The term “antibody” is intended to include B cell polypeptide products within immunoglobulin class polypeptides, which are capable of binding to specific molecular antigens and consist of two identical pairs of polypeptide chains, each pair having one heavy chain (approximately 50–70 kDa) and one light chain (approximately 25 kDa), with each amino-terminal portion of each chain containing a variable region of approximately 100–130 or more amino acids, and each carboxy-terminal portion of each chain containing a constant region. See, for example, Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). In specific embodiments, a specific molecular antigen may be bound by an antibody provided herein, comprising a polypeptide or epitope. Antibodies include, but are not limited to, synthetic antibodies, recombinant antibodies, camelized antibodies, intrabodies, anti-idiotype (anti-Id) antibodies, and any of the functional fragments described above (e.g., antigen-binding fragments). A functional fragment refers to a portion of the heavy or light chain polypeptide of an antibody that retains some or all of the binding activity of the antibody from which the fragment originates. Non-exclusive examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fv(scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab)2 fragments, F(ab')2 fragments, disulfide-bonded Fv(dsFv), Fd fragments, Fv fragments, diabodies, triabodies, tetrabodies, and minibodies.In particular, the antibodies provided herein include immunoglobulin molecules and molecules containing immunologically active portions of immunoglobulin molecules, such as antigen-binding domains or antigen-binding sites that bind to antigens (e.g., one or more CDRs of an antibody). Such antibody fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Pluckthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2nd ed. 1990). The antibodies provided herein may be of any class of immunoglobulin molecules (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). The antibodies may be agonist antibodies or antagonist antibodies.

[0015] The term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, the individual antibodies constituting the population are identical except for any naturally occurring variations that may be present in small amounts. Monoclonal antibodies are highly specific and directed to a single antigenic site. In contrast to polyclonal antibody preparations, which can contain different antibodies against different determinants (epitopes), each monoclonal antibody is directed to a single determinant on the antigen.

[0016] An "antigen" is a structure to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other natural or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen associates with cells and is present, for example, on or inside cells, for example, on or inside cancer cells.

[0017] A “wholesome” antibody includes an antigen-binding site and CL, as well as at least the heavy chain constant region, CH1, CH2, and CH3. The constant region may include the human constant region or its amino acid sequence variants. In certain embodiments, the wholesome antibody has one or more effector functions.

[0018] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” and similar terms refer to a portion of an antibody (e.g., CDR) containing amino acid residues that interact with an antigen and confer specificity and affinity to the binding substance for that antigen. As used herein, “antigen-binding fragment” includes a portion of an intact antibody, e.g., an “antibody fragment” containing the antigen-binding region or variable region of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies and di-diabodies (e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. 90:6444-48; Lu et al., 2005, J. Biol. Chem. 280:19665-72; Hudson et al. Examples include: al., 2003, Nat. Med. 9:129-34; International Publication No. 93 / 11161; and U.S. Patent Nos. 5,837,242 and 6,492,123; single-chain antibody molecules (see, for example, U.S. Patent Nos. 4,946,778; 5,260,203; 5,482,858; and 5,476,786); bivariable domain antibodies (see, for example, U.S. Patent No. 7,612,181); single variable domain antibodies (sdAb) (see, for example, Woolven et al., 1999, Immunogenetics 50:98-101; and Streltsov et al., 2004, Proc Natl Acad Sci USA. 101:12444-49); and multispecific antibodies formed from antibody fragments.

[0019] The term "bind" or "binding" refers to intermolecular interactions, including, for example, forming a complex. The interactions can be non-covalent interactions, including, for example, hydrogen bond interactions, ionic bond interactions, hydrophobic interactions, and / or van der Waals interactions. A complex can also include the association of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of all non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule such as an antigen is the affinity of the antibody or functional fragment for that epitope. The dissociation rate (k off , D , on , D ) of a binding molecule (e.g., an antibody) for a monovalent antigen and the association rate (k on ) ratio (k off / k on ) is the dissociation constant K D , which is inversely proportional to the affinity. The lower the K D value, the higher the affinity of the antibody. The value of K D varies for different complexes of antibody and antigen and depends on both k on and k off . The dissociation constant K D of the antibodies provided herein can be determined using any method provided herein or any other method well known to those of skill in the art. The affinity at one binding site does not necessarily reflect the true strength of the interaction between the antibody and the antigen. When a complex antigen containing multiple repeating antigenic determinants such as a multivalent antigen contacts an antibody containing multiple binding sites, the interaction between the antibody and the antigen at one site increases the probability of reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity.

[0020] In relation to antibodies or antigen-binding fragments described herein, terms such as "bound to," "specifically bound to," and similar terms are also used interchangeably herein and refer to the binding molecule of an antigen-binding domain that specifically binds to an antigen, such as a polypeptide. Antibodies or antigen-binding fragments that bind to or specifically bind to an antigen may cross-react with the relevant antigen. In certain embodiments, antibodies or antigen-binding fragments that bind to or specifically bind to an antigen do not cross-react with other antigens. Antibodies or antigen-binding fragments that bind to or specifically bind to an antigen can be identified, for example, by immunoassays, Octet®, Biacore®, or other techniques known to those skilled in the art. In some embodiments, an antibody or antigen-binding fragment binds to or specifically binds to an antigen if it binds to the antigen with a higher affinity than any cross-reactive antigen determined using experimental techniques such as radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISA). Typically, a specific or selective reaction is at least twice the background signal or noise, and may be more than 10 times the background. For considerations regarding binding specificity, see, for example, Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989). In certain embodiments, the degree of binding of an antibody or antigen-binding fragment to a “non-target” protein is less than approximately 10% of the binding of the binding molecule or antigen-binding domain to that particular target antigen, as determined, for example, by fluorescence-activated cell sorting (FACS) analysis or RIA. Terms such as “specific binding,” “specifically binding to,” or “specific to” mean binding that is measurably different from nonspecific interactions. Specific binding can be measured, for example, by determining the binding of a molecule by comparing it to the binding of a control molecule, which is a molecule of a similar structure that generally does not possess binding activity. For example, specific binding can be determined by competition with a control molecule similar to the target, e.g., an excess of unlabeled targets. In this case, specific binding is indicated if the binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled targets.Antibodies or antigen-binding fragments that bind to an antigen include those whose binding molecule can bind to the antigen with sufficient affinity so that it is useful as a diagnostic agent when targeting an antigen, for example. In certain embodiments, antibodies or antigen-binding fragments that bind to an antigen include those with a molecular weight of less than 1000 nM, less than 800 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM. The dissociation constant (K) is less than 0.3nM, less than 0.2nM, or less than 0.1nM, or 1000nM, 800nM, 500nM, 250nM, 100nM, 50nM, 10nM, 5nM, 4nM, 3nM, 2nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM, or 0.1nM. D ) has. In certain embodiments, the antibody or antigen-binding fragment binds to an antigen epitope that is conserved between antigens of different species (e.g., between the human species and the cynomolgus monkey species).

[0021] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a binding protein such as an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a binding molecule X for its binding partner Y is generally expressed by the dissociation constant (K). D ) can be expressed by. Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies generally tend to bind slowly to antigens and dissociate easily, while high affinity antibodies generally tend to bind more quickly to antigens and remain bound for a longer period. Various methods for measuring binding affinity are known in the art and any of them can be used for the purposes of this disclosure. Specific exemplary embodiments include: In one embodiment, "K D " or "K DThe value can be measured by assays known in the art, such as binding assays. D This can be measured, for example, by RIA performed using the Fab version of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). D or K D The values ​​can also be measured by using biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays, for example by Octet® using the Octet® QK384 system, or by Biacore® using the Biacore® TM-2000 or Biacore® TM-3000 system. "On rate" or "association rate" or "association rate" or "kon" can also be determined using the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, for example by using the Octet® QK384, Biacore® TM-2000, or Biacore® TM-3000 systems.

[0022] In certain embodiments, an antibody or antigen-binding fragment may be a “chimeric” sequence in which part of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody originating from a particular species or belonging to a particular antibody class or subclass, but the remainder of the chain(s) is identical or homologous to a corresponding sequence in an antibody originating from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies insofar as they exhibit the desired biological activity (see U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55).

[0023] In certain embodiments, the antibody or antigen-binding fragment may include a portion of a "humanized" form of a non-human (e.g., mouse) antibody, which is a chimeric antibody containing human immunoglobulin (e.g., recipient antibody) in which native CDR residues are replaced with residues from corresponding CDRs (e.g., donor antibodies) of non-human species such as mouse, rat, rabbit, or non-human primates, having desired specificity, affinity, and capabilities. In some cases, one or more FR region residues of the human immunoglobulin may be replaced by corresponding non-human residues. Furthermore, the humanized antibody may contain residues not found in the recipient antibody or donor antibody. These modifications are made to further refine antibody performance. The heavy or light chain of the humanized antibody may contain substantially all of at least one or more variable regions, with all or substantially all of the CDRs corresponding to the CDRs of the non-human immunoglobulin and all or substantially all of the FRs being FRs of the human immunoglobulin sequence. In certain embodiments, the humanized antibody contains at least a portion of the immunoglobulin constant region (Fc), typically at least a portion of the constant region (Fc) of human immunoglobulin. For further details, see Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1988, Nature 332:323-29; Presta, 1992, Curr. Op. Struct. Biol. 2:593-96; Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; U.S. Patent Nos. 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.

[0024] In certain embodiments, an antibody or antigen-binding fragment may include a “fully human antibody” or a portion of a “human antibody,” the terms of which are used interchangeably herein and refer to an antibody containing a human variable region and, for example, a human constant region. In specific embodiments, these terms refer to an antibody containing a variable region and a constant region of human origin. In certain embodiments, “fully human” antibodies may also include antibodies that bind to a polypeptide and are encoded by a nucleic acid sequence that is a naturally occurring somatic variant of a human germline immunoglobulin nucleic acid sequence. The term “fully human antibody” includes antibodies containing a variable region and a constant region corresponding to a human germline immunoglobulin sequence described by Kabat et al. (see Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242). “Human antibody” is one having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human, and / or one produced using any of the techniques for producing human antibodies. This definition of human antibodies specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, 1991, J.Mol.Biol.227:381; Marks et al., 1991, J.Mol.Biol.222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1:755-68). Methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77(1985); Boerner et al., 1991, J.Immunol.147(1):86-95; and van Dijk and van de Winkel, 2001, Curr.Opin.Pharmacol.5:368-74 are also available for the preparation of human monoclonal antibodies.Human antibodies can be prepared by administering an antigen to transgenic animals, such as mice, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene locus has been deactivated (see, for example, Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66; Bruggemann and Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58; and U.S. Patents 6,075,181 and 6,150,584 relating to XENOMOUSE® technology). See also, for example, Li et al., 2006, Proc. Natl. Acad. Sci. USA 103:3557-62 relating to human antibodies produced via human B-cell hybridoma technology.

[0025] In certain embodiments, an antibody or antigen-binding fragment may be part of a “recombinant human antibody,” which includes human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells, antibodies isolated from a recombinant combinatorial human antibody library, antibodies isolated from animals (e.g., mice or cattle) that are transgenic and / or transchromosomal with respect to the human immunoglobulin gene (see, for example, Taylor, L.D. et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced or isolated by any other means, including splicing the human immunoglobulin gene sequence to another DNA sequence. Such recombinant human antibodies may have variable and constant regions derived from human germline immunoglobulin sequences (see Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242). However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if transgenic animals for human Ig sequences are used, in vivo somatic mutagenesis), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, but are sequences that cannot naturally exist in vivo within the human antibody germline repertoire.

[0026] In certain embodiments, an antibody or antigen-binding fragment may be part of a “monoclonal antibody,” where as used herein, this term refers to an antibody obtained from a substantially homogeneous population of antibodies, for example, where the individual antibodies constituting the population are identical except for any naturally occurring mutations that may be present in small amounts, and each monoclonal antibody typically recognizes a single epitope on an antigen. In specific embodiments, “monoclonal antibody” as used herein is an antibody produced by a single hybridoma or other cell. The term “monoclonal” is not limited to a specific method for producing the antibody. For example, monoclonal antibodies useful in this disclosure may be prepared by the hybridoma method first described by Kohler et al., 1975, Nature 256:495, or may be produced using recombinant DNA methods in bacterial, eukaryotic, or plant cells (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J.Mol.Biol.222:581-97. Other methods for preparing clonal cell lines and the monoclonal antibodies expressed thereby are well known in the art. See, for example, Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed. 2002).

[0027] A typical quadruple antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgG, a quadruple unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, and the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has intrachain disulfide bridges at regular intervals. Each H chain has a variable domain (VH) at its N-terminus, followed by three constant domains (CH) for the α and γ chains respectively, and four CH domains for the μ and ε isotypes. Each L chain has a variable domain (VL) at its N-terminus, followed by a constant domain (CL) at the other end. The VL aligns with the VH, and the CL aligns with the first constant domain (CH1) of the heavy chain. Certain amino acid residues are thought to form the contact surface between the light chain variable domain and the heavy chain variable domain. The pairing of VH and VL forms a single antigen-binding site. For the structure and properties of various classes of antibodies, see, for example, Basic and Clinical Immunology 71 (Stites et al. eds., 8th ed. 1994); and Immunobiology (Janeway et al. eds., 5 th See ed.2001.

[0028] The term "Fab" or "Fab region" refers to the antibody region that binds to an antigen. Conventional IgG typically contains two Fab regions, each located on one of the two arms of the Y-shaped IgG structure. Each Fab region typically consists of one variable region and one constant region of the heavy chain and light chain, respectively. More specifically, the variable and constant regions of the heavy chain in the Fab region are the VH and CH1 regions, and the variable and constant regions of the light chain in the Fab region are the VL and CL regions. The VH, CH1, VL, and CL within the Fab region can be arranged in various ways to confer the antigen-binding ability according to this disclosure. For example, as with the Fab region of conventional IgG, the VH and CH1 regions may be on a single polypeptide, and the VL and CL regions may be on separate polypeptides. Alternatively, the VH, CH1, VL, and CL regions may all be on the same polypeptide and oriented in different orders, as will be described in more detail in the following sections.

[0029] The terms “variable region,” “variable domain,” “V region,” or “V domain” generally refer to a portion of an antibody’s light or heavy chain located at the amino terminus of the light or heavy chain, approximately 120–130 amino acids long in the heavy chain and approximately 100–110 amino acids long in the light chain, and used for the binding and specificity of each particular antibody to its specific antigen. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that specific segments of the variable region have significantly different sequences among antibodies. The V region mediates antigen binding and defines the specificity of a particular antibody to a particular antigen. However, variability is not uniformly distributed across the 110-amino acid span of the variable region. Instead, the V region consists of less variable (e.g., relatively invariant) stretches called framework regions (FR) of approximately 15–30 amino acids, separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions,” each approximately 9–12 amino acids long. The variable regions of the heavy and light chains each contain four FRs that primarily adopt a β-sheet shape, connected by three hypervariable regions that form loops connecting β-sheet structures and, in some cases, forming part of the β-sheet structure. The hypervariable regions of each chain are held together in close proximity by the FRs and, together with the hypervariable region of the other chain, contribute to the formation of the antibody's antigen-binding site (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed. 1991)). The constant region does not directly participate in antibody binding to the antigen but exhibits various effector functions, such as antibody involvement in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cell-mediated cytotoxicity (CDC). The sequence of the variable regions differs significantly between different antibodies. In specific embodiments, the variable regions are human variable regions.

[0030] The terms "Kabat variable region residue numbering" or "Kabat-like amino acid position numbering," and their variations, refer to the numbering system used for the heavy chain or light chain variable region of antibody edits, as previously cited by Kabat et al. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to the shortening or insertion into the FR or CDR of the variable domain. For example, the heavy chain variable domain may contain a single amino acid insertion after residue 52 (Kabat residue 52a) and three inserted residues after residue 82 (e.g., Kabat residues 82a, 82b, and 82c). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody sequence with a homology region of a "standard" Kabat numbering sequence. The Kabat numbering system is generally used to refer to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., cited above). The "EU numbering system" or "EU index" is generally used to refer to residues within the constant region of the immunoglobulin heavy chain (e.g., the EU index reported by Kabat et al., cited above). "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies. Other numbering systems have been described, for example, by AbM, Chothia, Contact, IMGT, and AHon.

[0031] When used in relation to antibodies, the term "heavy chain" refers to a polypeptide chain of approximately 50–70 kDa, with a variable region of approximately 120–130 or more amino acids at the amino-terminus and a constant region at the carboxy-terminus. The constant region can be one of five distinct types (e.g., isotypes) designated as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. The different heavy chains differ in size, with α, δ, and γ containing approximately 450 amino acids, and μ and ε containing approximately 550 amino acids. When combined with a light chain, these different types of heavy chains give rise to five well-known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, each containing four subclasses of IgG, namely IgG1, IgG2, IgG3, and IgG4.

[0032] When used in relation to antibodies, the term "light chain" refers to a polypeptide chain of approximately 25 kDa, with a variable region of approximately 100 to 110 or more amino acids in the amino-terminal region and a constant region in the carboxy-terminal region. The approximate length of a light chain is 211 to 217 amino acids. Based on the amino acid sequence of the constant domain, there are two distinct types, referred to as kappa (κ) or lambda (λ).

[0033] As used herein, the terms “hypervariable region,” “HVR,” “complementarity-determining region,” and “CDR” are used interchangeably. “CDR” refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of an immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of an antibody VL β-sheet framework. Therefore, a CDR is a variable region sequence scattered within a framework region sequence.

[0034] The CDR region is well known to those skilled in the art and is defined by well known numbering systems. For example, the Kabat complementarity determination region (CDR) is based on sequence variability and is the most commonly used (see, e.g., Kabat et al., cited above). Alternatively, Chothia refers to the location of structural loops (see, e.g., Chothia and Lesk, 1987, J.Mol.Biol.196:901-17). When numbered using Kabat's numbering rules, the end of a Chothia CDR-H1 loop differs between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places insertions at H35A and H35B; if neither 35A nor 35B exists, the loop ends at 32; if only 35A exists, the loop ends at 33; if both 35A and 35B exist, the loop ends at 34). The AbM hypervariable region represents a compromise between the Kabat CDR and the Chothia structural loop and is used by Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Dubel eds., 2d ed. 2010)). The “contact” hypervariable region is based on the analysis of available complex crystal structures. Another universal numbering system that has been developed and widely adopted is the ImMunoGeneTics (IMGT) Information System (registered trademark) (Lafranc et al., 2003, Dev. Comp. Immunol. 27(1):55-77). IMGT is an integrated information system specifically for human and other vertebrate immunoglobulins (IG), T cell receptors (TCRs), and major histocompatibility complexes (MHCs). Hereinafter, CDRs are referred to in terms of both amino acid sequence and position within the light or heavy chain. The "location" of CDRs within the structure of immunoglobulin variable domains is conserved across species and resides within structures called loops; therefore, CDRs and framework residues can be easily identified by using a numbering system that aligns the variable domain sequence according to its structural characteristics.This information can be used when transplanting and substituting CDR residues from one species of immunoglobulin into an acceptor framework, typically from a human antibody. Further numbering systems (AHon) have been developed by Honegger and Pluckthun, 2001, J.Mol.Biol.309:657-70. Correspondence between numbering systems, including Kabat numbering and IMGT-specific numbering systems, is well known to those skilled in the art (see, e.g., Kabat, ibid.; Chothia and Lesk, ibid.; Martin, ibid.; Lefranc et al., ibid.). The residues from each of these hypervariable regions or CDRs are shown below.

[0035] (Table 1) TIFF2026048848000006.tif77137

[0036] The boundaries of a given CDR may vary depending on the scheme used for identification. Therefore, unless otherwise specified, the terms “CDR” and “complementarity-determining region” of a given antibody or region, e.g., variable region, as well as individual CDRs of the antibody or region (e.g., “CDR-H1, CDR-H2”), should be understood to encompass the complementarity-determining region as defined by any of the known schemes described above. In some cases, a scheme for identifying one or more specific CDRs is specified, such as CDRs defined by the Kabat, Chothia, or Contact methods. In other cases, a specific amino acid sequence of the CDR is given.

[0037] The hypervariable region may include the following "extended hypervariable regions": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH.

[0038] The term "constant region" or "constant domain" refers to the carboxyl-terminal portions of the light and heavy chains that do not directly participate in antibody binding to the antigen but exhibit various effector functions, such as interaction with the Fc receptor. This term refers to the portion of the immunoglobulin molecule that contains a more conserved amino acid sequence compared to the other parts of the immunoglobulin that contain the antigen-binding site, the variable region. The constant region may include the CH1, CH2, and CH3 regions of the heavy chain, as well as the CL region of the light chain.

[0039] The term "framework" or "FR" refers to variable region residues adjacent to the CDR. FR residues are found, for example, in chimeric, humanized, human, domain antibodies, diabolic, linear, and bispecific antibodies. FR residues are hypervariable region residues or variable domain residues other than CDR residues.

[0040] In this specification, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain, including, for example, the natural sequence Fc region, the recombinant Fc region, and the mutant Fc region. While the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is often defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombinantizing the nucleic acid encoding the antibody heavy chain. Therefore, an intact antibody composition may include antibody populations with all K447 residues removed, antibody populations with and without K447 residues, and antibody populations containing mixtures of antibodies with and without K447 residues. A “functional Fc region” possesses the “effector function” of the natural sequence Fc region. Exemplary “effector functions” include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; and downregulation of cell surface receptors (e.g., B cell receptors). Such effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or antibody variable domain) and can be evaluated using various assays known to those skilled in the art. A “mutant Fc region” contains an amino acid sequence that differs from the amino acid sequence of the native Fc region by at least one amino acid modification (e.g., substitution, addition, or deletion). In certain embodiments, the mutant Fc region has at least one amino acid substitution compared to the native Fc region or the Fc region of the parent polypeptide, for example, about 1 to about 10 amino acid substitutions or about 1 to about 5 amino acid substitutions in the native Fc region or the Fc region of the parent polypeptide. The mutant Fc regions described herein may have at least about 80% homology to the natural sequence Fc region and / or the Fc region of the parent polypeptide, or at least about 90% homology to them, for example, at least about 95% homology to them.

