Treatment of locally advanced or metastatic urothelial carcinoma using an anti-191P4D12 antibody drug conjugate in combination with pembrolizumab.

Abstract

A method for treating cisplatin-eligible and ineligible patients with unresectable locally advanced or metastatic urothelial carcinoma is provided herein, using an antibody-drug conjugate (ADC) conjugated to the 191P4D12 protein in combination with pembrolizumab, wherein the anti-191P4D12 antibody is conjugated to one or more units of monomethyl auristatin E (MMAE).

Description

TECHNICAL FIELD

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 584,480 filed on September 21, 2023, U.S. Provisional Application No. 63 / 620,610 filed on January 12, 2024, U.S. Provisional Application No. 63 / 650,806 filed on May 22, 2024, U.S. Provisional Application No. 63 / 672,135 filed on July 16, 2024, and U.S. Provisional Application No. 63 / 694,044 filed on September 12, 2024, the entire disclosures of each of which are incorporated herein by reference in their entirety.

[0002] SEQUENCE LISTING This application contains an electronic Sequence Listing submitted herewith in XML file format, the entire content of which is incorporated herein by reference in its entirety. The Sequence Listing XML file submitted with this application is named "14369-311-228_SEQ_LISTING.xml", created on September 17, 2024, and has a size of 62,860 bytes.

[0003] 1. Field Provided herein are methods of treating cancer using an antibody-drug conjugate (ADC) that binds to 191P4D12 protein (Nectin-4). In particular, provided herein are methods of treating cisplatin-eligible and cisplatin-ineligible patients having unresectable locally advanced or metastatic urothelial cancer, using an antibody-drug conjugate (ADC) that binds to 191P4D12 protein in combination with pembrolizumab. BACKGROUND ART

[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.seer.cancer.gov / statfacts / html / all.html.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 (World Health Organization.Press Release.Sept 2018.who.int / cancer / PRGlobocanFinal.pdf.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, radiotherapy, 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 therapies 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 the development of novel cytotoxic compounds. The benefits of these new drugs are reflected in long-term survival; however, the outcomes for most patients with distant metastases remain poor, highlighting the need for new therapies.

[0006] 191P4D12 (also known as Nectin-4) is a 66 kDa type I transmembrane protein belonging to the nectin family of adhesion molecules. 191P4D12 consists of an extracellular domain (ECD) containing three immunoglobulin (Ig)-like subdomains, a transmembrane helix, and an intracellular domain (Takai et al., Annu Rev Cell Dev Biol (2008); 24:309-42). Nectins are thought to mediate Ca2+-independent intercellular adhesion through both homophilic and heterophilic trans interactions at adhesion junctions, which can recruit cadherins and regulate cytoskeletal rearrangement (Rikitake et al., Cell Mol Life Sci (2008); 65(2):253-63). Nectin-4 exhibits low sequence identity with other nectin family members, ranging from 25% to 30% in ECD (Reymond et al., Biol Chem (2001); 276(46): 43205-15).

[0007] The three Ig-like subdomains within the ECD of nectin-4 are referred to as V, C1, and C2. The C1 domain is involved in cis-interactions (homodimerization), while the V domain of most nectin molecules contributes to trans-interactions and cell-cell adhesion (Mandai et al., Curr Top Dev Biol (2015); 112:197-231; Takai et al., Nat Rev Mol Cell Biol (2008); 9(8):603-15).

[0008] Nectin-4 was originally identified by bioinformatics and cloned from human trachea (Reymond et al., J Biol Chem (2001) 276(46):43205-15). Nectin-4 was confirmed to be significantly upregulated in urothelial carcinoma using suppressive subtractive hybridization in a pool of urothelial carcinoma specimens. Characterization of expression in multiple tumor specimens, both at the ribonucleic acid (RNA) level and by immunohistochemistry (IHC), also showed high levels of nectin-4 in breast cancer, pancreatic cancer, lung cancer, and other cancers (Challita-Eid et al., Cancer Res (2016); 76(10):3003-13).

[0009] Nectin-4 has been identified as being expressed in several cancers, particularly urothelial carcinoma, breast cancer, lung cancer, pancreatic cancer, and ovarian cancer. Higher levels of expression are associated with disease progression and / or poor prognosis (Fabre-Lafay et al., BMC Cancer (2007); 7:73).

[0010] PD-1

[0011] PD-1 is recognized as an important molecule for immune regulation and maintenance of peripheral immune tolerance. PD-1 is moderately expressed in naive T, B, and NKT cells and is upregulated by T / B cell receptor signaling in lymphocytes, monocytes, and myeloid cells (Sharpe, Arlene H. et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology (2007); 8:239-245).