[0041] As used herein, “epitope” is a term of the art and refers to a local region of an antigen to which a binding molecule (e.g., an antibody) can specifically bind. Epitopes can be linear, conformational, nonlinear, or discontinuous epitopes. In the case of polypeptide antigens, for example, an epitope may be a sequence of amino acids in the polypeptide (a “linear” epitope), or an epitope may consist of amino acids derived from two or more discontinuous regions of the polypeptide (a “conformational,” “nonlinear,” or “discontinuous” epitope). In general, it will be understood by those skilled in the art that linear epitopes may or may not depend on secondary, tertiary, or quaternary structure. For example, in some embodiments, a binding molecule binds to a group of amino acids, whether or not they are folded into a native three-dimensional protein structure. In other embodiments, the binding molecule requires amino acid residues that constitute the epitope to exhibit a specific conformation (e.g., bent, twisted, rotated, or folded) in order to recognize and bind to the epitope.

[0042] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. Polymers may be linear or branched and may contain modified amino acids, or be interrupted by non-amino acids. The term also encompasses amino acid polymers modified naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other operation or modification. Polypeptides containing one or more analogues of amino acids, including but not limited to non-natural amino acids, as well as other modifications known in the art, are also included in the definition. Since the polypeptides of this disclosure may be based on antibodies or other members of the immunoglobulin superfamily, it will be understood that in certain embodiments, a “polypeptide” may exist as a single chain or as two or more associated chains.

[0043] As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or State government or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia for use in animals, more specifically in humans.

[0044] "Excipient" means a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavorants, humectants, lubricants, perfumes, preservatives, propellants, release agents, sterilants, sweeteners, solubilizers, wetting agents, and encapsulating materials or additives such as mixtures thereof. The term "excipient" can also refer to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), or vehicle.

[0045] In one aspect, each component is "pharmaceutically acceptable" in that it is compatible with the other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some aspects, the pharmaceutically acceptable excipient is non-toxic to the cells or mammals to which it is exposed, at the dosage and concentration used. In some aspects, the pharmaceutically acceptable excipient is an aqueous pH buffered solution.

[0046] The abbreviation "MMAE" refers to monomethyl auristatin E.

[0047] Unless otherwise specified, the term "alkyl" refers to saturated linear or branched hydrocarbons containing approximately 1 to approximately 20 carbon atoms (as well as all combinations and partial combinations of a range and a specific number of carbon atoms), with approximately 1 to approximately 8 carbon atoms being preferred. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.Alkyl groups, either alone or as part of another group, include -halogen, -O-(C1~C8alkyl), -O-(C2~C8alkenyl), -O-(C2~C8alkynyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -SO3R', -S(O)2R', -S(O)R', -OH, =O, -N3, -NH2, -N The group may be substituted with one or more groups, preferably one to three groups (and any further substituents selected from halogens), including but not limited to H(R'), -N(R')2, and -CN, where each R' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl, and the group may be -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C -C1-C8 alkyl, -C2-C8 alkenyl, and -C2-C8 alkynyl groups are -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -halogen, -O-(C1-C8 alkyl), -O-(C2-C8 alkenyl), -O-(C2-C8 alkynyl), -aryl, -C(O)R'', -OC(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C The group includes, but is not limited to, (O)N(R'')2, -NHC(O)R'', -SR'', -SO3R'', -S(O)2R'', -S(O)R'', -OH, -N3, -NH2, -NH(R''), -N(R'')2, and -CN, and may be further substituted with one or more groups, where each R'' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl.

[0048] Unless otherwise specified, the terms “alkenyl” and “alkynyl” refer to linear and branched carbon chains containing approximately 2 to approximately 20 carbon atoms (as well as all and partial combinations of a range and a specific number of carbon atoms), with approximately 2 to approximately 8 carbon atoms being preferred. An alkenyl chain has at least one double bond in the chain, and an alkynyl chain has at least one triple bond in the chain. Examples of alkenyl groups include, but are not limited to, ethylene or vinyl, allyl, -1-butenyl, -2-butenyl, -isobutyrenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, and -2,3-dimethyl-2-butenyl. Examples of alkynyl groups include, but are not limited to, acetylene, propargyl, acetylenyl, propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, and -3-methyl-1-butynyl.Alkenyl and alkynyl groups, either alone or as part of another group, include -halogen, -O-(C1~C8alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -SO3R', -S(O)2R', -S(O)R', -OH, =O, -N3, -NH2, -NH(R'), -N(R')2 and -CN, and may be substituted with one or more groups, preferably one to three groups (and any further substituents selected from halogens), where each R' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl, and the -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C1~C8 alkyl, -C2~C8 alkenyl, and -C2~C8 alkynyl groups are -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -halogen, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2C8 alkynyl), -aryl, -C(O)R'', -OC(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', - The constituents include, but are not limited to, C(O)N(R'')2, -NHC(O)R'', -SR'', -SO3R'', -S(O)2R'', -S(O)R'', -OH, -N3, -NH2, -NH(R''), -N(R'')2, and -CN, and may be further substituted with one or more substituents, where each R'' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl.

[0049] Unless otherwise specified, the term "alkylene" refers to a saturated branched or straight-chain hydrocarbon radical containing about 1 to about 20 carbon atoms (as well as all and partial combinations of a range and a specific number of carbon atoms), preferably about 1 to about 8 carbon atoms, and having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylenes include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decalene, and 1,4-cyclohexylene.Alkylene groups, either alone or as part of another group, include -halogen, -O-(C1~C8alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -SO3R', -S(O)2R', -S(O)R', -OH, =O, -N3, -NH2, and -N The group may be substituted with one or more groups, preferably one to three groups (and any further substituents selected from halogens), including but not limited to H(R'), -N(R')2, and -CN, where each R' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl, and the group may be -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C -C1-C8 alkynyl, -aryl, -C1-C8 alkyl, -C2-C8 alkenyl, and -C2-C8 alkynyl groups are -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -halogen, -O-(C1-C8 alkyl), -O-(C2-C8 alkenyl), -O-(C2-C8 alkynyl), -aryl, -C(O)R'', -OC(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C( The substituents include, but are not limited to, O)N(R'')2, -NHC(O)R'', -SR'', -SO3R'', -S(O)2R'', -S(O)R'', -OH, -N3, -NH2, -NH(R''), -N(R'')2, and -CN, and may be further substituted with one or more substituents, where each R'' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl.

[0050] Unless otherwise specified, the term "alkenylene" refers to an optionally substituted alkylene group that contains at least one carbon-carbon double bond. Exemplary alkenylene groups include, for example, ethenylene (-CH=CH-) and propenylene (-CH=CHCH2-).

[0051] Unless otherwise specified, the term "alkylene" refers to an optionally substituted alkylene group that contains at least one carbon-carbon triple bond. Exemplary alkylene groups include, for example, acetylene (-C≡C-), propargyl (-CH2C≡C-), and 4-pentinyl (-CH2CH2CH2C≡CH-).

[0052] Unless otherwise specified, the term "aryl" refers to monovalent aromatic hydrocarbon radicals consisting of 6 to 20 carbon atoms (as well as all and partial combinations of a range and a specific number of carbon atoms) derived by removing one hydrogen atom from one carbon atom in an aromatic ring system. Some aryl groups are represented as "Ar" in exemplary structures. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzenes, phenyl, naphthalene, anthracene, and biphenyl.

[0053] The aryl group, either alone or as part of another group, can be -halogen, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -SO3R', -S(O) The group may be substituted with one or more, preferably 1 to 5, or even 1 to 2, groups including but not limited to 2R', -S(O)R', -OH, -NO2, -N3, -NH2, -NH(R'), -N(R')2, and -CN, where each R' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl, and the aforementioned -C1~C8 alkyl, -C2~C8 alkenyl, -C2~ C8 alkynyl, O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), and -aryl groups are defined as -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -halogen, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R'', -OC(O)R'', -C(O)OR'', -C(O)NH2, and -C(O)NHR''. -C(O)N(R'')2, -NHC(O)R'', -SR'', -SO3R'', -S(O)2R'', -S(O)R'', -OH, -N3, -NH2, -NH(R''), -N(R'')2 and -CN, which may be further substituted with one or more substituents, where each R'' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl.

[0054] Unless otherwise specified, the term "arylene" refers to a divalent (i.e., derived by removing two hydrogen atoms from the same or two different carbon atoms in an aromatic ring system), potentially substituted aryl group, which may be in ortho, meta, or para configurations, as shown in the following structures with phenyl as an exemplary aryl group. Typical "-(C1~C8 alkylene)aryl", "-(C2~C8 alkenylene)aryl", and "-(C2~C8 alkynylene)aryl" groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethane-1-yl.

[0055] Unless otherwise specified, the term “heterocycle” refers to a monocyclic, bicyclic, or polycyclic ring system having 3 to 14 ring atoms (also called ring members), where at least one ring atom of at least one ring is a heteroatom selected from N, O, P, or S (as well as all and partial combinations of a range and a specific number of carbon atoms and heteroatoms). A heterocycle may have 1 to 4 ring heteroatoms independently selected from N, O, P, or S. One or more N, C, or S atoms in a heterocycle can be oxidized. A monocyclic heterocycle preferably has 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S), and a bicyclic heterocycle preferably has 5 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S). Heteroatom-containing rings can be aromatic or aromatic. Unless otherwise specified, heterocycles are bonded to their pendant group by any heteroatom or carbon atom that results in a stable structure. Heterocycles are described in Paquette, "Principles of Modern Heterocyclic Chemistry" (WABenjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950–present), especially volumes 13, 14, 16, 19, and 28; and J.Am.Chem.Soc.82:5566 (1960).Examples of "heterocyclic" groups include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indrenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, Pyrrolinil, tetrahydrofuranil, bis-tetrahydrofuranil, tetrahydropyranil, bis-tetrahydropyranil, tetrahydroquinolinil, tetrahydroisoquinolinil, decahydroquinolinil, octahydroisoquinolinil, azosinil, triazinil, 6H-1,2,5-thiadiadinil, 2H,6H-1,5,2-dithiadinil, thienyl, thianthrenil, pyranil, isobenzofuranil, clomenil, xane Tenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridadinyl, indolidinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, prinyl, 4H-quinolidinyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, β-carbolinyl, phenantridinyl, acridinyl, pyrimidinyl The following are examples of preferred "heterocyclic" groups: phenanthrolinyl, phenazinyl, phenothiazinyl, flazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxyindolyl, benzoxazolyl, and isatinoyl. Preferred "heterocyclic" groups include, but are not limited to, benzofuranyl, benzothiophenyl, indolyl, benzopyrazolyl, coumalinyl, isoquinolinyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridadinyl, isothiazolyl, isoxazolyl, and tetrazolyl.Heterocyclic groups, either alone or as part of another group, include -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -halogen, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -SO3R', -S( The group may include, but is not limited to, one or more groups, preferably one to two groups, including, -O-(C1-C8 alkyl), -O-(C2-C8 alkenyl), -N-(R'), and -CN, where each R' is independently selected from -H, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, or -aryl, and the -O-(C1-C8 alkyl), -O-(C2-C8 alkenyl), -O- (C2~C8 alkynyl), -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, and -aryl groups are -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -halogen, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R'', -OC(O)R'', -C(O)OR'', -C(O)NH2, -C(O)NHR'', -C The constituents include, but are not limited to, (O)N(R'')2, -NHC(O)R'', -SR'', -SO3R'', -S(O)2R'', -S(O)R'', -OH, -N3, -NH2, -NH(R''), -N(R'')2, and -CN, and may be further substituted with one or more substituents, where each R'' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or aryl.

[0056] As an example, and not an exhaustive list, carbon-bonded heterocycles can be bonded at the following positions: positions 2, 3, 4, 5, or 6 of pyridine; positions 3, 4, 5, or 6 of pyridazine; positions 2, 4, 5, or 6 of pyrimidine; positions 2, 3, 5, or 6 of pyrazine; positions 2, 3, 5, or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole; positions 2, 3, 4, or 5 of oxazole, imidazole, or thiazole; positions 3, 4, or 5 of isoxazole, pyrazole, or isothiazole; positions 2 or 3 of aziridine; positions 2, 3, or 4 of azetidine; positions 2, 3, 4, 5, 6, 7, or 8 of quinoline; or positions 1, 3, 4, 5, 6, 7, or 8 of isoquinoline. More typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0057] As an example, and not an exhaustive list, nitrogen-bonded heterocycles can be attached at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or 1H-indazole; position 2 of isoindole or isoindoline; position 4 of morpholine; and position 9 of carbazole or β-carbolin. More typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azetezyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0058] Unless otherwise specified, the term “carbocyclic” refers to saturated or unsaturated non-aromatic monocyclic, bicyclic, or polycyclic ring systems (and ranges and all and partial combinations of a specific number of carbon atoms) having 3 to 14 ring atoms, all of which are carbon atoms. Monocyclic carbocyclics preferably have 3 to 6 ring atoms, more preferably 5 or 6 ring atoms. Bicyclic carbocyclics preferably have 7 to 12 ring atoms arranged, for example, as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. The term “carbocyclic” includes, for example, monocyclic carbocyclics fused to an aryl ring (e.g., monocyclic carbocyclics fused to a benzene ring). Carbocyclics preferably have 3 to 8 carbocyclic atoms.The carbocyclic group can be alone or as part of another group, for example, -halogen, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -SO3R', -S(O)2R' The groups may be substituted with one or more groups, preferably one or two groups (and any further substituents selected from halogens), including but not limited to -S(O)R', -OH, =O, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl, and the -C1~C8 alkyl, -C2~C8 Alkenyl, -C2~C8 alkynyl, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), and -aryl groups are -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, -halogen, -O-(C1~C8 alkyl), -O-(C2~C8 alkenyl), -O-(C2~C8 alkynyl), -aryl, -C(O)R'', -OC(O)R'', -C(O)OR'', -C(O)NH2, -C(O) The substituents include, but are not limited to, NHR'', -C(O)N(R'')2, -NHC(O)R'', -SR'', -SO3R'', -S(O)2R'', -S(O)R'', -OH, -N3, -NH2, -NH(R''), -N(R'')2, and -CN, and may be further substituted with one or more substituents, where each R'' is independently selected from -H, -C1~C8 alkyl, -C2~C8 alkenyl, -C2~C8 alkynyl, or -aryl.

[0059] Examples of monocyclic and carbocyclic substituents include -cyclopropyl, -cyclobutyl, -cyclopentyl, -1-cyclopenta-1-enyl, -1-cyclopento-2-enyl, -1-cyclopento-3-enyl, cyclohexyl, -1-cyclohex-1-enyl, -1-cyclohex-2-enyl, -1-cyclohex-3-enyl, -cycloheptyl, -cyclooctyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrielinyl, and -cyclooctadienyl.

[0060] "Carbocyclo" refers to the substituted or alternative carbocyclic group defined above, which is divalent (i.e., derived by removing two hydrogen atoms from the same or two different carbon atoms of the carbocyclic system), whether used alone or as part of another group.

[0061] Unless otherwise indicated in the context, a hyphen (-) specifies the bond point to the pendant molecule. Thus, the terms "-(C1~C8 alkylene)aryl" or "-C1~C8 alkylene (aryl)" refer to the C1~C8 alkylene radical as defined herein, where the alkylene radical is bonded to the pendant molecule at one of the carbon atoms of the alkylene radical, and one of the hydrogen atoms bonded to the carbon atoms of the alkylene radical is replaced by an aryl radical as defined herein.

[0062] When a particular group is “substituted,” that group may have one or more substituents, preferably 1 to 5 substituents, more preferably 1 to 3 substituents, and most preferably 1 to 2 substituents, independently selected from a list of substituents. However, a group can generally have any number of substituents selected from halogens. Multiple substituted groups are also indicated as such. The definition of any substituent or variable at a particular position within a molecule is intended to be independent of its definition elsewhere within that molecule. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and by the methods described herein.

[0063] As used herein, protecting groups refer to groups that selectively block a single reaction site in a polyfunctional compound, either temporarily or permanently. Suitable hydroxy protecting groups for use in the present invention are pharmaceutically acceptable and may or may not need to be cleaved from the parent compound after administration to a subject in order for the compound to be active. Cleavage occurs due to normal metabolic processes in the body. Hydroxy protecting groups are well known in the art and are incorporated herein by reference in their entirety for all purposes, Protective Groups in Organic Synthesis by TW Greene and PGMWuts (John Wiley & Sons, 3) rdSee Edition) and also include, for example, ethers (including, for example, dialkylsilyl ethers, trialkylsilyl ethers, dialkylalkoxysilyl ethers, alkyl ethers and silyl ethers), esters, carbonates, carbamates, sulfonates, and phosphate protecting groups. Examples of hydroxy protecting groups include methyl ethers; methoxymethyl ether, methylthiomethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, p-nitrobenzyloxymethyl ether, o-nitrobenzyloxymethyl ether, (4-methoxyphenoxy)methyl ether, guaiacolmethyl ether, t-butoxymethyl ether, 4-pentenyloxymethyl ether, siloxymethyl ether, 2-methoxyethoxymethyl ether, 2,2,2-trichloroethoxymethyl ether, bis( 2-chloroethoxy)methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, menthoxymethyl ether, tetrahydropyranyl ether, 1-methoxycyclohexyl ether, 4-methoxytetrahydrothiopyranyl ether, 4-methoxytetrahydrothiopyranyl ether S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidine-4-yl ether, 1-(2-fluorophenyl)-4-methoxypiperidine-4-yl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether;Substituted ethyl ethers, e.g., 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-[2-(trimethylsilyl)ethoxy]ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ether, 1-methyl-1-benzyloxy-2-fluoroethyl ether, 1-methyl-1-phenoxyethyl ether, 2-trimethylsilyl ether, t-butyl ether, allyl ether, propargyl ether, p-chlorophenyl ether, p-methoxyphenyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, tripropylsilyl ether, dimethylisopropylsilyl ether, diethylisopropylsilyl ether, dimethylhexylsilyl ether, t-butyl ether Examples include, but are not limited to, methylmethylsilyl ether, diphenylmethylsilyl ether, benzoyl formate ester, acetate ester, chloroacetate ester, dichloroacetate ester, trichloroacetate ester, trifluoroacetate ester, methoxyacetate ester, triphenylmethoxyacetate ester, phenylacetate ester, benzoate ester, alkylmethyl carbonate, alkyl9-fluorenylmethyl carbonate, alkylethyl carbonate, alkyl2,2,2-trichloroethyl carbonate, 1,1,-dimethyl-2,2,2-trichloroethyl carbonate, alkyl sulfonate, methanesulfonate, benzyl sulfonate, tosylate, methylene acetal, ethylidene acetal, and t-butylmethylidene ketal. A preferred protecting group is formula -R; a ,Si(R a )(R a )(R a ), -C(O)R a , -C(O)OR a -C(O)NH(R a ), -S(O)2R a -S(O)2OH, P(O)(OH)2, and -P(O)(OH)OR a It is represented by, where R a C1~C20 Alkyl, C2~C 20 Alkenyl, C2~C 20 Alkinyl, -C1~C 20 Alkylene (carbon ring), -C2~C 20 Alkenylene (carbon ring), -C2~C 20 Alkynylene (carbon ring), -C6~C 10 Ariel, -C1~C 20 Alkylene (aryl), -C2~C 20 Alkenylene (aryl), -C2~C 20 Alkynylene (aryl), -C1~C 20 Alkylene (heterocyclic ring), -C2~C 20 Alkenylenes (heterocyclic rings), or -C2~C 20 The alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl, carbocyclic, and heterocyclic radicals may be substituted either alone or as part of another group.

[0064] The term "chemotherapeutic agent" refers to all chemical compounds effective in inhibiting tumor growth. Non-exclusive examples of chemotherapeutic agents include alkylating agents, e.g., nitrogen mustard, ethyleneimine compounds, and alkyl sulfonates; antimetabolites, e.g., folic acid, purine, or pyrimidine antagonists; mitotic inhibitors, e.g., antitubulin agents such as vinca alkaloids, auristatin, and podophyllotoxin derivatives; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, e.g., DNA sulcus binding agents; and growth factor receptor antagonists. Furthermore, chemotherapeutic agents include cytotoxic agents (as defined herein), antibodies, biological molecules, and small molecules.

[0065] The term “compound” means and includes chemical compounds themselves, as well as, whether explicitly stated or not, the following unless the context makes it clear that the following should be excluded: amorphous and crystalline forms of compounds, including polymorphs, which may be part of a mixture or isolated; free acid and free base forms of compounds, which are typically the forms shown in the structures provided herein; isomers of compounds, meaning optical isomers and tautomers, where optical isomers include enantiomers and diastereomers, chiral isomers and non-chiral isomers, and these optical isomers include isolated optical isomers and mixtures of optical isomers, including racemic and non-racemic mixtures; where isomers may be in isolated form or in mixtures with one or more other isomers. Possible; isotopes of compounds, including deuterium-containing compounds and tritium-containing compounds, and compounds containing radioisotopes, including therapeutically and diagnostically effective radioisotopes; polymeric forms of compounds, including dimers, trimers, etc.; salts of compounds, preferably pharmaceutically acceptable salts, including acid-addition salts and base-addition salts, salts having organic and inorganic counterions, and zwitterionic forms; where the compound is associated with two or more counterions, the two or more counterions may be the same or different; and solvates of compounds, including hemisorbates, monosorbates, disorbitates, etc., including organic solvent dihydrates and inorganic solvates, where the compound is associated with two or more solvent molecules, the two or more solvent molecules may be the same or different. In some examples, references made herein to the compounds of the present invention include explicit references to one or more of the above forms, e.g., salts and / or solvates; however, these references are for emphasis only and should not be construed as excluding other of the above forms identified above.

[0066] As used herein, the term “conservative substitution” refers to amino acid substitutions that are known to those skilled in the art and can generally be made without altering the biological activity of the resulting molecule. Those skilled in the art generally recognize that single amino acid substitutions in non-essential regions of polypeptides do not substantially alter biological activity (see, for example, Watson et al., MOLECULAR BIOLOGY OF THE GENE, The Benjamin / Cummings Pub.Co., p.224 (4th Edition 1987)). Such exemplary substitutions are preferably made according to the substitutions shown in Tables 2 and 3. For example, such changes include substituting any of isoleucine (I), valine (V), and leucine (L) with any other of these hydrophobic amino acids; substituting glutamic acid (E) with aspartic acid (D) and vice versa; substituting asparagine (N) with glutamine (Q) and vice versa; and substituting threonine (T) with serine (S) and vice versa. Other substitutions can also be considered conserved, depending on the environment of the particular amino acid and its role in the three-dimensional structure of the protein. For example, glycine (G) and alanine (A), as well as alanine (A) and valine (V), can often be interchangeable. Relatively hydrophobic methionine (M) can often be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are often interchangeable at positions where the different pKs of these two amino acid residues are not important, as their charge is a key feature of the amino acid residue. Furthermore, other substitutions can be considered "conservative" in certain environments (see, for example, Table 3 of this specification; pages 13-15, "Biochemistry," 2nd ED. Lubert Stryer ed (Stanford University); Henikoff et al., PNAS 1992 Vol 89 10915-10919; Lei et al., J Biol Chem 1995 May 19; 270(20): 11882-11886). Other substitutions are also permissible and may be determined empirically or according to known conservative substitutions.

[0067] (Table 2) Abbreviations of Amino Acids TIFF2026048848000008.tif112157

[0068] (Table 3) Amino Acid Substitution or Similarity Matrix Conforms to the GCG software 9.0 BLOSUM62 amino acid substitution matrix (block substitution matrix). The higher the value, the higher the likelihood of substitution being found in related native proteins. TIFF2026048848000009.tif135140

[0069] The terms “homologous” or “homologous” are intended to mean sequence similarity between two polynucleotides or two polypeptides. Similarity can be determined by comparing the positions in each sequence that can be aligned for comparison purposes. If two polypeptide sequences are not identical at a given position, the similarity or conservation of that position can be determined by evaluating the similarity of the amino acids at that position, for example, according to Table 3. The degree of similarity between sequences is a function of the number of matching or homologous positions shared by the sequences. Alignment of two sequences to determine the sequence similarity percentage can be performed using software programs known in the art, such as those described in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1999). Preferably, default parameters are used for alignment, an example of which is shown below. One alignment program known in the art that can be used is BLAST, set to default parameters. In particular, the programs are BLASTN and BLASTP, which use the following default parameters: Genetic code = standard; filter = none; strand = both; cutoff = 60; expected value = 10; matrix = BLOSUM62; description = 50 sequences; sort order = high score; database = non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translation+SwissProtein+SPupdate+PIR. Details of these programs can be found at the National Center for Biotechnology Information.

[0070] The term "homolog" of a given amino acid sequence or nucleic acid sequence is intended to indicate the corresponding sequence of a "homolog" that has substantial identity or homology to the given amino acid sequence or nucleic acid sequence.

[0071] The determination of the percentage of identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be achieved using mathematical algorithms. A preferred non-restrictive example of a mathematical algorithm used for comparing two sequences is the algorithm of Karlin and Altschul, 1990, Proc.Natl.Acad.Sci.USA87:2264, 5877, as modified in Karlin and Altschul, 1993, Proc.Natl.Acad.Sci.USA90:5873 5877. Such algorithms are incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J.Mol.Biol.215:403. BLAST nucleotide searches can be performed using NBLAST nucleotide program parameters set, for example, score=100 and word length=12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed using XBLAST program parameters set to, for example, score 50 and word length = 3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389 3402. Alternatively, iterative searches can be performed using PSI BLAST to detect distant relationships between molecules (ibid.). When using the BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of each program (e.g., XBLAST and NBLAST) can be used (see, for example, the National Center for Biotechnology Information (NCBI) on the World Wide Web, ncbi.nlm.nih.gov). Another non-restrictive example of a mathematical algorithm used for sequence comparison is the algorithm of Myers and Miller, 1988, CABIOS 4:11 17.Such algorithms are incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When using the ALIGN program to compare amino acid sequences, the PAM120 weighted residue table, gap length penalty 12, and gap penalty 4 can be used.

[0072] The percentage of identity between two sequences can be determined using the same techniques as described above, with or without allowing gaps. Typically, only exact matches are counted in the calculation of the percentage of identity.

[0073] The term "cytotoxic agent" refers to a substance that inhibits or prevents the expression activity, function, and / or causes cell destruction. This term is intended to include radioisotopes, chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and / or variants. Examples of cytotoxic agents include auristatin (e.g., auristatin E, auristatin F, MMAE, and MMAF), aureomycin, meitansinoids, lysine, lysine A chain, combrestatin, duocalmycin, dorastatin, doxorubicin, daunorubicin, taxol, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxyanthracine dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modesine A chain, α-sarcin, geronin, mitogenin, restrictosin, phenomycin, enomycin, curisin, crotin, calicheamicin, soapwort (Sapaonaria officinalis) inhibitors, and glucocorticoids and other chemotherapeutic agents, as well as At 211 , I 131 , I 125 , Y 90 Re 186 Re 188 Sm 153 , Bi 212 Or Bi213 , P 32 and Lu 177 Radioactive isotopes of Lu, including but not limited to these, can also be used. Antibodies can also be conjugated to anticancer prodrug activating enzymes that can convert prodrugs into their active form.

[0074] As used herein, the terms “effective dose” or “therapeutic dose” refer to the amount of the conjugate molecule (e.g., antibody) or pharmaceutical composition provided herein that is sufficient to produce the desired result.

[0075] The terms “subject” and “patient” may be used interchangeably. Where used herein, in certain embodiments, the subject is a mammal such as a non-primate (e.g., a cow, a pig, a horse, a cat, a dog, a rat, etc.) or a primate (e.g., a monkey and a human). In certain embodiments, the subject is a human. In one embodiment, the subject is a mammal diagnosed with a condition or disorder, e.g., a human. In another embodiment, the subject is a mammal at risk of developing a condition or disorder, e.g., a human.

[0076] "Administer" or "administer" means the act of physically delivering an extracorporeal substance to a patient by injection or other means, such as by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0077] As used herein, the terms “to treat,” “to treat,” and “to treat” refer to a reduction or improvement in the progression, severity, and / or duration of a disease or condition resulting from the administration of one or more treatments. Treatment may be determined by assessing whether there has been a reduction, relief, and / or reduction of one or more symptoms associated with the underlying disease, to the extent that improvement is observed in the patient, even though the patient may still have the underlying disease. The term “to treat” includes both management and improvement of the disease. The terms “to manage,” “to manage,” and “manage” refer to the beneficial effect that a subject derives from a treatment that does not necessarily result in a cure of the disease.

[0078] The terms “prevent,” “prevention,” and “prevention” refer to reducing the likelihood of developing (or having a recurrence of) a disease, disorder, condition, or one or more related symptoms (e.g., cancer).

[0079] The terms “cancer” or “cancer cell” are used herein to describe tissue or cells found in a neoplasm that have characteristics that distinguish them from normal tissue or tissue cells. Such characteristics include, but are not limited to, the degree of anaplasia, irregularity of shape, indistinctness of cell contour, nuclear size, changes in nuclear or cytoplasmic structure, other phenotypic changes, the presence of cellular proteins indicating cancer or a precancerous condition, an increase in the number of mitotic cells, and the ability to metastasize. Words related to “cancer” include carcinoma, sarcoma, tumor, epithelioma, leukemia, lymphoma, polyp, and sclerotic carcinoma, transformation, neoplasm, etc.

[0080] As used herein, “locally advanced” cancer refers to cancer that has spread from its place of origin to adjacent tissues or lymph nodes.

[0081] As used herein, “metastatic” cancer refers to cancer that has spread from its original site to other parts of the body.

[0082] The terms "about" and "approximately" mean within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of a given value or range.

[0083] As used in this disclosure and in the claims, the singular forms "a," "an," and "the" include the plural form unless the context clearly indicates otherwise.

[0084] Whenever an aspect is described herein using the term “including,” it is understood that other similar aspects described in terms of “consisting of” and / or “essentially consisting of” are also provided. Similarly, when an aspect is described herein using the phrase “essentially consisting of,” it is understood that other similar aspects described in terms of “consisting of” are also provided.

[0085] In this specification, the term "and / or" as used in phrases such as "A and / or B" is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0086] The term "variant" refers to a molecule that exhibits a variation from a described type or standard, such as a protein having one or more different amino acid residues at the corresponding position(s) of a specifically described protein (e.g., the 191P4D12 protein shown in Figure 1). Analogues are an example of a variant protein. Splice isoforms and single nucleotide polymorphisms (SNPs) are further examples of variants.

[0087] The “191P4D12 protein” and / or “191P4D12-related protein” of the present invention include those specifically identified herein (see Figure 1), as well as allelic variants, conserved substitution variants, analogs, and homologs that can be isolated / produced and characterized without excessive experimentation according to the methods outlined herein or readily available in the art. Fusion proteins combining parts or fragments of different 191P4D12 proteins, and fusion proteins of 191P4D12 proteins with heterologous polypeptides are also included. Such 191P4D12 proteins are collectively referred to as 191P4D12-related proteins, the proteins of the present invention, or 191P4D12. The term "191P4D12-related protein" refers to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than 25 amino acids, or at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, and This also refers to a polypeptide fragment or 191P4D12 protein sequence of 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 330, at least 335, at least 339 or more amino acids.

[0088] As used herein, “peripheral neuropathy” refers to a disorder characterized by inflammation or degeneration of peripheral sensory or motor nerves. Disorders characterized by inflammation or degeneration of peripheral sensory nerves are referred to as peripheral sensory neuropathy. Disorders characterized by inflammation or degeneration of peripheral motor nerves are referred to as peripheral motor neuropathy. Peripheral neuropathy, being a disorder of nerves, can present with a variety of signs or symptoms in subjects with peripheral neuropathy. When used, for example, in relation to subjects, peripheral neuropathy is a grouped term and includes hypoesthesia, gait disturbance, muscle weakness, neuralgia, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and peripheral sensorimotor neuropathy. Peripheral neuropathy can be evaluated, reviewed, described, and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) grading v4.0, as further described below. In some aspects, peripheral neuropathy can be evaluated, reviewed, described, and classified according to Table 6 below.

[0089] As used herein, “hyperglycemia” refers to a disorder characterized by clinical laboratory results showing elevated blood glucose levels. Hyperglycemia is usually a sign of diabetes mellitus or impaired glucose tolerance. As further described below, hyperglycemia can be assessed, reviewed, explained, and classified according to CTCAE grading v4.0. In some embodiments, hyperglycemia can be assessed, reviewed, explained, and classified according to Table 5 below.

[0090] As used herein, “skin reaction” refers to the response to ADC treatment that appears on the skin of the subject. Such a response may be a direct consequence of ADC treatment, e.g., injury and other lesions caused by ADC to the skin of the subject. Such a response may also be an indirect consequence of ADC treatment, e.g., inflammation, necrosis, apoptosis, and / or an immune response to primary or direct injury or lesion caused by ADC. Skin reactions include, for example, maculopapular rash, pruritus, symmetric drug-induced intertriginous and flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmar-plantar erythematous dysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin. As further described below, skin reactions may be evaluated, examined, described, and classified according to CTCAE grading v4.0. In some aspects, skin reactions may be evaluated, examined, described, and classified according to Table 9 below.

[0091] As used herein, “dysgeusia” refers to a disorder characterized by an abnormal sensory experience of the taste of food, which may be associated with a reduced sense of smell. “Anorexia” refers to a disorder characterized by a loss of appetite. Dysgeusia and anorexia can be evaluated, examined, described, and classified according to Table 11 below, as further described below.

[0092] As used herein, “keratitis” refers to a disorder characterized by inflammation of the cornea of ​​the eye. “Dry eye” refers to a disorder characterized by dryness of the cornea and conjunctiva. “Blurred vision” refers to a disorder characterized by blurred or indistinct vision. As further described below, keratitis, dry eye, and blurred vision may be evaluated, examined, described, and classified according to CTCAE grading v4.0 and / or Table 11 below.

[0093] As used herein, "febrile neutropenia" refers to a condition where ANC < 1000 / mm² 3This refers to a disorder characterized by a single temperature reading >38.3°C (101°F) or a sustained temperature reading ≥38°C (100.4°F) for more than one hour. As further described below, febrile neutropenia can be evaluated, reviewed, described, and classified according to the CTCAE grading v4.0 and / or Table 13 below.

[0094] As used herein, “thrombocytopenia” refers to a condition characterized by abnormally low levels of platelets in the blood. Thrombocytopenia is often determined based on the number of platelets. Therefore, thrombocytopenia is the condition in question characterized by a decrease in the number of platelets in a blood sample to a range below normal. As used herein, “anemia” refers to a disorder characterized by a decrease in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous membranes, shortness of breath, palpitations, a soft systolic murmur, lethargy, and fatigue. As further described below, thrombocytopenia and anemia can be evaluated, examined, described, and classified according to CTCAE grading v4.0 and / or Table 13 below.

[0095] As used herein, “fatigue” refers to a disorder characterized by a state of general weakness in which the individual is unable to demonstrate the ability to muster enough energy to accomplish daily activities. Fatigue can be assessed, reviewed, described, and classified according to the CTCAE grading v4.0 and / or Table 15 below, as further described below.

[0096] As used herein, “diarrhea” refers to a disorder characterized by frequent, watery bowel movements. Diarrhea may be evaluated, reviewed, described, and classified according to the CTCAE grading v4.0 and / or Table 17 below, as further described below. In addition, diarrhea may be evaluated, reviewed, described, and classified according to the National Cancer Institute, Gastrointestinal Complications (PDQ®) - Health Professional Version, updated November 28, 2018, which is incorporated herein by reference in its entirety.

[0097] 5.2 Methods of treating cancer 5.2.1 Methods for treating cancer with various settings Methods for treating various cancers, including bladder cancer, using antibody-drug conjugates (ADCs) conjugated to 191P4D12 are provided herein. Methods for treating urothelial carcinoma using antibody-drug conjugates (ADCs) conjugated to 191P4D12 are also provided herein. Methods for treating solid tumors using antibody-drug conjugates (ADCs) conjugated to 191P4D12 are further provided herein. In certain embodiments, urothelial carcinoma is locally advanced or metastatic urothelial carcinoma. In certain embodiments, bladder cancer is locally advanced or metastatic bladder cancer. In certain embodiments, solid tumor is locally advanced or metastatic solid tumor. In other embodiments, urothelial carcinoma is locally advanced or metastatic urothelial carcinoma in patients who have been administered programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors and have received platinum-containing chemotherapy in a neoadjuvant / adjuvant setting in a locally advanced or metastatic setting. In some embodiments, bladder cancer is locally advanced or metastatic bladder cancer in patients who have received a programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy in a neoadjuvant / adjuvant setting for locally advanced or metastatic cancer. In some embodiments, solid tumors are locally advanced or metastatic solid tumors in patients who have received a programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy in a neoadjuvant / adjuvant setting for locally advanced or metastatic cancer. In some embodiments, the ADC is enfortumab vedotin (also known as anti-191P4D12-ADC, Ha22-2(2,4)6.1vcMMAE, ASG-22CE, ASG-22ME, or AGS-22M6E). In some embodiments, the ADC is administered in three 28-day cycles. In some specific embodiments, the ADC is administered on days 1, 8, and 15 of each 28-day cycle.

[0098] In one aspect, the present invention provides a method for preventing or treating cancer in a subject, comprising the step of (a) administering a first regimen to the subject comprising an effective amount of an antibody-drug conjugate (ADC), wherein the ADC comprises an antibody or antigen-binding fragment conjugated to one or more units of monomethyl auristatin E (MMAE) and conjugated to 191P4D12, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDR comprising an amino acid sequence of a complementarity-determining region (CDR) of a heavy chain variable region shown at SEQ ID NO:22, and a light chain variable region comprising a CDR comprising an amino acid sequence of a CDR of a light chain variable region shown at SEQ ID NO:23, wherein the subject has urothelial carcinoma or bladder cancer and is undergoing immune checkpoint inhibitor therapy and chemotherapy.

[0099] In some aspects of the methods provided herein, the ADC is administered three times within a 28-day cycle. In some aspects of the methods provided herein, the ADC is administered on days 1, 8, and 15 of a 28-day cycle. In some aspects of the methods provided herein, urothelial carcinoma is locally advanced urothelial carcinoma. In some aspects of the methods provided herein, bladder cancer is locally advanced bladder cancer. In some aspects of the methods provided herein, urothelial carcinoma is metastatic urothelial carcinoma. In some aspects of the methods provided herein, bladder cancer is metastatic bladder cancer. In some aspects of the methods provided herein, the immune checkpoint inhibitor therapy is a PD-1 inhibitor. In some aspects of the methods provided herein, the immune checkpoint inhibitor therapy is a PD-L1 inhibitor. In some aspects of the methods provided herein, the chemotherapy is platinum-containing chemotherapy. In some aspects of the methods provided herein, the platinum-containing chemotherapy is platinum-containing chemotherapy in a neoadjuvant setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in a neoadjuvant setting and a locally advanced setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in a neoadjuvant setting and a metastatic setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in an adjuvant setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in an adjuvant setting and a locally advanced setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in an adjuvant setting and a metastatic setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in a locally advanced setting. In some aspects of the methods provided herein, platinum-containing chemotherapy is platinum-containing chemotherapy in a metastatic setting. In some embodiments of the methods provided herein, the first regimen comprises an ADC dose of approximately 1.25 milligrams / kilogram (mg / kg) of the subject's body weight. In some embodiments of the methods provided herein, the subject has a body weight of less than 100 kg.In some embodiments of the methods provided herein, the first regimen comprises an ADC dose of about 1.25 milligrams / kilogram (mg / kg) of body weight of the subject, the subject having a body weight of less than 100 kg. In some embodiments of the methods provided herein, the first regimen comprises an ADC dose of about 125 mg to the subject, the subject having a body weight of 100 kg or more. This disclosure provides that the embodiments described in this paragraph may be, but are not limited to, specific embodiments of the aspects described in the preceding paragraph.

[0100] In some aspects, the present invention provides a method for preventing or treating cancer in a subject, comprising the step of administering an effective amount of an antibody-drug conjugate to the subject, wherein the antibody-drug conjugate comprises an antibody or antigen-binding fragment conjugated to one or more units of monomethyl auristatin E (MMAE) and conjugated to 191P4D12, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a complementation-determining region (CDR) comprising the amino acid sequence of the CDR of the heavy chain variable region shown in SEQ ID NO:22, and a light chain variable region comprising a CDR comprising the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:23, wherein the subject has locally advanced or metastatic urothelial carcinoma, is receiving a PD-1 or PD-L1 inhibitor, and is receiving platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting. In some aspects, a method for preventing or treating cancer in a subject is also provided herein, comprising the step of administering an effective amount of an antibody-drug conjugate to the subject, wherein the antibody-drug conjugate comprises an antibody or antigen-binding fragment conjugated to one or more units of monomethyl auristatin E (MMAE) and conjugated to 191P4D12, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a complementation-determining region (CDR) comprising the amino acid sequence of the CDR of the heavy chain variable region shown in SEQ ID NO:22, and a light chain variable region comprising a CDR comprising the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:23, wherein the subject has locally advanced or metastatic bladder cancer, is receiving a PD-1 or PD-L1 inhibitor, and is receiving platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting.

[0101] In all methods provided herein, specifically those described in the preceding two paragraphs, the therapeutic agents that may be used are those described in this section (Section 5.2) and Section 5.3; the selection of patients for treatment is described herein and illustrated in this section (Section 5.2) and Section 6; the administration regimens and pharmaceutical compositions for administering the therapeutic agents are described in this section (Section 5.2), Section 5.4 and Section 6 below; the biomarkers that can be used to identify therapeutic agents, select patients, determine the outcomes of these methods, and / or to use these methods as criteria in any way are described herein and illustrated in this section (Section 5.2) and Section 6; and the therapeutic outcomes of the methods provided herein may be improvements to the biomarkers described herein, for example, the biomarkers described and illustrated in this section (Section 5.2) and Section 6. Therefore, those skilled in the art will understand that the methods provided herein include all permutations and combinations of patients, therapeutic agents, administration regimens, biomarkers, and therapeutic outcomes as described above and below.

[0102] In certain embodiments, the methods provided herein are used to treat subjects having cancer that expresses 191P4D12 RNA, 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein. In certain embodiments, the methods provided herein are used to treat subjects having cancer that expresses both 191P4D12 RNA and 191P4D12 protein, for example, locally advanced or metastatic urothelial carcinoma or locally advanced or metastatic bladder cancer in subjects receiving PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting. In some embodiments, 191P4D12 RNA expression in cancer is determined by polynucleotide hybridization, sequencing (assessing the relative abundance of the sequence), and / or PCR (including RT-PCR). In some embodiments, 191P4D12 protein expression in cancer is determined by IHC, analysis in fluorescence-activated cell sorting (FACS), and / or Western blotting. In some embodiments, 191P4D12 protein expression in cancer is determined by multiple methods. In some embodiments, 191P4D12 protein expression in cancer is determined by two methods of IHC.