[0012] Two known ligands for PD-1, PD-L1(B7-H1) and PD-L2(B7-DC), are expressed in human cancers occurring in various tissues. For example, in large sample sets of ovarian cancer, kidney cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma, PD-L1 expression has been shown to correlate with poor prognosis and shortened overall survival, regardless of subsequent treatment (Dong, Haidong et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002 Aug;8(8):793-800; Yang, Wanhua et al., PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci. 2008 Jun;49(6(2008):49:2518-2525; Ghebeh, Hazem et al., The B7-H1(PD-L1)T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal Carcinoma:correlation with important high-risk prognostic factors.Neoplasia(2006)8:190-198, Hamanishi, Junzo et al.,Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+T lymphocytes are prognostic factors of human ovarian cancer.Proc.Natl.Acad.Sci.USA(2007):104:3360-3365, Thompson, R Houston, and Eugene D Kwon, Significance of B7-H1 overexpression in kidney cancer.Clinical genitourin Cancer(2006):5:206-211、Nomi,Takeo et al.,Clinical significance and therapeutic potential of the programmed death-1 ligand / programmed death-1 pathway in human pancreatic cancer.Clinical Cancer Research(2007);13:2151-2157、Ohigashi,Yuichiro et al.,Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer.Clin.Cancer Research(2005):11:2947-2953、Inman,Brant A et al.,PD-L1(B7-H1)expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression.Cancer(2007):109:1499-1505、Shimauchi,Takatoshi et al.,Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+T-cells in adult T-cell Leukemia / Lymphoma.Int.J.Cancer(2007):121:2585-2590、Gao,Qiang et al.,Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.Clinical Cancer Research(2009)15:971-979, Nakanishi, Juro et al., Overexpression of B7-H1(PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers.Cancer Immunol Immunother.(2007)56:1173-1182, Hino et al., Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma.Cancer(2010):00:1-9). Similarly, PD-1 expression in tumor-infiltrating lymphocytes has been found to represent dysfunctional T cells in breast cancer and melanoma (Ghebeh, Hazem et al., Foxp3+tregs and B7-H1+ / PD-1+T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer. 2008 Feb 23;8:57; Ahmadzadeh, Mojgan et al., Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood (2009) 114:1537-1544), and to correlate with poor prognosis in renal cancer (Thompson, R Houston et al., PD-1 is expressed by tumor infiltrating cells and is associated with poor outcome for patients with renal carcinoma.Clinical Cancer Research (2007) 15:1757-1761). Therefore, it has been proposed that PD-L1-expressing tumor cells interact with PD-1-expressing T cells, attenuating T cell activation and evasion of immune surveillance mechanisms, thereby contributing to a reduced immune response against tumors.

[0013] Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands, PD-L1 and PD-L2, are approved for the treatment of cancer. Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA) is a potent humanized immunoglobulin G4 (IgG4) mAb that binds to the programmed cell death 1 (PD-1) receptor with high specificity and thus inhibits its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity for PD-1 and potent receptor blocking activity. Keytruda® (pembrolizumab) is indicated for the treatment of patients across several indications, including as a first-line treatment for patients with unresectable or metastatic CRC with high microsatellite instability or mismatch repair deficiency (MSI-H / dMMR). Pembrolizumab is currently the standard of care for first-line treatment of MSI-H / dMMR mCRC.

[0014] urothelial cancer

[0015] According to the International Agency for Research on Cancer (IARC), urothelial carcinoma is the ninth most common cancer worldwide, killing more than 165,000 people annually. In Europe, approximately 151,000 new cases of urothelial carcinoma are diagnosed each year, resulting in 52,000 deaths. In Japan, more than 22,000 new cases are diagnosed annually, resulting in 7,600 deaths (Cancer Fact Sheets: All cancers excluding Non-Melanoma Skin. International Agency for Research on Cancer 2017. (searched from gco.iarc.fr / today / fact-sheets-cancers?cancer=29&type=0&sex=0), accessed December 19, 2017). In the United States, the National Cancer Institute estimates that there were more than 79,000 new cases of bladder cancer diagnosed in 2017, and more than 16,800 deaths from the disease (National Cancer Institute 2018).

[0016] Metastatic urothelial carcinoma has a 5-year mortality rate of approximately 85% (American Cancer Society (ACS) 2016).

[0017] Urothelial carcinoma is the most common type of bladder cancer (90 percent of cases) and can also be found in urothelial cells lining the renal pelvis (where urine collects in the kidney), ureters (the tubes connecting the kidneys to the bladder), and urethra.