[0103] In certain embodiments, the methods provided herein are used to treat subjects having cancer, the cancer expressing 191P4D12 RNA, the 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein, and the cancer being sensitive to cytotoxic agents that block microtubule polymerization (such as Vinca and MMAE). In certain embodiments, the methods provided herein are used to treat subjects having cancer expressing both 191P4D12 RNA and 191P4D12 protein and being sensitive to cytotoxic agents that block microtubule polymerization (such as Vinca and MMAE), the cancer including, for example, locally advanced or metastatic urothelial carcinoma or locally advanced or metastatic bladder cancer in adults receiving PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy in a neoadjuvant / adjuvant setting.

[0104] In some embodiments, subjects who can be treated by the methods provided herein are subjects having locally advanced or metastatic urothelial carcinoma, the subjects receiving PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting. In some embodiments, subjects who can be treated by the methods provided herein are subjects having locally advanced or metastatic bladder cancer, the subjects receiving PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting.

[0105] In certain embodiments, cancers that can be treated by the methods provided herein include locally advanced or metastatic urothelial carcinoma in subjects receiving PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting. In certain embodiments, cancers that can be treated by the methods provided herein include locally advanced or metastatic bladder cancer in subjects receiving PD-1 or PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced or metastatic setting in a neoadjuvant / adjuvant setting.

[0106] In some embodiments, locally advanced or metastatic urothelial carcinoma is identified histologically, cytologically, or both histologically and cytologically. In some embodiments, locally advanced or metastatic bladder cancer is identified histologically, cytologically, or both histologically and cytologically.

[0107] In some embodiments, subjects that can be treated by the methods provided herein include subjects who have received one or more other treatments for cancer. In some embodiments, subjects that can be treated by the methods provided herein include subjects who have received one or more other treatments for cancer and whose cancer has progressed or recurred after such one or more treatments. Such one or more treatments include, for example, immune checkpoint inhibitor therapy, chemotherapy, and one or more lines of both immune checkpoint inhibitor therapy and chemotherapy. In some embodiments, subjects that can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after therapy with programmed cell death protein 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, platinum-containing chemotherapy, or any permutation or combination of two or more therapies from the therapies provided in this paragraph and the therapies described herein. In some embodiments, subjects that can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after therapy with PD-1 inhibitors. In some embodiments, subjects that can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after therapy with PD-L1 inhibitors. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a neoadjuvant setting. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in an adjuvant setting. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a locally advanced setting in a neoadjuvant setting. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a metastatic setting in a neoadjuvant setting.In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a locally advanced setting with adjuvant therapy. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a metastatic setting with adjuvant therapy. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a metastatic setting. In some embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after platinum-containing chemotherapy in a locally advanced setting.

[0108] In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy. In other specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a neoadjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in an adjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a locally advanced setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a metastatic setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a locally advanced setting in a neoadjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a metastatic setting in a neoadjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a locally advanced setting in an adjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-1 inhibitors and platinum-containing chemotherapy in a metastatic setting in an adjuvant setting.

[0109] In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a neoadjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in an adjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a metastatic setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced setting in a neoadjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a metastatic setting in a neoadjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a locally advanced setting in an adjuvant setting. In some specific embodiments, subjects who can be treated by the methods provided herein include subjects whose cancer has progressed or recurred after treatment with PD-L1 inhibitors and platinum-containing chemotherapy in a metastatic setting in an adjuvant setting.

[0110] In certain embodiments, subjects who can be treated in the manner provided herein include, for example, patients whose cancer has progressed or recurred within one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, fifteen months, sixteen months, seventeen months, eighteen months, eighteen months, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty months, twenty-one months, twenty-two months, twenty-three months, or twenty-four months after other treatment, including any or any combination of the treatments described in the preceding thirteen paragraphs. In certain embodiments, the cancer of the subject progressed or recurred within six months after platinum-based therapy. In further embodiments, the cancer of the subject progressed or recurred within twelve months after platinum-based therapy.

[0111] In some embodiments, subjects that can be treated by the methods provided herein have specific phenotypic or genotypic characteristics. In some embodiments, subjects have any permutations and combinations of the phenotypic or genotypic characteristics described herein.

[0112] In some embodiments, phenotypic or genotypic features are determined histologically, cytologically, or both histologically and cytologically. In some embodiments of the methods provided herein, the histological and / or cytological determination of phenotypic and / or genotypic features is performed based on the most recently analyzed tissue as described in the American Society of Clinical Oncology / American Society of Pathology (ASCO / CAP) guidelines, which are incorporated herein by reference in their entirety. In some embodiments, phenotypic or genotypic features are determined by sequencing, including next-generation sequencing (e.g., NGS from Illumina, Inc.), DNA hybridization, and / or RNA hybridization.

[0113] In some embodiments, one or more other treatments for cancer received by the subject, or from which the subject's cancer progressed or recurred, are PD-1 inhibitors or PD-L1 inhibitors. In certain embodiments, the PD-1 inhibitor is pembrolizumab. In certain embodiments, the PD-1 inhibitor is nivolumab. In other embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is avelumab. In certain embodiments, the PD-L1 inhibitor is durvalumab. Other examples of PD-I / PD-L1 inhibitors include, but are not limited to, those described in U.S. Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT International Publication Nos. 2003042402, 2008156712, 2010089411, 2010036959, 2011066342, 2011159877, 2011082400, and 2011161699, all of which are incorporated herein by reference in their entirety.

[0114] In certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody and is marketed under the trade name Opdivo®. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name Keytruda®. In yet another embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In yet another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind to Fcγ receptor I is specifically engineered, and which has a unique binding signature with high affinity for PD-1 and excellent target specificity.

[0115] In further embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In one embodiment, the anti-PD-L1 antibody is avelumab (BAVENCIO®). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and Tecentriq®).

[0116] In some embodiments, the subject that can be treated by the methods provided herein is a mammal. In some embodiments, the subject that can be treated by the methods provided herein is a human.

[0117] 5.2.2 Treatment methods including dose adjustments based on hyperglycemia and / or blood glucose levels This disclosure further provides that the ADC dose administered to treat a target cancer can be modified based on certain criteria, such as the subject's hyperglycemia. In some embodiments, the subject treated by the methods provided herein has hyperglycemia. In some specific embodiments, the subject treated by the methods provided herein has diabetic ketoacidosis (DKA). In other specific embodiments, the subject treated by the methods provided herein has a condition that increases the risk of hyperglycemia, such as a higher body mass index and / or a higher baseline A1C.

[0118] Hyperglycemia can be assessed based on blood glucose levels. In some embodiments, the method provided herein further includes (b) determining the blood glucose level of the subject, and (c) withholding administration of the antibody-drug conjugate if the blood glucose level in (b) is higher than 250 mg / dL. In certain embodiments, the method provided herein further includes (d) waiting for a period of time sufficient for the blood glucose level to decrease to 250 mg / dL or less. In certain further embodiments, the method provided herein further includes (e) determining the blood glucose level of the subject, and (f) administering a second regimen containing an effective amount of antibody-drug conjugate to the subject if the blood glucose level in (e) is 250 mg / dL or less.

[0119] This disclosure provides that, under certain criteria for serious adverse events in a subject, the administration of ADCs for cancer treatment should be permanently discontinued. In some embodiments of the methods provided herein, if the blood glucose level determined in either of the method steps, for example, step (b) or (e) of determining the blood glucose level of a subject as described in the preceding paragraph, exceeds 500 mg / dL, the administration of ADCs is permanently discontinued. In certain embodiments, if the determined blood glucose level exceeds 500 mg / dL, the administration of ADCs is permanently discontinued regardless of other criteria.

[0120] This disclosure provides that a method step for dose modification based on blood glucose levels can be repeated. This disclosure further provides that a method step for dose modification based on blood glucose levels can be repeated in accordance with the rules described and provided herein. In some aspects of the method provided herein, method steps (a) to (f) can be repeated, which are: (a) administering a first regimen containing an effective amount of ADC to a subject; (b) determining the blood glucose level of the subject; (c) withholding administration of the antibody-drug conjugate if the blood glucose level in (b) is higher than 250 mg / dL; (d) waiting for a period of time sufficient for the blood glucose level to fall to 250 mg / dL or less; (e) determining the blood glucose level of the subject; and (f) administering a second regimen containing an effective amount of antibody-drug conjugate to a subject if the blood glucose level in (e) is 250 mg / dL or less. In some embodiments of the method provided herein, steps (a), (b), (c), (e), and (f) can be repeated, which are: (a) administering a first regimen containing an effective amount of ADC to a subject; (b) determining the subject's blood glucose level; (c) refraining from administering the antibody-drug conjugate if the blood glucose level in (b) is higher than 250 mg / dL; (e) determining the subject's blood glucose level; and (f) administering a second regimen containing an effective amount of antibody-drug conjugate to a subject if the blood glucose level in (e) is 250 mg / dL or less. In some embodiments of the method provided herein, steps (b), (c), (d), (e) and (f) can be repeated, which are: (b) determining the blood glucose level of the subject; (c) withholding administration of the antibody-drug conjugate if the blood glucose level in (b) is higher than 250 mg / dL; (d) waiting for a period of time sufficient for the blood glucose level to fall to 250 mg / dL or less; (e) determining the blood glucose level of the subject; and (f) administering a second regimen containing an effective amount of antibody-drug conjugate to the subject if the blood glucose level in (e) is 250 mg / dL or less.In some embodiments of the method provided herein, steps (b), (c), (e), and (f) can be repeated, which are: (b) determining the blood glucose level of the subject; (c) refraining from administering the antibody-drug conjugate if the blood glucose level in (b) is higher than 250 mg / dL; (e) determining the blood glucose level of the subject; and (f) administering a second regimen containing an effective amount of the antibody-drug conjugate to the subject if the blood glucose level in (e) is 250 mg / dL or less.

[0121] This disclosure provides that the ADC dose in a second regimen based on blood glucose levels is maintained to be the same as the ADC dose in the first regimen. In some embodiments, if the second regimen is administered after blood glucose levels have returned to 250 mg / dL or less, the ADC dose in the second regimen is the same as the ADC dose in the first regimen. In some specific embodiments, if the second regimen is administered after blood glucose levels have returned to 250 mg / dL or less, the ADC dose in the second regimen is approximately 1.25 mg / kg (mg / kg) of target body weight for subjects weighing less than 100 kg or approximately 125 mg for subjects weighing 100 kg or more.

[0122] Alternatively, hyperglycemia as a dose change criterion, as described in the previous paragraph, can be determined based on the CTCAE grading v4.0 described in National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, which is incorporated herein by reference in its entirety. Thus, hyperglycemia can be classified into the five grades shown in Table 4 below.

[0123] (Table 4) Common Terminology Criteria for Adverse Events Related to Hyperglycemia (CTCAE) Grading v4.0 TIFF2026048848000010.tif56170ULN: Normal upper limit

[0124] Alternatively, in some embodiments, the grade of hyperglycemia is determined according to a scale in which grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening.

[0125] Based on the hyperglycemia grades in Table 4, in some embodiments, the method provided herein further includes (b') determining the hyperglycemia of the subject, e.g., the hyperglycemia grade, and (c') withholding administration of the antibody-drug conjugate if the hyperglycemia grade in (b') is grade 3 or higher. In certain embodiments, the method provided herein further includes (d') waiting for a period of time sufficient for the hyperglycemia to decrease to grade 2 or lower. In some further embodiments, the method provided herein further includes (e') determining the hyperglycemia of the subject, e.g., the hyperglycemia grade, and (f') administering a second regimen containing an effective amount of antibody-drug conjugate to the subject if the hyperglycemia in (e') is grade 2 or lower.

[0126] Similarly, under certain criteria for severe hyperglycemia in a subject, the administration of ADCs for cancer treatment should be permanently discontinued. In some embodiments of the methods provided herein, if the hyperglycemia determined in any of the method steps, including, for example, step (b') or (e') of determining the hyperglycemia grade of the subject as described in the preceding paragraph, is grade 4 or higher, the administration of ADCs is permanently discontinued. In certain embodiments, if the hyperglycemia is grade 4 or higher, the administration of ADCs is permanently discontinued regardless of other criteria.

[0127] The method steps for dose modification based on hyperglycemia criteria can also be repeated. The disclosure further provides that the method steps for dose modification based on hyperglycemia criteria can be repeated in accordance with the rules described and provided herein. In some embodiments of the methods provided herein, the above method steps (a), (b'), (c'), (d'), (e'), and (f') can be repeated. In some embodiments of the methods provided herein, the above method steps (a), (b'), (c'), (e'), and (f') can be repeated. In some embodiments of the methods provided herein, the above method steps (b'), (c'), (d'), (e'), and (f') can be repeated. In some embodiments of the methods provided herein, the above method steps (b'), (c'), (e'), and (f') can be repeated.

[0128] This disclosure provides that the ADC dose in a second regimen based on hyperglycemia is maintained to be the same as the ADC dose in the first regimen. In some embodiments, if the second regimen is administered after hyperglycemia has returned to grade 2 or lower, the ADC dose in the second regimen is the same as the ADC dose in the first regimen. In some specific embodiments, if the second regimen is administered after hyperglycemia has returned to grade 2 or lower, the ADC dose in the second regimen is approximately 1.25 milligrams / kg (mg / kg) of target body weight for subjects weighing less than 100 kg or approximately 125 mg for subjects weighing 100 kg or more.

[0129] Based on some aspects provided herein and described above, dose modification schemes for the methods provided herein based on blood glucose levels and / or hyperglycemia are summarized in Table 5 below.

[0130] (Table 5) Dosage modification schemes for methods provided herein based on blood glucose levels and / or hyperglycemia TIFF2026048848000011.tif48157*Patients with blood glucose levels >500 mg / dL (grade 4) that are considered unrelated to ADC treatment may continue administration once their blood glucose levels improve to ≤250 mg / dL (≤grade 2) and the patient is clinically and metabolically stable.

[0131] As shown in Table 5 above, in some embodiments, subjects with grade 4 hyperglycemia are considered unrelated to ADC treatment, and if the subject's blood glucose improves to ≤250 mg / dL (or hyperglycemia improves to grade 2 or less) and the patient is clinically and metabolically stable, there is no need to permanently discontinue ADC administration when the hyperglycemia determined in any of the method steps is grade 4 or higher. As shown in Table 5 above, in some embodiments, subjects with grade 4 hyperglycemia are considered unrelated to ADC treatment, and if the subject's blood glucose improves to ≤250 mg / dL or hyperglycemia improves to grade 2 or less and the patient is clinically and metabolically stable, there is no need to permanently discontinue ADC administration when the blood glucose determined in any of the method steps exceeds 500 mg / dL. In some embodiments, if a subject with grade 4 hyperglycemia is considered unrelated to ADC treatment, and the subject's blood glucose improves to ≤250 mg / dL (or hyperglycemia improves to grade 2 or less), and the patient is clinically and metabolically stable, ADC administration can be resumed at the same dose level as the first regimen, even after hyperglycemia determined in any of the method steps is grade 4 or higher. In some embodiments, if blood glucose levels are considered unrelated to ADC, and the subject's blood glucose improves to ≤250 mg / dL (or hyperglycemia improves to grade 2 or less), and the patient is clinically and metabolically stable, ADC administration can be resumed at the same dose level as the first regimen, even after blood glucose levels determined in any of the method steps exceed 500 mg / dL.

[0132] In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 1 to 10 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 1 to 10 weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 1 to 4 months. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 1 day. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 2 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 3 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 4 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 5 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 6 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 7 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 8 days. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 9 days. In some embodiments of the methods provided herein, the period sufficient for hyperglycemia to improve to grade 2 or less, or for blood glucose to decrease to 250 mg / dL or less, is 10 days.In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is one week. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is two weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is three weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is four weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is five weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is six weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 7 weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 8 weeks. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 1 month. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 2 months. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 3 months. In some embodiments of the methods provided herein, the period of time sufficient for hyperglycemia to improve to grade 2 or below, or for blood glucose to decrease to 250 mg / dL or below, is 4 months.

[0133] This disclosure provides that blood glucose levels and hyperglycemia in the methods provided herein can be determined at varying frequencies and intervals depending on the needs of the method and the practices of the art. In some embodiments of the methods provided herein, blood glucose levels are determined daily. In some embodiments of the methods provided herein, blood glucose levels are determined every two days, every three days, every four days, or every five days or every six days. In some embodiments of the methods provided herein, blood glucose levels are determined weekly, every two weeks, every three weeks, or every four weeks. In some embodiments of the methods provided herein, blood glucose levels are determined monthly, every two months, or every three months. In some embodiments of the methods provided herein, hyperglycemia is determined daily. In some embodiments of the methods provided herein, hyperglycemia is determined every two days, every three days, every four days, or every five days or every six days. In some embodiments of the methods provided herein, hyperglycemia is determined weekly, every two weeks, every three weeks, or every four weeks. In some aspects of the methods provided herein, hyperglycemia is determined monthly, every two months, or every three months.

[0134] 5.2.3 Treatment methods including dose changes based on peripheral neuropathy This disclosure also provides that the ADC dose administered to treat a target cancer can be modified based on other criteria, such as peripheral neuropathy in the target. In some embodiments, the target treated by the methods provided herein has peripheral neuropathy. In some embodiments, the target treated by the methods provided herein has peripheral sensory neuropathy. In some embodiments, the target treated by the methods provided herein has peripheral motor neuropathy. In some embodiments, the target treated by the methods provided herein has peripheral sensorimotor neuropathy. In some embodiments, peripheral neuropathy is used as a criterion for modifying the ADC dose. In some embodiments, peripheral sensory neuropathy is used as a criterion for modifying the ADC dose. In some embodiments, peripheral motor neuropathy is used as a criterion for modifying the ADC dose. In some embodiments, peripheral sensorimotor neuropathy is used as a criterion for modifying the ADC dose. In some embodiments, peripheral neuropathy, primarily peripheral sensory neuropathy, is used as a criterion for modifying the ADC dose. In some embodiments, peripheral neuropathy, of which about 50% is peripheral sensory neuropathy, is used as a criterion for modifying the ADC dose. In some aspects, peripheral neuropathy, in which 49% of cases involve peripheral sensory neuropathy, is used as a criterion for changing the ADC dose.

[0135] Peripheral neuropathy, including peripheral motor neuropathy, peripheral sensory neuropathy, and / or peripheral sensorimotor neuropathy, as criteria for dose adjustment, can be determined based on the CTCAE grading v4.0 described in National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, which is incorporated herein by reference in its entirety. Accordingly, peripheral neuropathy can be classified into the five grades shown in Table 6 below.

[0136] (Table 6) Common Terminology Criteria for Adverse Events Related to Peripheral Neuropathy (CTCAE) Grading v4.0 * TIFF2026048848000012.tif85170* Peripheral neuropathy is a grouped term that includes hypoesthesia, gait disturbance, muscle weakness, neuralgia, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and / or peripheral sensorimotor neuropathy. ADL: Activities of daily living

[0137] Alternatively, in some embodiments, the grading of peripheral neuropathy, including, for example, grades of peripheral motor neuropathy, peripheral sensory neuropathy, and / or peripheral sensorimotor neuropathy, is determined according to a scale in which Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening.

[0138] In some embodiments, based on the peripheral neuropathy grade, for example, the peripheral neuropathy grades listed in Table 6, the method provided herein further includes (g) determining the peripheral neuropathy of the subject, and (h) withholding administration of the antibody-drug conjugate if the peripheral neuropathy in (g) is grade 2 or higher. In certain embodiments, the method provided herein further includes (i) waiting for a period of time sufficient for the peripheral neuropathy to decrease to grade 1 or lower. In some further embodiments, the method provided herein further includes (j) determining the peripheral neuropathy of the subject, and (k) administering a second regimen containing an effective dose of ADC to the subject if the peripheral neuropathy in (j) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0139] This disclosure provides permanent discontinuation of ADC administration for cancer treatment under certain criteria for serious adverse events in subjects, such as Grade 3 or higher peripheral neuropathy. In some embodiments of the methods provided herein, ADC administration is permanently discontinued if the peripheral neuropathy in (g) or (j) is Grade 3 or higher. In certain embodiments, ADC administration is permanently discontinued if the peripheral neuropathy is Grade 3 or higher, regardless of other criteria.

[0140] This disclosure provides that method steps for dose modification based on criteria for peripheral neuropathy can be repeated. This disclosure further provides that method steps for dose modification based on criteria for peripheral neuropathy can be repeated in accordance with the rules described and provided herein. In some aspects of the methods provided herein, method steps (a), (g), (h), (i), (j), and (k) can be repeated, which are: (a) administering a first regimen containing an effective dose of ADC to a subject; (g) determining the peripheral neuropathy of the subject; (h) withholding administration of the antibody-drug conjugate if the peripheral neuropathy in (g) is grade 2 or higher; (i) waiting for a period of time sufficient for the peripheral neuropathy to decrease to grade 1 or lower; (j) determining the peripheral neuropathy of the subject; and (k) administering a second regimen containing an effective dose of ADC if the peripheral neuropathy in (j) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (a), (g), (h), (j), and (k) can be repeated, which are steps of (a) administering a first regimen containing an effective dose of ADC to a subject, (g) determining the subject's peripheral neuropathy, (h) refraining from administering the antibody-drug conjugate if the peripheral neuropathy in (g) is grade 2 or higher, (j) determining the subject's peripheral neuropathy, and (k) administering a second regimen containing an effective dose of ADC to a subject if the peripheral neuropathy (j) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.In some embodiments of the method provided herein, steps (g), (h), (i), (j), and (k) can be repeated, which are: (g) determining the peripheral neuropathy of the subject; (h) withholding administration of the antibody-drug conjugate if the peripheral neuropathy of (g) is grade 2 or higher; (i) waiting for a period of time sufficient for the peripheral neuropathy to decrease to grade 1 or lower; (j) determining the peripheral neuropathy of the subject; and (k) administering a second regimen containing an effective amount of ADC to the subject if the peripheral neuropathy of (j) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (g), (h), (j), and (k) can be repeated, which are: (g) determining the peripheral neuropathy of the subject; (h) refraining from administering the antibody-drug conjugate if the peripheral neuropathy in (g) is grade 2 or higher; (j) determining the peripheral neuropathy of the subject; and (k) administering a second regimen containing an effective amount of ADC to the subject if the peripheral neuropathy (j) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0141] In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 1 to 10 days. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 1 to 10 weeks. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 1 to 4 months. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 1 day. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 2 days. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 3 days. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 4 days. In some aspects of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 5 days. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 6 days. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 7 days. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 8 days. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 9 days. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 10 days. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 1 week. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 2 weeks. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 3 weeks. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 4 weeks.In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 5 weeks. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 6 weeks. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 7 weeks. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 8 weeks. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 1 month. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 2 months. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 3 months. In some embodiments of the methods provided herein, the period of time sufficient for peripheral neuropathy to decrease to grade 1 or below is 4 months.

[0142] This disclosure provides that the modified dose may depend on the number of times the conditions for administration of a second regimen based on the criteria for peripheral neuropathy have been met. Accordingly, in some embodiments, the method further includes the step of determining the number of times the conditions for administration of a second regimen have been met based on the criteria for peripheral neuropathy. This disclosure provides that the ADC dose may be modified according to the scheme described in Table 7 below.

[0143] (Table 7) Dose modification schemes for the methods provided herein based on peripheral neuropathy * TIFF2026048848000013.tif52164*For example, see Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600;Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600 (Protocol), both of which are incorporated herein by reference in their entirety.

[0144] The dose reductions or changes mentioned in Table 8 above and in the paragraphs above and below relating to peripheral neuropathy are shown below.

[0145] (Table 8) Starting dose and dose reduction schedule * TIFF2026048848000014.tif54164* Patients requiring dose reduction may be reinstated by one dose level if toxicity does not require discontinuation of the study drug and has returned to baseline or ≤ Grade 1 (i.e., a patient reduced to 0.75 mg / kg may be reinstated to 1 mg / kg only). Reinstation is not permitted if toxicity recurs.

[0146] In some embodiments of the methods provided herein, the ADC dose in the first regimen is the starting dose before dose reduction or dose change due to peripheral neuropathy. In some embodiments, such an ADC dose in the first regimen and starting dose is 1.25 mg / kg for subjects with a body weight of less than 100 kg or 125 mg for subjects with a body weight of 100 kg or more.

[0147] As is evident from the above description and from Tables 7 and 8, in some embodiments of the methods provided herein, the second regimen may be identical to the first regimen if the second regimen is administered for the first time in (k). In some embodiments of the methods provided herein, the second regimen in (k) may be identical to the first regimen if the second regimen is administered for the first time in (k) or if it has been administered once or multiple times. In some embodiments of the methods provided herein, if the second regimen has been administered once in (k) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen has been administered once in (k) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject. In some embodiments of the methods provided herein, if the second regimen is administered twice with (k) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen is administered twice with (k) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject. In some embodiments of the methods provided herein, if the second regimen is administered three times with (k) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen is administered three times with (k) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

[0148] This disclosure provides that if peripheral neuropathy does not require discontinuation of the study drug and the peripheral neuropathy returns to baseline or ≤ grade 1, the need for dose reduction may be to increase the dose by one dose level according to Table 8 (for example, a patient whose dose was reduced to 0.75 mg / kg may only be increased to 1 mg / kg). Accordingly, in some aspects of the methods provided herein, the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg or by approximately 25 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) the peripheral neuropathy has returned to grade 1 or less. Specifically, in some embodiments of the methods provided herein, the ADC dose in the second regimen is increased from 0.5 mg / ml to 0.75 mg / ml for subjects weighing less than 100 kg, or from 50 mg to 75 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) peripheral neuropathy has returned to grade 1 or lower. In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 0.75 mg / ml to 1 mg / ml for subjects weighing less than 100 kg, or from 75 mg to 100 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) peripheral neuropathy has returned to grade 1 or lower.In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 1 mg / ml to 1.25 mg / ml for subjects weighing less than 100 kg, or from 100 mg to 125 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) peripheral neuropathy has returned to grade 1 or lower.

[0149] This disclosure provides that in the methods provided herein, peripheral neuropathy, including peripheral motor neuropathy, peripheral sensory neuropathy, and / or peripheral sensorimotor neuropathy, can be determined at varying frequencies and intervals according to the needs of the method and / or the practices of the art. In some embodiments of the methods provided herein, peripheral neuropathy is determined daily. In some embodiments of the methods provided herein, peripheral neuropathy is determined every two days, every three days, every four days, or every five days or every six days. In some embodiments of the methods provided herein, peripheral neuropathy is determined weekly, every two weeks, every three weeks, or every four weeks. In some embodiments of the methods provided herein, peripheral neuropathy is determined monthly, every two months, or every three months. In some embodiments of the methods provided herein, peripheral sensory neuropathy is determined daily. In some aspects of the methods provided herein, peripheral sensory neuropathy is determined every two days, every three days, every four days, or every five days or every six days. In some aspects of the methods provided herein, peripheral sensory neuropathy is determined weekly, every other week, every three weeks, or every four weeks. In some aspects of the methods provided herein, peripheral sensory neuropathy is determined monthly, every two months, or every three months. In some aspects of the methods provided herein, peripheral motor neuropathy is determined daily. In some aspects of the methods provided herein, peripheral motor neuropathy is determined every two days, every three days, every four days, or every five days or every six days. In some aspects of the methods provided herein, peripheral motor neuropathy is determined weekly, every other week, every three weeks, or every four weeks. In some aspects of the methods provided herein, peripheral motor neuropathy is determined monthly, every two months, or every three months. In some aspects of the methods provided herein, peripheral sensorimotor neuropathy is determined daily. In some aspects of the methods provided herein, peripheral sensorimotor neuropathy is determined every two days, every three days, every four days, or every five days, or every six days. In some aspects of the methods provided herein, peripheral sensorimotor neuropathy is determined weekly, every other week, every three weeks, or every four weeks.In some aspects of the methods provided herein, peripheral sensorimotor neuropathy is determined monthly, every two months, or every three months.

[0150] 5.2.4 Treatment methods including dose adjustments based on skin reactions This disclosure also provides that the ADC dose administered to treat the target cancer can be modified based on other criteria, such as the subject's skin reaction. In some embodiments, the subject treated by the method provided herein has a skin reaction. In some embodiments, the subject treated by the method provided herein has one or more skin reactions. In some embodiments, the subject treated by the method provided herein has a maculopapular rash. In some embodiments, the subject treated by the method provided herein has pruritus. In some embodiments, the subject treated by the method provided herein has a symmetric drug-induced intertriginous rash. In some embodiments, the subject treated by the method provided herein has flexural rash (SDRIFE). In some embodiments, the subject treated by the method provided herein has bullous dermatitis. In some embodiments, the subject treated by the method provided herein has exfoliative dermatitis. In some embodiments, the subject treated by the method provided herein has dermatitis. In some embodiments, the subject treated by the method provided herein has palmar-plantar erythematous dysesthesia. In some embodiments, the subject treated by the method provided herein has a pustular rash. In some embodiments, the subject treated by the method provided herein has an acne-like rash. In some embodiments, the subject treated by the method provided herein has a papular-pustular rash. In some embodiments, the subject treated by the method provided herein has dry skin. In some embodiments, the subject treated by the method provided herein has one or more any permutations or combinations of skin reactions selected from the group consisting of maculopapular, pruritus, symmetrical drug-induced intertriginous and flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmar-plantar erythematous dysesthesia, pustular rash, acne-like rash, papular-pustular rash, and dry skin.

[0151] In some embodiments, a skin reaction is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, one or more skin reactions are used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, maculopapular rash is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, pruritus is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, drug-related intertrigo is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, flexural rash (SDRIFE) is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, bullous dermatitis is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, exfoliative dermatitis is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, dermatitis is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, palmar-plantar erythematous dysphoria is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, pustular rash is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, acneiform rash is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, papular-pustular rash is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, dry skin is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, one or more any permutations or combinations of skin reactions selected from the group consisting of maculopapular rash, pruritus, symmetrical drug-induced intertriginous rash, SDRIFE, bullous dermatitis, exfoliative dermatitis, palmar-plantar erythematous dysphoria, pustular rash, acneiform rash, papular-pustular rash, and dry skin is used as a criterion for changing the ADC dose in the method provided herein.

[0152] Skin reactions, including maculopapular rash, pruritus, symmetrical drug-induced intertriginous rash, SDRIFE, bullous dermatitis, exfoliative dermatitis, palmar-plantar erythematous dysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin, can be determined based on the grading scale described in the National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, which is incorporated herein by reference in its entirety. Therefore, skin reactions can be classified into the five grades shown in Table 9 below.

[0153] (Table 9) CTCAE definitions and grading of skin reactions v4.0 TIFF2026048848000015.tif133170TIFF2026048848000016.tif128170ADL:Activities of daily living

[0154] Alternatively, in some embodiments, the grade of a skin reaction, including, for example, grades of maculopapular rash, pruritus, symmetric drug-induced intertriginous rash, SDRIFE, bullous dermatitis, exfoliative dermatitis, palmar-plantar erythematous dysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin, is determined according to a scale in which grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening.

[0155] Based on a skin reaction grade, for example, the skin reaction grades listed in Table 9, in some embodiments the method provided herein further includes (l) determining the skin reaction of the subject and (m) withholding the administration of the ADC if the skin reaction in (l) is grade 3 or higher. In certain embodiments the method provided herein further includes (n) waiting for a period of time sufficient for the skin reaction to decrease to grade 1 or lower. In some further embodiments the method provided herein includes (o) determining the skin reaction of the subject and (p) administering a second regimen containing an effective amount of ADC to the subject if the skin reaction in (o) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC than the first regimen.

[0156] This disclosure provides for permanently discontinuing the administration of ADCs for cancer treatment under certain criteria for serious adverse events in subjects, such as skin reactions of grade 4 or higher. In some embodiments of the methods provided herein, if the skin reaction in step (l) or (o) of the method described above is of grade 4 or higher, the administration of ADCs is permanently discontinued. In certain embodiments, if the skin reaction is of grade 4 or higher, the administration of ADCs is permanently discontinued regardless of other criteria.

[0157] In other embodiments of the methods provided herein, if a grade 3 skin reaction occurs multiple times in the method, administration of ADC for cancer treatment is permanently discontinued. In other embodiments of the methods provided herein, if a grade 3 skin reaction occurs multiple times in method step (l) or (o), administration of ADC for cancer treatment is permanently discontinued. In some embodiments of the methods provided herein, if a grade 3 skin reaction recurs in method step (l) or (o), administration of ADC is permanently discontinued. In some embodiments of the methods provided herein, if a grade 3 skin reaction recurs in the method, administration of ADC is permanently discontinued. In certain embodiments, if a grade 3 skin reaction occurs multiple times, administration of ADC is permanently discontinued regardless of other criteria.

[0158] This disclosure provides that a method step for dose modification based on criteria for skin reaction can be repeated. This disclosure further provides that a method step for dose modification based on criteria for skin reaction can be repeated in accordance with the rules described and provided herein. In some aspects of the method provided herein, method steps (a), (l), (m), (n), (o), and (p) can be repeated, which are steps of (a) administering a first regimen containing an effective amount of ADC to a subject, (l) determining the subject's skin reaction, (m) withholding ADC administration if the skin reaction in (l) is grade 3 or higher, (n) waiting for a period of time sufficient for the skin reaction to decrease to grade 1 or lower, (o) determining the subject's skin reaction, and (p) administering a second regimen containing an effective amount of ADC to a subject if the skin reaction in (o) is grade 1 or lower, wherein the second regimen contains the same or a lower ADC dose as the first regimen. In some embodiments of the method provided herein, steps (a), (l), (m), (o), and (p) can be repeated, which are steps of (a) administering a first regimen containing an effective amount of ADC to a subject, (l) determining the subject's skin reaction, (m) withholding ADC administration if the skin reaction in (l) is grade 3 or higher, (o) determining the subject's skin reaction, and (p) administering a second regimen containing an effective amount of ADC to a subject if the skin reaction in (o) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (l), (m), (n), (o), and (p) can be repeated, which are: (l) determining the skin reaction of the subject; (m) withholding the administration of ADC if the skin reaction in (l) is grade 3 or higher; (n) waiting for a period of time sufficient for the skin reaction to decrease to grade 1 or lower; (o) determining the skin reaction of the subject; and (p) administering a second regimen containing an effective amount of ADC to the subject if the skin reaction in (o) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.In some embodiments of the method provided herein, steps (l), (m), (o), and (p) can be repeated, which are: (l) determining the skin reaction of the subject; (m) withholding the administration of ADC if the skin reaction of (l) is grade 3 or higher; (o) determining the skin reaction of the subject; and (p) administering a second regimen containing an effective amount of ADC to the subject if the skin reaction of (o) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0159] In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 1 to 10 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 1 to 10 weeks. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 1 to 4 months. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 1 day. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 2 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 3 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 4 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 5 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 6 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 7 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 8 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 9 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 10 days. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 1 week. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 2 weeks. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 3 weeks. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 4 weeks. In some embodiments of the methods provided herein, the period sufficient for the skin reaction to decrease to grade 1 or lower is 5 weeks.In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 6 weeks. In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 7 weeks. In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 8 weeks. In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 1 month. In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 2 months. In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 3 months. In some embodiments of the methods provided herein, the period of time sufficient for the skin reaction to decrease to grade 1 or lower is 4 months.

[0160] This disclosure provides that the modified dose may depend on the number of times the conditions for administration of a second regimen based on skin reaction criteria have been met. Therefore, in some embodiments, the method further includes the step of determining the number of times the conditions for administration of a second regimen based on skin reaction criteria have been met. This disclosure provides that the ADC dose may be modified according to the scheme described in Table 10 below.

[0161] (Table 10) Dose modification schemes for the methods provided herein based on skin reactions 1 TIFF2026048848000017.tif561671 For example, see Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600;Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600 (Protocol), both of which are incorporated herein by reference in their entirety. 2. Mild rashes associated with ADC treatment can be treated with topical supportive therapy as needed. Topical corticosteroids are used together with antihistamines for pruritus as needed. 3. Grade 3 rashes associated with infections that do not restrict daily living activities or require systemic antibiotics do not require treatment interruption if the symptoms are not severe and can be managed with supportive care.

[0162] In some embodiments, dose reductions or modifications mentioned in Table 10 above and in the paragraphs relating to skin reactions above and below are shown in Table 8 above.

[0163] In some embodiments of the methods provided herein, the ADC dose in the first regimen is the starting dose before dose reduction or dose change based on skin reactions. Based on Table 8, in some embodiments, such an ADC dose in the first regimen and starting dose is 1.25 mg / kg for subjects with a body weight of less than 100 kg or 125 mg for subjects with a body weight of 100 kg or more.

[0164] As is evident from the above description and from Tables 10 and 8, in some embodiments of the methods provided herein, the second regimen may be identical to the first regimen if it is administered for the first time at (p). In some embodiments of the methods provided herein, the second regimen at (p) may be identical to the first regimen if it is administered for the first time at (p) or if it has been administered once or multiple times. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times at (p) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times at (p) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (p) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject weight. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (p) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject. In some embodiments of the methods provided herein, if the second regimen has been administered three or more times as (p) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject weight. In some embodiments of the methods provided herein, if the second regimen has been administered three or more times as (p) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

[0165] Alternatively, according to Tables 10 and 8 above, in some embodiments of the methods provided herein and based on skin reaction criteria, if the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is approximately 1.0 mg / kg body weight. In some embodiments of the methods provided herein and based on skin reaction criteria, if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is approximately 100 mg per subject. In some embodiments of the methods provided herein and based on skin reaction criteria, if the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is approximately 1.0 mg / kg body weight when the second regimen is administered for the first time or after one or more administrations. In some embodiments of the methods provided herein and based on skin reaction criteria, if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is approximately 100 mg to the subject when the second regimen is administered for the first time or once or multiple times. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times as (p) and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg body weight. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times as (p) and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg to the subject. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (p) and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg body weight. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (p) and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

[0166] This disclosure provides that if a skin reaction does not require discontinuation of the study drug and the skin reaction returns to baseline or ≤ Grade 1, the need for dose reduction may be to increase the dose by one dose level according to Table 8 (for example, a patient whose dose was reduced to 0.75 mg / kg may only be increased to 1 mg / kg). Accordingly, in some aspects of the methods provided herein, the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg or by approximately 25 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) the skin reaction has returned to Grade 1 or less. Specifically, in some embodiments of the methods provided herein, the ADC dose in the second regimen is increased from 0.5 mg / ml to 0.75 mg / ml for subjects weighing less than 100 kg, or from 50 mg to 75 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) the skin reaction has returned to grade 1 or lower. In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 0.75 mg / ml to 1 mg / ml for subjects weighing less than 100 kg, or from 75 mg to 100 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) the skin reaction has returned to grade 1 or lower.In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 1 mg / ml to 1.25 mg / ml for subjects weighing less than 100 kg, or from 100 mg to 125 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) the skin reaction has returned to grade 1 or lower.

[0167] This disclosure provides that skin reactions, including maculopapular rash, pruritus, symmetric drug-associated intertriginous eruption (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmoplantar erythematous dysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin, in the methods provided herein may be determined at varying frequencies and intervals according to the needs of the method and / or the practices of the art. In some embodiments of the methods provided herein, skin reactions are determined daily. In some embodiments of the methods provided herein, skin reactions are determined every two days, every three days, every four days, or every five days, every six days. In some embodiments of the methods provided herein, skin reactions are determined weekly, every two weeks, every three weeks, or every four weeks. In some embodiments of the methods provided herein, skin reactions are determined monthly, every two months, or every three months.

[0168] In some embodiments of the methods provided herein, one or more of the following specific skin reactions are determined daily: for example, maculopapular rash, pruritus, symmetric drug-associated intertriginous and flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmoplantar erythrodysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin. In some embodiments of the methods provided herein, one or more of the following specific skin reactions are determined every 2 days, every 3 days, every 4 days, or every 5 days, or every 6 days. In some embodiments of the methods provided herein, one or more of the following specific skin reactions, including, for example, maculopapular rash, pruritus, symmetrical drug-associated intertriginous and flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmoplantar erythrodysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin, are determined weekly, bi-weekly, every three weeks, or every four weeks. In some embodiments of the methods provided herein, one or more of the following specific skin reactions, including, for example, maculopapular rash, pruritus, symmetrical drug-associated intertriginous and flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmoplantar erythrodysesthesia, pustular rash, acneiform rash, papular-pustular rash, and / or dry skin, are determined monthly, every two months, or every three months.

[0169] 5.2.5 Treatment methods including dose changes based on non-hematological toxicity This disclosure also provides that the ADC dose administered to treat the target cancer can be modified based on other criteria, such as the non-hematological toxicity of the target. In some embodiments, the target treated by the method provided herein has non-hematological toxicity. In some embodiments, the target treated by the method provided herein has one or more non-hematological toxicities. In some embodiments, the target treated by the method provided herein has dysgeusia. In some embodiments, the target treated by the method provided herein has anorexia. In some embodiments, the target treated by the method provided herein has decreased appetite. In some embodiments, the target treated by the method provided herein has ocular disorders. In some embodiments, the target treated by the method provided herein has punctate keratitis. In some embodiments, the target treated by the method provided herein has keratitis. In some embodiments, the target treated by the method provided herein has keratopathy. In some embodiments, the target treated by the method provided herein has limbal stem cell deficiency. In some embodiments, the target treated by the method provided herein has dry eye. In some embodiments, subjects treated by the methods provided herein have blurred vision. In some embodiments, subjects treated by the methods provided herein have one or more arbitrary permutations or combinations of non-hematological toxicities selected from the group consisting of dysgeusia, anorexia, decreased appetite, and ocular disorders. In some embodiments, subjects treated by the methods provided herein have one or more arbitrary permutations or combinations of non-hematological toxicities selected from the group consisting of dysgeusia, anorexia, decreased appetite, punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision.

[0170] In some embodiments, non-hematological toxicity is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, one or more non-hematological toxicities are used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, dysgeusia is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, anorexia is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, decreased appetite is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, ocular disorders are used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, punctate keratitis is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, keratitis is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, keratopathy is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, limbal stem cell deficiency is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, dry eye is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, blurred vision is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, one or any permutation or combination of non-hematological toxicities selected from the group consisting of dysgeusia, anorexia, decreased appetite, and ocular disorders is used as a criterion for changing the ADC dose in the method provided herein. In some embodiments, one or any permutation or combination of non-hematological toxicities selected from the group consisting of dysgeusia, anorexia, decreased appetite, punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision is used as a criterion for changing the ADC dose in the method provided herein.

[0171] As is clear from the above description, in some embodiments, non-hematological toxicities include, but are not limited to, dysgeusia, anorexia, decreased appetite, and ocular disorders. In some embodiments, ocular disorders (i.e., disorders of the eye) include, but are not limited to, punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision. Therefore, in certain embodiments, non-hematological toxicities include, but are not limited to, dysgeusia, anorexia, decreased appetite, punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision. Non-hematological toxicities, including dysgeusia, anorexia, decreased appetite, and ocular disorders (i.e., ocular disorders such as punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision), can be determined based on the grading scale described in the National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, which is incorporated herein by reference in its entirety. In some specific embodiments, the grading for non-hematological toxicities is determined as shown in Table 11 below.

[0172] (Table 11) CTCAE definitions and grading v4.0 for various types of non-hematological toxicities TIFF2026048848000018.tif191170ADL: Activities of Daily Living; TPN: Total Parenteral Nutrition

[0173] Alternatively, in some embodiments, the grade of non-hematological toxicity, including, for example, grades of taste disturbance, loss of appetite, decreased appetite, eye disorders, punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and / or blurred vision, is determined according to a scale in which grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening.

[0174] In some aspects of the methods provided herein, the non-hematological toxicity is taste disturbance. In some aspects of the methods provided herein, the non-hematological toxicity is loss of appetite. In some aspects of the methods provided herein, the non-hematological toxicity is decreased appetite. In some aspects of the methods provided herein, the non-hematological toxicity is eye damage. In some aspects of the methods provided herein, the non-hematological toxicity is punctate keratitis. In some aspects of the methods provided herein, the non-hematological toxicity is keratitis. In some aspects of the methods provided herein, the non-hematological toxicity is keratopathy. In some aspects of the methods provided herein, the non-hematological toxicity is limbal stem cell deficiency. In some aspects of the methods provided herein, the non-hematological toxicity is dry eye. In some aspects of the methods provided herein, the non-hematological toxicity is blurred vision.

[0175] Based on the non-hematological toxicity grade, for example, the non-hematological toxicity grades listed in Table 11, in some embodiments, the method provided herein further includes the steps of (q) determining the non-hematological toxicity of the subject, and if the non-hematological toxicity of (q) is grade 3 or higher, withholding the administration of the ADC. In certain embodiments, the method provided herein further includes the step of (t) waiting for a period of time sufficient for the non-hematological toxicity to decrease to grade 1 or lower. In some further embodiments, the method provided herein includes the steps of (u) determining the non-hematological toxicity of the subject, and (v) if the non-hematological toxicity of (u) is grade 1 or lower, administering a second regimen to the subject containing an effective amount of ADC, wherein the second regimen contains the same or a lower dose of ADC than the first regimen.

[0176] This disclosure provides for permanently discontinuing the administration of ADCs for cancer treatment under certain criteria for serious adverse events in subjects, such as non-hematological toxicity of grade 4 or higher. In some embodiments of the methods provided herein, if the non-hematological toxicity of step (q) or (u) described above is grade 4 or higher, the administration of ADCs is permanently discontinued. In certain embodiments, if the non-hematological toxicity is grade 4 or higher, the administration of ADCs is permanently discontinued regardless of other criteria.

[0177] This disclosure provides that method steps for dose modification based on non-hematological toxicity criteria can be repeated. This disclosure further provides that method steps for dose modification based on non-hematological toxicity criteria can be repeated in accordance with the rules described and provided herein. In some embodiments of the methods provided herein, method steps (a), (q), (s), (t), (u) and (v) can be repeated, which are steps of (a) administering a first regimen containing an effective dose of ADC to a subject, (q) determining the non-hematological toxicity of the subject, withholding ADC administration if the non-hematological toxicity of (q) is grade 3 or higher, (t) waiting for a period of time sufficient for the non-hematological toxicity to decrease to grade 1 or lower, (u) determining the non-hematological toxicity of the subject, and (v) administering a second regimen containing an effective dose of ADC if the non-hematological toxicity of (u) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (a), (q), (s), (u), and (v) can be repeated, which are: (a) administering a first regimen containing an effective dose of ADC to a subject; (q) determining the subject's non-hematological toxicity; (s) withholding ADC administration if the non-hematological toxicity of (q) is grade 3 or higher; (u) determining the subject's non-hematological toxicity; and (v) administering a second regimen containing an effective dose of ADC to a subject if the non-hematological toxicity of (u) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (q), (s), (t), (u), and (v) can be repeated, which are: (q) determining the non-hematological toxicity of the subject; (s) withholding ADC administration if the non-hematological toxicity of (q) is grade 3 or higher; (t) waiting for a period sufficient for the non-hematological toxicity to decrease to grade 1 or lower; (u) determining the non-hematological toxicity of the subject; and (v) administering a second regimen containing an effective amount of ADC to the subject if the non-hematological toxicity of (u) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC than the first regimen.In some embodiments of the method provided herein, steps (q), (s), (u), and (v) can be repeated, which are steps (q) determining the non-hematological toxicity of the subject, (s) withholding the administration of ADC if the non-hematological toxicity of (q) is grade 3 or higher, (u) determining the non-hematological toxicity of the subject, and (v) administering a second regimen containing an effective amount of ADC to the subject if the non-hematological toxicity of (u) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0178] In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 1 to 10 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 1 to 10 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 1 to 4 months. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 1 day. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 2 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 3 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 4 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 5 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 6 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 7 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 8 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 9 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 10 days. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 1 week. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 2 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 3 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 4 weeks.In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 5 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 6 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 7 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 8 weeks. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 1 month. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 2 months. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 3 months. In some embodiments of the methods provided herein, the period sufficient for non-hematological toxicity to decrease to grade 1 or below is 4 months.

[0179] This disclosure provides that the modified dose may depend on the number of times the conditions for administration of a second regimen based on non-hematological toxicity criteria have been met. Accordingly, in some embodiments, the method further includes the step of determining the number of times the conditions for administration of a second regimen have been met based on non-hematological toxicity criteria. This disclosure provides that the ADC dose may be modified according to the scheme described in Table 12 below.

[0180] (Table 12) Dose modification schemes for methods provided herein based on non-hematological toxicity 1 TIFF2026048848000019.tif431671 For example, see Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600;Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600 (Protocol), both of which are incorporated herein by reference in their entirety.

[0181] In some embodiments, dose reductions or modifications mentioned in Table 12 above and in the paragraphs relating to non-hematological toxicity above and below are shown in Table 8 above.

[0182] In some embodiments of the methods provided herein, the ADC dose in the first regimen is the starting dose before dose reduction or dose change based on non-hematological toxicity. Based on Table 8, in some embodiments, such an ADC dose in the first regimen and starting dose is 1.25 mg / kg for subjects with a body weight of less than 100 kg or 125 mg for subjects with a body weight of 100 kg or more.

[0183] As is evident from the above description and from Tables 12 and 8, in some embodiments of the methods provided herein, the second regimen may be identical to the first regimen if the second regimen is administered for the first time in (v). In some embodiments of the methods provided herein, the second regimen in (v) may be identical to the first regimen if the second regimen is administered for the first time in (v) or if it has been administered once or multiple times. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times in (v) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times in (v) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (v) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (v) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject. In some embodiments of the methods provided herein, if the second regimen has been administered three or more times as (v) and the subject weighs less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen has been administered three or more times as (v) and the subject weighs 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

[0184] Alternatively, according to Tables 12 and 8 above, in some embodiments of the methods provided herein and based on non-hematological toxicity criteria, if the subject has a body weight of less than 100 kg, the ADC dose in the second regimen in (v) is approximately 1.0 mg / kg body weight. In some embodiments of the methods provided herein and based on non-hematological toxicity criteria, if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen in (v) is approximately 100 mg per subject. In some embodiments of the methods provided herein and based on non-hematological toxicity criteria, if the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is approximately 1.0 mg / kg body weight when the second regimen is administered for the first time in (v) or when it has been administered once or multiple times. In some embodiments of the methods provided herein and based on non-hematological toxicity criteria, if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is approximately 100 mg to the subject when the second regimen is administered for the first time in (v) or once or multiple times. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times in (v) and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen has been administered once or multiple times in (v) and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg to the subject. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (v) and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg body weight. In some embodiments of the methods provided herein, if the second regimen has been administered two or more times as (v) and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

[0185] This disclosure provides that if non-hematological toxicity does not require discontinuation of the study drug and non-hematological toxicity returns to baseline or ≤ grade 1, the need for dose reduction may be to increase the dose by one dose level according to Table 8 (for example, a patient whose dose was reduced to 0.75 mg / kg may only be increased to 1 mg / kg). Accordingly, in some aspects of the methods provided herein, the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg or by approximately 25 mg for subjects weighing 100 kg or more, provided that (1) ADC administration is not permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) non-hematological toxicity returns to grade 1 or less. Specifically, in some embodiments of the methods provided herein, the ADC dose in the second regimen is increased from 0.5 mg / ml to 0.75 mg / ml for subjects weighing less than 100 kg, or from 50 mg to 75 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) non-hematological toxicity has returned to grade 1 or less. In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 0.75 mg / ml to 1 mg / ml for subjects weighing less than 100 kg, or from 75 mg to 100 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) non-hematological toxicity has returned to grade 1 or less.In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 1 mg / ml to 1.25 mg / ml for subjects weighing less than 100 kg, or from 100 mg to 125 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) non-hematological toxicity has returned to grade 1 or less.

[0186] This disclosure provides that non-hematological toxicities in the methods provided herein, including dysgeusia, anorexia, decreased appetite, ocular disorders, punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and / or blurred vision, may be determined at varying frequencies and intervals according to the needs of the method and / or the practices of the art. In some embodiments of the methods provided herein, non-hematological toxicities are determined daily. In some embodiments of the methods provided herein, non-hematological toxicities are determined every two days, every three days, every four days, or every five days or every six days. In some embodiments of the methods provided herein, non-hematological toxicities are determined weekly, every two weeks, every three weeks, or every four weeks. In some embodiments of the methods provided herein, non-hematological toxicities are determined monthly, every two months, or every three months.

[0187] 5.2.6 Treatment methods including dose changes based on non-hematological toxicity This disclosure also provides that the ADC dose administered to treat the target cancer can be modified based on other criteria, such as the hematological toxicity of the subject. In some embodiments, the subject treated by the methods provided herein has hematological toxicity. In some embodiments, the subject treated by the methods provided herein has one or more hematological toxicity. In some embodiments, the subject treated by the methods provided herein has anemia. In some embodiments, the subject treated by the methods provided herein has thrombocytopenia. In some embodiments, the subject treated by the methods provided herein has neutropenia. In some embodiments, the subject treated by the methods provided herein has febrile neutropenia. In some embodiments, the subject treated by the methods provided herein has one or more any permutations or combinations of hematological toxicity selected from the group consisting of anemia, thrombocytopenia, neutropenia, and febrile neutropenia.

[0188] In some embodiments, hematological toxicity is used as a criterion for changing the ADC dose in the methods provided herein. In some embodiments, one or more hematological toxicities are used as a criterion for changing the ADC dose in the methods provided herein. In some embodiments, anemia is used as a criterion for changing the ADC dose in the methods provided herein. In some embodiments, thrombocytopenia is used as a criterion for changing the ADC dose in the methods provided herein. In some embodiments, neutropenia is used as a criterion for changing the ADC dose in the methods provided herein. In some embodiments, febrile neutropenia is used as a criterion for changing the ADC dose in the methods provided herein. In some embodiments, one or more arbitrary permutations or combinations of hematological toxicities selected from the group consisting of anemia, thrombocytopenia, neutropenia, and febrile neutropenia are used as a criterion for changing the ADC dose in the methods provided herein.

[0189] As is evident from the above description, in some embodiments, hematological toxicity includes, but is not limited to, anemia, thrombocytopenia, neutropenia, and febrile neutropenia. Hematological toxicity, including anemia, thrombocytopenia, neutropenia, and febrile neutropenia, as dose change criteria, can be determined based on the grading scale described in National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, which is incorporated herein by reference in its entirety. In some specific embodiments, the grading for hematological toxicity is determined as shown in Table 13 below.

[0190] (Table 13) CTCAE definitions and grading for various types of hematological toxicity v4.0 TIFF2026048848000020.tif129170LLN: Lower limit of normal; ANC: Absolute neutrophil count; Hgb: Hemoglobin

[0191] Alternatively, in some embodiments, the grade of hematological toxicity, including, for example, grades of anemia, thrombocytopenia, neutropenia, and febrile neutropenia, is determined according to a scale in which grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening.

[0192] In some embodiments of the methods provided herein, the hematological toxicity is anemia. In some embodiments of the methods provided herein, the hematological toxicity is thrombocytopenia. In some embodiments of the methods provided herein, the hematological toxicity is neutropenia. In some embodiments of the methods provided herein, the hematological toxicity is febrile neutropenia.

[0193] Based on the hematological toxicity grade, for example, the hematological toxicity grades listed in Table 13, in some embodiments the method provided herein further includes the steps of (w) determining the hematological toxicity of the subject and (x) withholding the administration of ADC if the hematological toxicity of (w) is grade 2 or higher. In certain embodiments the method provided herein further includes the step of (y) waiting for a period of time sufficient for the hematological toxicity to decrease to grade 1 or lower. In some further embodiments the method provided herein includes the steps of (z) determining the hematological toxicity of the subject and (aa) administering a second regimen to the subject containing an effective amount of ADC if the hematological toxicity of (z) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC than the first regimen.

[0194] This disclosure provides for permanently discontinuing the administration of ADCs for cancer treatment under certain criteria for serious adverse events in subjects, such as hematological toxicity of grade 4 or higher. In some embodiments of the methods provided herein, if the hematological toxicity of step (w) or (z) described above is grade 4 or higher, the administration of ADCs is permanently discontinued. In certain embodiments, if the hematological toxicity is grade 4 or higher, the administration of ADCs is permanently discontinued regardless of other criteria.

[0195] This disclosure provides that method steps for dose modification based on hematological toxicity criteria can be repeated. This disclosure further provides that method steps for dose modification based on hematological toxicity criteria can be repeated in accordance with the rules described and provided herein. In some aspects of the methods provided herein, method steps (a), (w), (x), (y), (z) and (aa) can be repeated, which are steps of (a) administering a first regimen containing an effective dose of ADC to a subject, (w) determining the hematological toxicity of the subject, (x) withholding ADC administration if the hematological toxicity of (w) is grade 2 or higher, (y) waiting for a period of time sufficient for the hematological toxicity to decrease to grade 1 or lower, (z) determining the hematological toxicity of the subject, and (aa) administering a second regimen containing an effective dose of ADC if the hematological toxicity of (z) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (a), (w), (x), (z), and (aa) can be repeated, which are steps (a) administering a first regimen containing an effective dose of ADC to a subject, (w) determining the hematological toxicity of the subject, (x) withholding ADC administration if the hematological toxicity of (w) is grade 2 or higher, (z) determining the hematological toxicity of the subject, and (aa) administering a second regimen containing an effective dose of ADC if the hematological toxicity of (z) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (w), (x), (y), (z), and (aa) can be repeated, which are: (w) determining the hematological toxicity of the subject; (x) withholding ADC administration if the hematological toxicity of (w) is grade 2 or higher; (y) waiting for a period sufficient for the hematological toxicity to decrease to grade 1 or lower; (z) determining the hematological toxicity of the subject; and (aa) administering a second regimen containing an effective amount of ADC to the subject if the hematological toxicity of (z) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.In some embodiments of the method provided herein, steps (w), (x), (z), and (aa) can be repeated, which are: (w) a step of determining hematological toxicity in a subject; (x) a step of withholding ADC administration if the hematological toxicity of (w) is grade 2 or higher; (z) a step of determining hematological toxicity in a subject; and (aa) a step of administering a second regimen containing an effective amount of ADC to the subject if the hematological toxicity of (z) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0196] In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 1 to 10 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 1 to 10 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 1 to 4 months. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 1 day. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 2 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 3 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 4 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 5 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 6 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 7 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 8 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 9 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 10 days. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 1 week. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 2 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 3 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 4 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 5 weeks.In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 6 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 7 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 8 weeks. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 1 month. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 2 months. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 3 months. In some embodiments of the methods provided herein, the period sufficient for hematological toxicity to decrease to grade 1 or below is 4 months.

[0197] This disclosure provides that the modified dose may depend on the number of times the conditions for administration of a second regimen, based on hematological toxicity criteria, have been met. Accordingly, in some embodiments, the method further includes the step of determining the number of times the conditions for administration of a second regimen, based on hematological toxicity criteria, have been met. This disclosure provides that the ADC dose may be modified according to the scheme described in Table 14 below.

[0198] (Table 14) Dose modification schemes for the methods provided herein based on hematological toxicity TIFF2026048848000021.tif57135

[0199] In some embodiments, dose reductions or modifications mentioned in Table 14 above and in the paragraphs relating to hematological toxicity above and below are shown in Table 8 above.

[0200] In some embodiments of the methods provided herein, the ADC dose in the first regimen is the starting dose before dose reduction or dose change due to hematological toxicity. Based on Table 8, in some embodiments, such an ADC dose in the first regimen and starting dose is 1.25 mg / kg for subjects with a body weight of less than 100 kg or 125 mg for subjects with a body weight of 100 kg or more.

[0201] As is evident from the above description and from Tables 14 and 8, in some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 4 or higher and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg body weight. In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 4 or higher and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

[0202] In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2, the second regimen of (aa) is identical to the first regimen. In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2 and the second regimen is being administered for the first time, the second regimen of (aa) is identical to the first regimen. In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2, the second regimen of (aa) is identical to the first regimen when the second regimen is being administered to (aa) for the first time or when it has been administered once or multiple times.

[0203] In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2 and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 1.0 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2 and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (aa) is reduced to approximately 100 mg for the subject. In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2 and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 1.0 mg / kg of subject body weight when the second regimen is administered for the first time in (aa) or after one or more administrations. In some embodiments of the methods provided herein, if the hematological toxicity of (w) is grade 3 or grade 2 and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (aa) is reduced to approximately 100 mg for the subject when the second regimen is administered for the first time with (aa) or when it has been administered once or multiple times.

[0204] In some embodiments of the methods provided herein, if the second regimen is modified to an ADC dose of approximately 1.0 mg / kg or 100 mg based on hematological toxicity, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 0.75 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen is modified to an ADC dose of approximately 1.0 mg / kg or 100 mg based on hematological toxicity, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 75 mg for the subject. In some embodiments of the methods provided herein, if the second regimen is modified to an ADC dose of approximately 1.0 mg / kg or 100 mg based on hematological toxicity, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 0.75 mg / kg of subject body weight, regardless of how many times the second regimen has been administered. In some embodiments of the methods provided herein, the second regimen is modified to an ADC dose of approximately 1.0 mg / kg or 100 mg based on hematological toxicity, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (aa) is reduced to approximately 75 mg for the subject, regardless of how many times the second regimen has been administered.

[0205] In some embodiments of the methods provided herein, if the second regimen is modified to an ADC dose of approximately 0.75 mg / kg or 75 mg based on hematological toxicity and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 0.5 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen is modified to an ADC dose of approximately 0.75 mg / kg or 75 mg based on hematological toxicity and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 50 mg for the subject. In some embodiments of the methods provided herein, if the second regimen is modified to an ADC dose of approximately 0.75 mg / kg or 75 mg based on hematological toxicity and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (aa) is reduced to approximately 0.5 mg / kg of subject body weight, regardless of how many times the second regimen has been administered. In some embodiments of the methods provided herein, the second regimen is modified to an ADC dose of approximately 0.75 mg / kg or 75 mg based on hematological toxicity, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (aa) is reduced to approximately 50 mg for the subject, regardless of how many times the second regimen has been administered.

[0206] This disclosure provides that if hematological toxicity does not require discontinuation of the study drug and hematological toxicity returns to baseline or ≤ grade 1, the need for dose reduction may be to increase the dose by one dose level according to Table 8 (for example, a patient whose dose was reduced to 0.75 mg / kg may only be increased to 1 mg / kg). Accordingly, in some aspects of the methods provided herein, the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg or by approximately 25 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) hematological toxicity has returned to grade 1 or less. Specifically, in some embodiments of the methods provided herein, the ADC dose in the second regimen is increased from 0.5 mg / ml to 0.75 mg / ml for subjects weighing less than 100 kg, or from 50 mg to 75 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) hematological toxicity has returned to grade 1 or less. In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 0.75 mg / ml to 1 mg / ml for subjects weighing less than 100 kg, or from 75 mg to 100 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) hematological toxicity has returned to grade 1 or less.In some aspects of the methods provided herein, the ADC dose in the second regimen is increased from 1 mg / ml to 1.25 mg / ml for subjects weighing less than 100 kg, or from 100 mg to 125 mg for subjects weighing 100 kg or more, provided that (1) ADC administration has not been permanently discontinued, (2) the ADC dose in the second regimen is lower than the ADC dose in the first regimen, and (3) hematological toxicity has returned to grade 1 or less.

[0207] This disclosure provides that hematological toxicity, including grades such as anemia, thrombocytopenia, neutropenia, and / or febrile neutropenia, in the methods provided herein may be determined at varying frequencies and intervals according to the needs of the method and / or the practices of the art. In some embodiments of the methods provided herein, hematological toxicity is determined daily. In some embodiments of the methods provided herein, hematological toxicity is determined every two days, every three days, every four days, or every five days, or every six days. In some embodiments of the methods provided herein, hematological toxicity is determined weekly, every two weeks, every three weeks, or every four weeks. In some embodiments of the methods provided herein, hematological toxicity is determined monthly, every two months, or every three months.

[0208] 5.2.7 Treatment methods including dose adjustments based on fatigue This disclosure also provides that the ADC dose administered to treat a target cancer can be modified based on other criteria, such as fatigue of the subject. In some embodiments, the subject treated by the method provided herein has fatigue. In some embodiments, fatigue is used as a criterion for modifying the ADC dose in the method provided herein.

[0209] Fatigue as a criterion for dose change can be determined based on the grading scale described in National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03 / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, which is incorporated herein by reference in its entirety. In some specific embodiments, the grading for fatigue is determined as shown in Table 15 below.

[0210] (Table 15) CTCAE definition and grading of fatigue v4.0 TIFF2026048848000022.tif44143ADL: Activities of Daily Living; N / A: Not applicable

[0211] Based on the fatigue grade, in some embodiments, the method provided herein further includes (ab) determining the fatigue of the subject, and (ac) withholding the administration of ADC if the fatigue of (ab) is grade 3 or higher. In certain embodiments, the method provided herein further includes (ad) waiting for a period of time sufficient for the fatigue to decrease to grade 1 or lower. In some further embodiments, the method provided herein includes (ae) determining the fatigue of the subject, and (af) administering a second regimen to the subject containing an effective amount of ADC if the fatigue of (ae) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0212] This disclosure provides for permanently discontinuing the administration of ADCs for cancer treatment under certain criteria for serious adverse events in subjects, such as fatigue of grade 4 or higher. In some embodiments of the methods provided herein, if fatigue in step (ab) or (ae) of the above method is of grade 4 or higher, the administration of ADCs is permanently discontinued. In certain embodiments, if fatigue is of grade 4 or higher, the administration of ADCs is permanently discontinued regardless of other criteria.

[0213] This disclosure provides that a method step for dose modification based on fatigue criteria can be repeated. This disclosure further provides that a method step for dose modification based on fatigue criteria can be repeated in accordance with the rules described and provided herein. In some aspects of the method provided herein, method steps (a), (ab), (ac), (ad), (ae), and (af) can be repeated, which are steps of (a) administering a first regimen containing an effective dose of ADC to a subject, (ab) determining the subject's fatigue, and (ac) withholding ADC administration if the fatigue in (ab) is grade 3 or higher, (ad) waiting for a period sufficient for the fatigue to decrease to grade 1 or lower, (ae) determining the subject's fatigue, and (af) administering a second regimen containing an effective dose of ADC if the fatigue in (ae) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (a), (ab), (ac), (ae), and (af) can be repeated, which are steps (a) administering a first regimen containing an effective amount of ADC to a subject, (ab) determining the subject's fatigue, and (ac) withholding ADC administration if the fatigue in (ab) is grade 3 or higher, (ae) determining the subject's fatigue, and (af) administering a second regimen containing an effective amount of ADC to a subject if the fatigue in (ae) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. In some embodiments of the method provided herein, steps (ab), (ac), (ad), (ae), and (af) can be repeated, which are steps (ab) determining the fatigue of the subject, (ac) withholding the administration of ADC if the fatigue in (ab) is grade 3 or higher, (ad) waiting for a period sufficient for the fatigue to decrease to grade 1 or lower, (ae) determining the fatigue of the subject, and (af) administering a second regimen containing an effective amount of ADC to the subject if the fatigue in (ae) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.In some embodiments of the method provided herein, steps (ab), (ac), (ae), and (af) can be repeated, which are steps (ab) determining the fatigue of the subject, and (ac) withholding the administration of ADC if the fatigue in (ab) is grade 3 or higher, (ae) determining the fatigue of the subject, and (af) administering a second regimen containing an effective amount of ADC to the subject if the fatigue in (ae) is grade 1 or lower, wherein the second regimen contains the same or a lower dose of ADC as the first regimen.

[0214] In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 1 to 10 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 1 to 10 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 1 to 4 months. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 1 day. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 2 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 3 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 4 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 5 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 6 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 7 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 8 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 9 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 10 days. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 1 week. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 2 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 3 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 4 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 5 weeks.In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 6 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 7 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 8 weeks. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 1 month. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 2 months. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 3 months. In some embodiments of the methods provided herein, the period of time sufficient for fatigue to decrease to grade 1 or below is 4 months.

[0215] This disclosure provides that the modified dose may depend on the number of times the conditions for administering a second regimen based on fatigue criteria have been met. Therefore, in some embodiments, the method further includes the step of determining the number of times the conditions for administering a second regimen based on fatigue criteria have been met. This disclosure provides that the ADC dose may be modified according to the scheme described in Table 16 below.

[0216] (Table 16) Dose modification scheme for methods provided herein based on fatigue 1 TIFF2026048848000023.tif531351 For example, see Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600;Rosenberg JE, et al. J Clin Oncol. 2019;37:2592-2600 (Protocol), both of which are incorporated herein by reference in their entirety.

[0217] In some embodiments, the dose reductions or modifications mentioned in Table 16 above and in the fatigue-related paragraphs above and below are shown in Table 8 above.

[0218] In some embodiments of the methods provided herein, the ADC dose in the first regimen is the starting dose before dose reduction or dose change due to fatigue. Based on Table 8, in some embodiments, such an ADC dose in the first regimen and starting dose is 1.25 mg / kg for subjects with a body weight of less than 100 kg or 125 mg for subjects with a body weight of 100 kg or more.

[0219] As is evident from the above description and from Tables 16 and 8, in some embodiments of the methods provided herein, if fatigue in (ab) is grade 3, the second regimen in (af) is identical to the first regimen. In some embodiments of the methods provided herein, if fatigue in (ab) is grade 3 and the second regimen is being administered for the first time, the second regimen in (af) is identical to the first regimen. In some embodiments of the methods provided herein, if fatigue in (ab) is grade 3, the second regimen in (af) is identical to the first regimen when the second regimen is being administered to (af) for the first time or when it has been administered once or multiple times.

[0220] In some embodiments of the methods provided herein, if fatigue in (ab) is grade 3 and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (af) is reduced to approximately 1.0 mg / kg body weight. In some embodiments of the methods provided herein, if fatigue in (ab) is grade 3 and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (af) is reduced to approximately 100 mg for the subject. In some embodiments of the methods provided herein, if fatigue in (ab) is grade 3 and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (af) is reduced to approximately 1.0 mg / kg body weight when the second regimen is administered for the first time in (af) or when it has been administered once or multiple times. In some embodiments of the methods provided herein, if fatigue in (ab) is grade 3 and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (af) is reduced to approximately 100 mg for the subject when the second regimen is administered for the first time in (af) or when it has been administered once or multiple times.

[0221] In some embodiments of the methods provided herein, if the second regimen is modified based on fatigue to an ADC dose of approximately 1.0 mg / kg or 100 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (af) is reduced to approximately 0.75 mg / kg of subject body weight. In some embodiments of the methods provided herein, if the second regimen is modified based on fatigue to an ADC dose of approximately 1.0 mg / kg or 100 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (af) is reduced to approximately 75 mg for the subject. In some embodiments of the methods provided herein, if the second regimen is modified based on fatigue to an ADC dose of approximately 1.0 mg / kg or 100 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (af) is reduced to approximately 0.75 mg / kg of subject body weight, regardless of how many times the second regimen has been administered. In some embodiments of the methods provided herein, the second regimen is modified to an ADC dose of approximately 1.0 mg / kg or 100 mg based on fatigue, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen of (af) is reduced to approximately 75 mg for the subject, regardless of how many times the second regimen has been administered.

[0222] In some embodiments of the methods provided herein, if the second regimen is modified based on fatigue to an ADC dose of approximately 0.75 mg / kg or 75 mg and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen of (af) is reduced to approximately 0.5 mg / kg of subject body weight. In some embodiments of the metho...

Claims

1. A method for preventing or treating cancer in a human subject, comprising the step of administering to the subject a first regimen comprising an effective amount of an antibody-drug conjugate (ADC), The ADC comprises an antibody or antigen-binding fragment conjugated to one or more units of monomethyl auristatin E (MMAE) that binds to 191P4D12, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region containing a complementarity-determining region (CDR) including the amino acid sequence of the CDR of the heavy chain variable region shown in SEQ ID NO:22, and a light chain variable region containing a CDR including the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:

23. The subject has urothelial carcinoma, The subject is receiving immune checkpoint inhibitor therapy and chemotherapy. method.

2. The method according to claim 1, wherein the ADC is administered three times within a 28-day cycle.

3. The method according to claim 1 or 2, wherein the ADC is administered on day 1, day 8, and day 15 of a 28-day cycle.

4. The method according to any one of claims 1 to 3, wherein the urothelial carcinoma is locally advanced urothelial carcinoma.

5. The method according to any one of claims 1 to 3, wherein the urothelial carcinoma is metastatic urothelial carcinoma.

6. The method according to any one of claims 1 to 5, wherein the immune checkpoint inhibitor therapy is a programmed death receptor 1 (PD-1) inhibitor.

7. The method according to any one of claims 1 to 5, wherein the immune checkpoint inhibitor therapy is a programmed death ligand 1 (PD-L1) inhibitor.

8. The method according to any one of claims 1 to 7, wherein the chemotherapy is a platinum-containing chemotherapy.

9. The method according to claim 8, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in a neoadjuvant setting.

10. The method according to claim 8, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in an adjuvant setting.

11. The method according to any one of claims 8 to 10, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in a locally progressive setting.

12. The method according to any one of claims 8 to 10, wherein the platinum-containing chemotherapy is platinum-containing chemotherapy in a metastatic setting.

13. The method according to any one of claims 1 to 12, wherein the first regimen comprises an ADC dose of approximately 1.25 milligrams / kilogram (mg / kg) of body weight.

14. The method according to claim 13, wherein the subject has a weight of less than 100 kg.

15. The method according to any one of claims 1 to 12, wherein the first regimen comprises an ADC dose of approximately 125 mg to the subject, and the subject has a body weight of 100 kg or more.

16. (b) A step to determine the target blood glucose level, (c) If the blood glucose level in (b) is higher than 250 mg / dL, the administration of the antibody drug conjugate is withheld. The method according to any one of claims 1 to 15, further comprising:

17. (d) A waiting period of time sufficient for blood glucose levels to drop to 250 mg / dL or less. The method according to claim 16, further comprising:

18. (e) A step to determine the target blood glucose level, (f) If the blood glucose level in (e) is 250 mg / dL or less, the procedure involves administering a second regimen containing an effective amount of antibody-drug conjugate to the target. The method according to claim 16 or 17, further comprising:

19. The method according to any one of claims 16 to 18, wherein if the blood glucose level in (b) or (e) exceeds 500 mg / dL, the administration of ADC is permanently discontinued.

20. The method according to any one of claims 16 to 19, further comprising the step of repeating (a) to (f).

21. The method according to any one of claims 16 to 20, wherein the subject has hyperglycemia.

22. The method according to claim 21, wherein the subject has diabetic ketoacidosis (DKA).

23. The method according to any one of claims 16 to 22, wherein the subject further has a higher body mass index and / or a higher baseline A1C.

24. The method according to any one of claims 18 to 23, wherein the second regimen is identical to the first regimen.

25. A method according to any one of claims 16 to 24, wherein blood glucose levels are determined daily.

26. The method according to any one of claims 16 to 24, wherein blood glucose levels are determined every two days, every three days, every four days, every five days, or every six days.

27. The method according to any one of claims 16 to 24, wherein blood glucose levels are determined weekly, every other week, once every three weeks, or once every four weeks.

28. The method according to any one of claims 16 to 24, wherein blood glucose levels are determined monthly, every two months, or every three months.

29. (g) A step to determine the target peripheral nerve disorder, If peripheral neuropathy in (h) and (g) is grade 2 or higher, the administration of the antibody drug conjugate is withheld. The method according to any one of claims 1 to 28, further comprising:

30. (i) A waiting period of time sufficient for peripheral neuropathy to decrease to grade 1 or below. The method according to claim 29, further comprising:

31. (j) A process to determine the target peripheral nerve disorder, (k) If the peripheral neuropathy (j) is grade 1 or less, a step of administering a second regimen containing an effective dose of ADC to the subject, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to claim 29 or 30, further comprising:

32. The method according to any one of claims 29 to 31, wherein if the peripheral neuropathy in (g) or (j) is of grade 3 or higher, administration of ADC is permanently discontinued.

33. The method according to any one of claims 29 to 32, wherein the peripheral nerve disorder is mainly sensory nerve disorder.

34. The method according to any one of claims 29 to 31 and 33, further comprising the step of repeating (g) to (k).

35. The method according to any one of claims 31 and 33 to 34, further comprising the step of determining the number of times the conditions for administering a second regimen have been met.

36. The method according to any one of claims 31 and 33 to 35, wherein, in (k), when the second regimen is administered for the first time, the second regimen is identical to the first regimen.

37. The method according to any one of claims 31 and 33 to 36, wherein in (k), if the second regimen has been administered once and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight.

38. The method according to any one of claims 31 and 33 to 36, wherein in (k), if the second regimen has been administered once and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

39. The method according to any one of claims 31 and 33 to 38, wherein in (k), the second regimen has been administered twice and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight.

40. The method according to any one of claims 31 and 33 to 38, wherein in (k), if the second regimen has been administered once and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

41. The method according to any one of claims 31 and 33 to 40, wherein in (k), the second regimen has been administered three times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight.

42. The method according to any one of claims 31 and 33 to 40, wherein in (k), the second regimen has been administered three times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

43. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Peripheral neuropathy has returned to Grade 1 or lower. The method according to any one of claims 31 and 33 to 42, wherein the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more.

44. A method according to any one of claims 29 to 43, wherein peripheral neuropathy is determined on a daily basis.

45. The method according to any one of claims 29 to 43, wherein peripheral neuropathy is determined every two days, every three days, every four days, every five days, or every six days.

46. The method according to any one of claims 29 to 43, wherein peripheral neuropathy is determined weekly, every other week, once every three weeks, or once every four weeks.

47. The method according to any one of claims 29 to 43, wherein peripheral neuropathy is determined monthly, every two months, or every three months.

48. (l) A step to determine the target skin reaction, If the skin reaction of (m)(l) is grade 3 or higher, the administration of ADC is withheld. The method according to any one of claims 1 to 47, further comprising:

49. (n) A waiting period sufficient for the skin reaction to decrease to grade 1 or lower. The method according to claim 48, further comprising:

50. (o) A step to determine the target skin reaction, If the skin reaction of (p)(o) is grade 1 or less, a step of administering a second regimen containing an effective amount of ADC to the subject, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to claim 48 or 49, further comprising:

51. The method according to any one of claims 48 to 50, wherein if the skin reaction of (l) or (o) is grade 4 or higher, administration of the ADC is permanently discontinued.

52. The method according to any one of claims 48 to 51, wherein the skin reaction is selected from the group consisting of maculopapular rash, pruritus, symmetric drug-associated intertriginous / flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythematous dysphoria.

53. The method according to any one of claims 48 to 51, wherein the skin reaction of grade 3 or higher is selected from the group consisting of symmetric drug-associated intertriginous and flexural rash (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar and plantar erythrodysesthesia.

54. The method according to any one of claims 48 to 50 and 52 to 53, further comprising the step of repeating (l) to (p).

55. The method according to claim 54, wherein if a grade 3 skin reaction recurs in (l) or (o), the administration of the ADC is permanently discontinued.

56. The method according to any one of claims 48-50 and 52-55, further comprising the step of determining the number of times the conditions for administering a second regimen have been met.

57. The method according to any one of claims 48 to 50 and 52 to 56, wherein, in (p), when the second regimen is administered for the first time, the second regimen is identical to the first regimen.

58. The method according to any one of claims 48-50 and 52-57, wherein in (p), the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight.

59. The method according to any one of claims 48-50 and 52-57, wherein in (p), the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

60. The method according to any one of claims 48-50 and 52-59, wherein in (p), the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight.

61. The method according to any one of claims 48-50 and 52-59, wherein in (p), the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

62. The method according to any one of claims 48-50 and 52-61, wherein in (p), the second regimen has been administered three or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

63. The method according to any one of claims 48-50 and 52-61, wherein in (p), the second regimen has been administered three or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

64. The method according to any one of claims 48-50 and 52-56, wherein, in (p), if the subject has a body weight of less than 100 kg, the second regimen includes an ADC dose of approximately 1.0 mg / kg of subject body weight.

65. The method according to any one of claims 48 to 50 and 52 to 56, wherein in (p), if the subject has a body weight of 100 kg or more, the second regimen comprises an ADC dose of approximately 100 mg for the subject.

66. The method according to any one of claims 48-50, 52-56, and 64-65, wherein in (p), the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight.

67. The method according to any one of claims 48-50, 52-56, and 64-65, wherein in (p), the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

68. The method according to any one of claims 48-50, 52-56, and 64-67, wherein in (p), the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

69. The method according to any one of claims 48-50, 52-56, and 64-67, wherein in (p), the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

70. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Skin reaction has returned to Grade 1 or lower The method according to any one of claims 50 and 52 to 69, wherein the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more.

71. The method according to any one of claims 48 to 70, wherein the skin reaction is determined on a daily basis.

72. The method according to any one of claims 48 to 70, wherein the skin reaction is determined once every two days, once every three days, once every four days, or once every five days, or once every six days.

73. The method according to any one of claims 48 to 70, wherein the skin reaction is determined weekly, every other week, once every three weeks, or once every four weeks.

74. The method according to any one of claims 48 to 70, wherein the skin reaction is determined monthly, every two months, or every three months.

75. (q) A process to determine the non-hematological toxicity of the subject, If the non-hematological toxicity of (s)(q) is grade 3 or higher, the administration of ADC is withheld. The method according to any one of claims 1 to 74, further comprising:

76. (t) A process that involves waiting for a sufficient period of time for non-hematological toxicity to decrease to grade 1 or below. The method according to claim 75, further comprising:

77. (u) A process to determine the non-hematological toxicity of the subject, (v) If the non-hematological toxicity of (u) is grade 1 or less, a step of administering a second regimen containing an effective dose of ADC to the subject, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to claim 75 or 76, further comprising:

78. The method according to any one of claims 75 to 77, wherein if the non-hematological toxicity of (q) or (u) is grade 4 or higher, administration of the ADC is permanently discontinued.

79. The method according to any one of claims 75 to 78, wherein the non-hematological toxicity is taste disturbance.

80. The method according to any one of claims 75 to 78, wherein the non-hematological toxicity is loss of appetite.

81. The method according to any one of claims 75 to 78, wherein the non-hematological toxicity is loss of appetite.

82. The method according to any one of claims 75 to 78, wherein the non-hematological toxicity is ocular palsy.

83. The method according to claim 79, wherein the ocular disorder is one or more selected from the group consisting of punctate keratitis, keratitis, keratopathy, limbal stem cell deficiency, dry eye, and blurred vision.

84. The method according to any one of claims 75 to 77 and 79 to 83, further comprising the step of repeating (q) to (v).

85. The method according to any one of claims 75-77 and 79-84, further comprising the step of determining the number of times the conditions for administering a second regimen have been met.

86. The method according to any one of claims 75 to 77 and 79 to 85, wherein the second regimen is identical to the first regimen.

87. The method according to any one of claims 75 to 77 and 79 to 86, wherein, in (v), the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight.

88. The method according to any one of claims 75 to 77 and 79 to 86, wherein, in (v), the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

89. The method according to any one of claims 75 to 77 and 79 to 88, wherein, in (v), the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight.

90. The method according to any one of claims 75 to 77 and 79 to 88, wherein, in (v), the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

91. The method according to any one of claims 75-77 and 79-90, wherein, in (v), the second regimen has been administered three or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

92. The method according to any one of claims 75 to 77 and 79 to 90, wherein in (v), if the second regimen has been administered three or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

93. (v) The method according to any one of claims 75 to 77 and 79 to 85, wherein, if the subject has a body weight of less than 100 kg, the second regimen comprises an ADC dose of approximately 1.0 mg / kg of subject body weight.

94. (v) The method according to any one of claims 75 to 77 and 79 to 85, wherein if the subject has a body weight of 100 kg or more, the second regimen comprises an ADC dose of approximately 100 mg for the subject.

95. The method according to any one of claims 75-77, 79-85, and 93-94, wherein, in (v), the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight.

96. The method according to any one of claims 75-77, 79-85, and 93-94, wherein, in (v), the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

97. The method according to any one of claims 75-77, 79-85, and 93-96, wherein, in (v), the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of body weight.

98. The method according to any one of claims 75-77, 79-85, and 93-96, wherein in (v), if the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

99. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Non-hematological toxicity has returned to Grade 1 or lower. The method according to any one of claims 77 and 79 to 98, wherein the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more.

100. The method according to any one of claims 75 to 99, wherein non-hematological toxicity is determined daily.

101. The method according to any one of claims 75 to 99, wherein non-hematological toxicity is determined every two days, every three days, every four days, every five days, or every six days.

102. The method according to any one of claims 75 to 99, wherein non-hematological toxicity is determined weekly, bi-weekly, once every three weeks, or once every four weeks.

103. The method according to any one of claims 75 to 99, wherein non-hematological toxicity is determined monthly, every two months, or every three months.

104. (w) A process to determine the blood toxicity of the subject, If the hematological toxicity of (x)(w) is grade 2 or higher, the administration of ADC is withheld. The method according to any one of claims 1 to 103, further comprising:

105. (y) A process of waiting for a sufficient period of time for hematological toxicity to decrease to grade 1 or below. The method according to claim 104, further comprising:

106. (z) A process to determine the blood toxicity of the subject, A step of administering a second regimen containing an effective dose of ADC to a subject if the hematological toxicity of (aa)(z) is grade 1 or less, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to claim 104 or 105, further comprising:

107. The method according to any one of claims 104 to 106, wherein if the hematological toxicity of (w) or (z) is grade 4 or higher, administration of the ADC is permanently discontinued.

108. The method according to any one of claims 104 to 107, wherein the hematological toxicity is thrombocytopenia.

109. The method according to any one of claims 104 to 107, wherein the hematological toxicity is selected from the group consisting of anemia, thrombocytopenia, neutropenia, and febrile neutropenia.

110. The method according to any one of claims 104 to 106 and 108 to 109, further comprising the step of repeating (w) to (aa).

111. The method according to any one of claims 106 and 108-110, wherein if the hematological toxicity of (w) is grade 4 or higher and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight.

112. The method according to any one of claims 106 and 108-110, wherein if the hematological toxicity of (w) is grade 4 or higher and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

113. The method according to any one of claims 106 and 108-110, wherein the hematological toxicity of (w) is grade 3 or grade 2.

114. The method according to any one of claims 106 and 108 to 110, wherein the hematological toxicity of (w) is grade 3 thrombocytopenia or grade 2 thrombocytopenia.

115. The method according to claim 113 or 114, further comprising the step of determining the number of times the conditions for administering a second regimen have been met.

116. The method according to any one of claims 113 to 115, wherein in (aa), the second regimen is identical to the first regimen.

117. The method according to any one of claims 113 to 116, wherein in (aa), if the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of body weight.

118. The method according to any one of claims 113 to 116, wherein in (aa), if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

119. The method according to any one of claims 113 to 118, wherein in (aa), the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of body weight.

120. The method according to any one of claims 113 to 118, wherein in (aa), the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

121. The method according to any one of claims 113 to 120, wherein in (aa), the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

122. The method according to any one of claims 113 to 120, wherein in (aa), the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

123. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Hematological toxicity has returned to Grade 1 or lower. The method according to any one of claims 106 and 108 to 122, wherein the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more.

124. A method according to any one of claims 104 to 123, wherein hematological toxicity is determined daily.

125. The method according to any one of claims 104 to 123, wherein hematological toxicity is determined every two days, every three days, every four days, every five days, or every six days.

126. The method according to any one of claims 104 to 123, wherein hematological toxicity is determined weekly, bi-weekly, once every three weeks, or once every four weeks.

127. The method according to any one of claims 104 to 123, wherein hematological toxicity is determined monthly, every two months, or every three months.

128. (ab) A process to determine the fatigue of the subject, If fatigue in (ac) and (ab) is grade 3 or higher, the administration of ADC is withheld. The method according to any one of claims 1 to 127, further comprising:

129. (ad) A process that involves waiting for a sufficient period of time for fatigue to decrease to grade 1 or below. The method according to claim 128, further comprising:

130. (ae) A process to determine the fatigue of the subject, A step of administering a second regimen containing an effective dose of ADC to a patient whose fatigue is grade 1 or less, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to claim 128 or 129, further comprising:

131. The method according to any one of claims 128 to 130, wherein if fatigue of (ab) or (ae) is grade 4 or higher, administration of ADC is permanently discontinued.

132. The method according to any one of claims 128 to 130, further comprising the step of repeating (ab) to (af).

133. The method according to any one of claims 128-130 and 132, further comprising the step of determining the number of times the conditions for administering a second regimen have been met.

134. The method according to any one of claims 128-130 and 132-133, wherein if the fatigue of (ab) is grade 3, the second regimen is identical to the first regimen.

135. The method according to any one of claims 128-130 and 132-134, wherein if the fatigue of (ab) is grade 3 and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight.

136. The method according to any one of claims 128-130 and 132-134, wherein if the fatigue of (ab) is grade 3 and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

137. The method according to any one of claims 128-130 and 132-136, wherein in (af), the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject body weight.

138. The method according to any one of claims 128-130 and 132-136, wherein in (af), the second regimen is administered at an ADC dose of approximately 1.0 mg / kg or 100 mg, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

139. The method according to any one of claims 128-130 and 132-138, wherein in (af), the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg, and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

140. The method according to any one of claims 128-130 and 132-138, wherein in (af), the second regimen is administered at an ADC dose of approximately 0.75 mg / kg or 75 mg, and if the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

141. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Fatigue has returned to Grade 1 or lower The method according to any one of claims 130 and 132 to 140, wherein the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more.

142. A method according to any one of claims 128 to 141, wherein fatigue is determined on a daily basis.

143. The method according to any one of claims 128 to 141, wherein fatigue is determined once every two days, once every three days, once every four days, or once every five days or once every six days.

144. The method according to any one of claims 128 to 141, wherein fatigue is determined weekly, every other week, once every three weeks, or once every four weeks.

145. The method according to any one of claims 128 to 141, wherein fatigue is determined monthly, every two months, or every three months.

146. (ag) The process of determining the target diarrhea, If diarrhea of ​​(ah)(ag) is grade 3 or higher, the administration of ADC should be withheld. The method according to any one of claims 1 to 145, further comprising:

147. (ai) A waiting period of time sufficient for diarrhea to decrease to grade 1 or below. The method according to claim 146, further comprising:

148. (aj) The process of determining the target diarrhea, A step of administering a second regimen containing an effective dose of ADC to a patient whose diarrhea is of grade 1 or less, wherein the second regimen contains the same or a lower dose of ADC as the first regimen. The method according to claim 146 or 147, further comprising:

149. The method according to any one of claims 146 to 148, wherein if diarrhea of ​​(ag) or (ai) is grade 4 or higher and the diarrhea does not improve to grade 2 or lower within 72 hours with adjunctive treatment, administration of ADC is permanently discontinued.

150. The method according to any one of claims 146 to 148, further comprising the step of repeating (ag) to (ak).

151. The method according to any one of claims 146-148 and 150, further comprising the step of determining the number of times the conditions for administering a second regimen have been met.

152. The method according to any one of claims 146 to 148 and 150 to 151, wherein in (ak), the second regimen is identical to the first regimen.

153. The method according to any one of claims 146-148 and 150-152, wherein in (ak), the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 1.0 mg / kg of subject body weight.

154. The method according to any one of claims 146-148 and 150-152, wherein in (ak), the second regimen has been administered once or more times, and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 100 mg for the subject.

155. The method according to any one of claims 146-148 and 150-154, wherein in (ak), the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject body weight.

156. The method according to any one of claims 146-148 and 150-154, wherein in (ak), the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

157. The method according to any one of claims 146-148 and 150-156, wherein in (ak), the second regimen has been administered three or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

158. The method according to any one of claims 146-148 and 150-156, wherein in (ak), the second regimen has been administered three or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

159. The method according to any one of claims 146-148 and 150-151, wherein in (ak), if the subject has a body weight of less than 100 kg, the second regimen includes an ADC dose of approximately 1.0 mg / kg of subject body weight.

160. The method according to any one of claims 146-148 and 150-151, wherein in (ak), if the subject has a body weight of 100 kg or more, the second regimen includes an ADC dose of approximately 100 mg for the subject.

161. The method according to any one of claims 146-148, 150-151, and 159-160, wherein in (ak), the second regimen has been administered once or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.75 mg / kg of subject body weight.

162. The method according to any one of claims 146-148, 150-151, and 159-160, wherein in (ak), the second regimen has been administered once or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 75 mg for the subject.

163. The method according to any one of claims 146-148, 150-151, and 159-162, wherein in (ak), the second regimen has been administered two or more times and the subject has a body weight of less than 100 kg, the ADC dose in the second regimen is reduced to approximately 0.5 mg / kg of subject body weight.

164. The method according to any one of claims 146-148, 150-151, and 159-162, wherein in (ak), the second regimen has been administered two or more times and the subject has a body weight of 100 kg or more, the ADC dose in the second regimen is reduced to approximately 50 mg for the subject.

165. (1) ADC administration has not been permanently discontinued, (2) The ADC dose in the second regimen is lower than the ADC dose in the first regimen, (3) Diarrhea has returned to Grade 1 or lower The method according to any one of claims 148 and 150-164, wherein the ADC dose in the second regimen is increased by approximately 0.25 mg / kg for subjects weighing less than 100 kg, or by approximately 25 mg for subjects weighing 100 kg or more.

166. A method according to any one of claims 146 to 165, wherein diarrhea is determined on a daily basis.

167. The method according to any one of claims 146 to 165, wherein diarrhea is determined to occur once every two days, once every three days, once every four days, or once every five days or once every six days.

168. The method according to any one of claims 146 to 165, wherein diarrhea is determined weekly, every other week, once every three weeks, or once every four weeks.

169. The method according to any one of claims 146 to 165, wherein diarrhea is determined to occur monthly, once every two months, or once every three months.

170. The method according to any one of claims 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:9, CDR H2 containing the amino acid sequence of SEQ ID NO:10, CDR H3 containing the amino acid sequence of SEQ ID NO:11; CDR L1 containing the amino acid sequence of SEQ ID NO:12, CDR L2 containing the amino acid sequence of SEQ ID NO:13, and CDR L3 containing the amino acid sequence of SEQ ID NO:

14.

171. The method according to any one of claims 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:16, CDR H2 containing the amino acid sequence of SEQ ID NO:17, CDR H3 containing the amino acid sequence of SEQ ID NO:18; CDR L1 containing the amino acid sequence of SEQ ID NO:19, CDR L2 containing the amino acid sequence of SEQ ID NO:20, and CDR L3 containing the amino acid sequence of SEQ ID NO:

21.

172. The method according to any one of claims 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR H2 consisting of the amino acid sequence of SEQ ID NO:10, CDR H3 consisting of the amino acid sequence of SEQ ID NO:11; CDR L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:

14.

173. The method according to any one of claims 1 to 169, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:16, CDR H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR H3 consisting of the amino acid sequence of SEQ ID NO:18; CDR L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:

21.

174. The method according to any one of claims 1 to 173, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:22 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

23.

175. The method according to any one of claims 1 to 174, wherein the antibody comprises a heavy chain containing an amino acid sequence in the range from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7, and a light chain containing an amino acid sequence in the range from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:

8.

176. The method according to any one of claims 1 to 175, wherein the antigen-binding fragment is a Fab, F(ab')2, Fv, or scFv fragment.

177. The method according to any one of claims 1 to 176, wherein the antibody is a fully human antibody.

178. The method according to any one of claims 1 to 177, wherein an antibody or its antigen-binding fragment is recombinantly produced.

179. The method according to any one of claims 1 to 178, wherein an antibody or antigen-binding fragment is linked to each unit of monomethyl auristatin E (MMAE) via a linker.

180. The method according to claim 179, wherein the linker is an enzymatically cleavable linker, and the linker forms a bond with the sulfur atom of the antibody or its antigen-binding fragment.

181. The method according to claim 179 or 180, wherein the linker has the formula -Aa-Ww-Yy-, where -A- is an extension unit and a is 0 or 1; -W- is an amino acid unit and w is an integer in the range of 0 to 12; and -Y- is a spacer unit and y is 0, 1 or 2.

182. The method according to claim 181, wherein the extension unit has the structure of the following formula (1), the amino acid unit is valinecitrulline, and the spacer unit is a PAB group comprising the structure of the following formula (2): 。

183. The method according to claim 181 or 182, wherein the extension unit forms a bond with the sulfur atom of the antibody or its antigen-binding fragment, and the spacer unit is linked to the MMAE via a carbamate group.

184. The method according to any one of claims 1 to 183, wherein the antibody is a fully human monoclonal antibody and the antibody is IgG1.

185. The method according to any one of claims 1 to 184, wherein the ADC comprises 1 to 10 units of MMAE per antibody or antigen-binding fragment.

186. The method according to any one of claims 1 to 185, wherein the ADC comprises 2 to 8 units of MMAE per antibody or antigen-binding fragment.

187. The method according to any one of claims 1 to 186, wherein the ADC comprises 3 to 5 units of MMAE per antibody or antigen-binding fragment.

188. The method according to any one of claims 1 to 187, wherein the ADC comprises 3 to 4 units of MMAE per antibody or antigen-binding fragment.

189. The method according to any one of claims 1 to 188, wherein the ADC comprises about 4 units of MMAE per antibody or antigen-binding fragment.

190. The ADC has the following structure: The compound is such that L- represents an antibody or its antigen-binding fragment, and p is 1 to 10. The method according to any one of claims 1 to 185.

191. The method according to claim 190, wherein p is between 2 and 8.

192. The method according to claim 190 or 191, wherein p is 3 to 5.

193. The method according to any one of claims 190 to 192, wherein p is 3 to 4.

194. The method according to any one of claims 190 to 193, wherein p is approximately 4.

195. The method according to any one of claims 190 to 193, wherein p is approximately 3.

8.

196. The method according to any one of claims 1 to 195, wherein the ADC is formulated into a pharmaceutical composition comprising about 20 mM L-histidine, about 0.02% (w / v) TWEEN-20, about 5.5% (w / v) trehalose dihydrate, and hydrochloride, the pH of the pharmaceutical composition being about 6.0 at 25°C.

197. The method according to any one of claims 1 to 195, wherein the ADC is formulated into a pharmaceutical composition comprising about 9 mM histidine, about 11 mM histidine hydrochloride monohydrate, about 0.02% (w / v) TWEEN-20, and about 5.5% (w / v) trehalose dihydrate, the pH of the pharmaceutical composition being about 6.0 at 25°C.

198. The method according to any one of claims 1 to 195, wherein the ADC is formulated at approximately 10 mg / ml in a pharmaceutical composition comprising approximately 1.4 mg / ml histidine, approximately 2.31 mg / ml histidine hydrochloride monohydrate, approximately 0.2 mg / ml polysorbate 20 (TWEEN-20), and approximately 55 mg / ml trehalose dihydrate, the pH of the pharmaceutical composition being approximately 6.0 at 25°C.

199. The method according to any one of claims 1 to 195, wherein the ADC is formulated into a vial containing a pharmaceutical composition comprising about 20 mg of the ADC, about 2.8 mg of histidine, about 4.62 mg of histidine hydrochloride monohydrate, about 0.4 mg of polysorbate 20 (TWEEN-20), and about 110 mg of trehalose dihydrate.

200. The method according to any one of claims 1 to 195, wherein the ADC is formulated into a vial containing a pharmaceutical composition comprising approximately 30 mg of the ADC, approximately 4.2 mg of histidine, approximately 6.93 mg of histidine hydrochloride monohydrate, approximately 0.6 mg of polysorbate 20 (TWEEN-20), and approximately 165 mg of trehalose dihydrate.

201. The method according to any one of claims 1 to 200, wherein the ADC is administered by intravenous (IV) injection or infusion.

202. The method according to any one of claims 1 to 201, wherein an ADC, or an ADC formulated into a pharmaceutical composition, is administered by intravenous (IV) injection or infusion over a period of approximately 30 minutes.

203. A method for treating cancer in a subject, comprising the step of administering a treatment regimen to the subject, wherein the treatment regimen is a. A step of administering one or more doses of an antibody-drug conjugate (ADC) to a target, wherein the one or more doses are administered at a first dose level containing an effective amount of ADC; b. A step of determining whether a subject experiences an adverse reaction in response to the administration of the ADC in (a), wherein the adverse reaction is selected from the group consisting of hyperglycemia, peripheral neuropathy, skin reactions, non-hematological toxicity, and hematological toxicity; c. A step of administering one or more subsequent doses of ADC, each containing an effective amount of ADC, based on the decision in (b), or discontinuing the administration of ADC, i. If it is determined that the subject has not experienced any adverse reactions to the ADC, or that any adverse reactions are below a specified level, administer one or more subsequent doses of the ADC to the subject at the first dose level; ii. If it is determined that the subject has experienced an adverse reaction to the prescribed level or higher of the ADC, the treatment regimen shall be permanently discontinued, or the administration of one or more subsequent doses of the ADC shall be withheld for a period sufficient to allow the adverse reaction to decrease to the desired level, and then the administration of one or more subsequent doses of the ADC shall be at the first dose level or a dose level reduced compared to the first dose level. Process; and d. Optionally, repeat (a) to (c) once or more times, with each repeat of (a) to (c) defining a treatment round, and the first dose level in (a) of each subsequent treatment round is either the first dose level in (a) from the previous round or the reduced dose level in c(ii) from the previous round, and if the subject is found to have recurrent adverse reactions in two consecutive treatment rounds, the process involves reducing one or more subsequent doses of ADC administered in c(ii) compared to the dose administered in (a) during that treatment round, or permanently discontinuing ADC administration. Including, here, i. The subjects are optionally selected from the group of locally advanced or metastatic urothelial carcinoma, have urothelial carcinoma and have been previously treated with immune checkpoint inhibitors and chemotherapeutic agents, the immune checkpoint inhibitor is optionally a programmed death receptor 1 (PD-1) inhibitor or a programmed death ligand 1 (PD-L1) inhibitor, and the immune checkpoint inhibitor is optionally administered in a neoadjuvant or adjuvant setting; and ii. The ADC comprises an antibody or antigen-binding fragment conjugated to 191P4D12 and one or more units of monomethyl auristatin E (MMAE), wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a complementarity-determining region (CDR) comprising a heavy chain variable region CDR shown in SEQ ID NO:22, and a light chain variable region comprising a light chain variable region CDR shown in SEQ ID NO:

23. method.

204. A. The treatment regimen includes (a) to (d); B. The first dose level of the first treatment round is the starting dose level shown in the dose reduction schedule below; and C. The method according to claim 203, wherein the reduced dose level in c(ii) for each treatment round is reduced to the first dose reduction, second dose reduction, or third dose reduction level shown in the following dose reduction schedule, depending on whether the dose reduction in c(ii) is the first, second, or third dose reduction of the overall treatment round: 。

205. I. The adverse reaction in (b) is hyperglycemia, and the step to determine this includes the step to determine the blood glucose level of the subject; II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the target blood glucose level is 250 mg / dL or less, administer one or more subsequent doses at the first dose level; ii. If the target blood glucose level exceeds 250 mg / dL, administration of one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the blood glucose level to 250 mg / dL or less, and then one or more subsequent doses of ADC should be administered at the first dose level; and iii. If the target blood glucose level exceeds 500 mg / dL, the treatment regimen should be permanently discontinued. The method according to claim 203 or 204.

206. I. The determination of adverse reactions in (b) includes the step of determining whether the subject experiences new or worsening symptoms of peripheral neuropathy; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the patient does not experience symptoms of peripheral neuropathy or has symptoms of peripheral neuropathy of less than grade 2, administer one or more subsequent doses of ADC at the first dose level; ii. If the subject experiences the first onset of Grade 2 peripheral neuropathy symptoms at the first dose level administered in (a), one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the peripheral neuropathy symptoms to Grade 1 or lower, and then one or more subsequent doses of ADC should be resumed at the dose level administered in (a); iii. If the subject has recurrent symptoms of peripheral neuropathy after two consecutive treatment rounds at the same dose level in (a), reduce the dose by one dose level according to the dose reduction schedule; and iv. If the patient experiences symptoms of Grade 3 or higher peripheral neuropathy, permanently discontinue the treatment regimen. The method according to claim 204.

207. I. The determination of adverse reactions in (b) includes a step of determining whether the subject experiences a skin reaction; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the subject does not experience a skin reaction or has a skin reaction of less than grade 3, administer one or more subsequent doses of ADC at the first dose level; ii. If the subject experiences a grade 3 skin reaction, one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the skin reaction to grade 1 or lower, and then the administration of one or more subsequent doses of ADC should be resumed at the dose level administered in (a), or reduced by one dose level according to the dose reduction schedule; iii. If the patient experiences a grade 4 skin reaction or has a recurrent grade 3 skin reaction after multiple doses of ADC, permanently discontinue the treatment regimen. The method according to claim 204.

208. I. The determination of adverse reactions in (b) includes a step of determining whether the subject has symptoms of non-hematological toxicity; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the patient experiences non-hematological toxicity of less than grade 3, administer one or more subsequent doses of ADC at the first dose level; ii. If the patient experiences a Grade 3 non-hematological toxicity, one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the non-hematological toxicity to Grade 1 or lower, and then administration of one or more subsequent doses of ADC should be resumed at the dose level administered in (a), or reduced by one dose level according to the dose reduction schedule; iii. If the patient experiences grade 4 non-hematological toxicity, permanently discontinue the treatment regimen. The method according to claim 204.

209. I. The determination of adverse reactions in (b) includes the step of determining whether the subject has symptoms of hematological toxicity, where hematological toxicity is optionally thrombocytopenia; and II. The decision to continue or discontinue ADC administration in (c) is made as follows: i. If the patient experiences hematological toxicity of less than grade 3 and the hematological toxicity is not thrombocytopenia, administer one or more subsequent doses of ADC at the first dose level; ii. If the patient experiences a grade 2 or grade 3 hematological toxicity, and the hematological toxicity is thrombocytopenia, one or more subsequent doses of ADC should be withheld for a period sufficient to reduce the thrombocytopenia to grade 1 or lower, and then administration of one or more subsequent doses of ADC should be resumed at the dose level administered in (a), or reduced by one dose level according to the dose reduction schedule; iii. If the patient experiences a Grade 4 non-hematological toxicity that is not thrombocytopenia, reduce one or more subsequent doses of the ADC at the dose level administered in (a) by one dose level according to the dose reduction schedule, or permanently discontinue the treatment regimen. The method according to claim 204.

210. The method according to any one of claims 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:9, CDR H2 containing the amino acid sequence of SEQ ID NO:10, CDR H3 containing the amino acid sequence of SEQ ID NO:11; CDR L1 containing the amino acid sequence of SEQ ID NO:12, CDR L2 containing the amino acid sequence of SEQ ID NO:13, and CDR L3 containing the amino acid sequence of SEQ ID NO:

14.

211. The method according to any one of claims 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 containing the amino acid sequence of SEQ ID NO:16, CDR H2 containing the amino acid sequence of SEQ ID NO:17, CDR H3 containing the amino acid sequence of SEQ ID NO:18; CDR L1 containing the amino acid sequence of SEQ ID NO:19, CDR L2 containing the amino acid sequence of SEQ ID NO:20, and CDR L3 containing the amino acid sequence of SEQ ID NO:

21.

212. The method according to any one of claims 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR H2 consisting of the amino acid sequence of SEQ ID NO:10, CDR H3 consisting of the amino acid sequence of SEQ ID NO:11; CDR L1 consisting of the amino acid sequence of SEQ ID NO:12, CDR L2 consisting of the amino acid sequence of SEQ ID NO:13, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:

14.

213. The method according to any one of claims 203 to 209, wherein the antibody or its antigen-binding fragment comprises CDR H1 consisting of the amino acid sequence of SEQ ID NO:16, CDR H2 consisting of the amino acid sequence of SEQ ID NO:17, CDR H3 consisting of the amino acid sequence of SEQ ID NO:18; CDR L1 consisting of the amino acid sequence of SEQ ID NO:19, CDR L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR L3 consisting of the amino acid sequence of SEQ ID NO:

21.

214. The method according to any one of claims 203 to 213, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:22 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

23.

215. The ADC has the following structure: The compound is such that L- represents an antibody or its antigen-binding fragment, and p is 1 to 10. The method according to any one of claims 203 to 214.

216. The method according to claim 215, wherein p is 3 to 5.

217. The method according to claim 215 or 216, wherein p is 3 to 4.

218. The method according to any one of claims 215 to 217, wherein p is approximately 4.

219. The method according to any one of claims 215 to 217, wherein p is approximately 3.8.

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