[0018] For metastatic urothelial carcinoma in patients with adequate renal function, therapies as first-line treatment consist of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or cis-diaminedichloroplatin(II) (cisplatin)-based combinations such as gemcitabine and cisplatin, with an objective response rate (ORR) of up to 55%, of which complete response (CR) is approximately 12% (von der Maase 2000). Despite initial chemotherapy sensitivity, patients do not become cured, and outcomes for metastatic urothelial carcinoma after these regimens are poor, with a median progression-free survival of 7 months and a median overall survival (OS) of 14 months. Long-term survival is poor (approximately 15%), and the prognosis is particularly poor for patients with visceral metastases, with a 5-year survival rate of 7% (von der Maase 2005, Bellmunt 2011).

[0019] Nearly half of patients with urothelial carcinoma are unsuitable for cisplatin-based chemotherapy due to renal impairment, poor performance status, or comorbidities (Dash et al. Cancer (2006); 107(3):506-13). While there is no defined standard of treatment as first-line therapy for these patients, current options typically include cis-dianmine (cyclobutane 1,1-dicarboxylate) platinum (carboplatin)-based regimens or monotherapy with taxanes or gemcitabine (Cathomas 2015). Long-term survival rates are even lower in this setting (De Santis et al. J Clin Oncol (2009); 27(33):5634-9). In April 2017, the U.S. Food and Drug Administration (FDA) approved atezolizumab (TECENTRIQ®), an anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (CPI), as a first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (LA / mUC) who were ineligible for cisplatin. This accelerated approval was based on an open-label, single-arm study demonstrating long response durations, activity in this difficult-to-treat population, and an objective response rate (ORR) of 23%, similar across different target expression levels (Balar 2017). The median overall survival (OS) for these patients was 15.9 months, but this was a single-arm study, and any OS benefits need to be confirmed in a randomized experience (Balar et al., Lancet (2017); 389(10064): 67-76).

[0020] Pembrolizumab (Keytruda®) received accelerated approval from the FDA in May 2017 as a first-line treatment for patients with LA / MUC who are ineligible for cisplatin. The study results on which this approval was based showed an ORR of 29% and the median duration of response was not reached at the time of analysis (median follow-up period was 7.8 months) (Pembrolizumab Prescribing Information, Merck Sharp and Dohme Corp., 2017). In May 2018, the FDA issued a warning regarding reduced survival in patients with low PD-L1 expression treated with pembrolizumab or atezolizumab in first-line settings compared to platinum-based chemotherapy. Subsequently, the prescribing information for these two CPIs was revised to require high PD-L1 expression in first-line metastatic urothelial carcinoma patients eligible for platinum-containing chemotherapy. This development further limited the options for patients with metastatic urothelial carcinoma who have low PD-L1 expression.

[0021] Other options for patients ineligible for first-line cisplatin typically include carboplatin-based regimens or monotherapy with taxanes or gemcitabine (Cathomas et al., Hematol Oncol Clin North Am(2015);29(2):329-40.).

[0022] There are few treatment options available for the second-line treatment of metastatic diseases. In the European Union, the small molecule tubulin inhibitor vinflunine (Javlor®) was approved in 2009 based on its moderate activity (overall response rate of 9%), moderate 2-month survival benefit (6.9 months with vinflunine + best supportive care (BSC) vs. 4.6 months with BSC alone, hazard ratio 0.88), and favorable safety profile (Bellmunt et al. Clin Oncol (2009);27(27):4454-61). In May 2016, the US FDA rapidly approved atezolizumab as first-line salvage therapy after platinum therapy for la / mUC, followed by EU approval in September 2017. In February 2017, nivolumab (Opdivo®) became the second immunotherapy to be rapidly approved by the FDA, followed by EU approval in June 2017. In March and May 2017, the FDA granted accelerated approval to avelumab (Bavencio®) and durvalumab (Imfinzi®), both PD-L1 blocking antibodies indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Pembrolizumab received regular approval from the FDA in May 2017 as a second-line treatment (Keytruda Prescribing Information, Merck, May 2017). This approval was based on the first randomized experience reporting CPI in a setting of locally advanced or metastatic urothelial carcinoma after platinum administration. In a phase 3 trial involving 542 patients, the overall survival (OS) was 10.3 months compared to 7.4 months with taxane chemotherapy or vinflunin. Furthermore, the objective response rate (ORR) was 21% with pembrolizumab and 11% with chemotherapy. There was no statistically significant difference in progression-free survival (PFS) between the two groups (Bellmunt et al., N Engl J Med (2017); 376(11): 1015-26). It was approved in the EU for the same indication in September 2017 and in Japan in January 2018.Other programmed cell death protein 1 (PD-1) and PD-L1 inhibitors are currently being evaluated as first- and second-line therapies in clinical trials for urothelial carcinoma (Mullane et al., Curr Opin Urol (2016); 26(6): 556-63).

[0023] While CPIs offer a new approach to treating metastatic urothelial carcinoma, tumor response has been observed in only a small number of patients, and improvements in long-term survival have lasted only a few months. For example, in May 2017, Roche announced that its second-line atezolizumab confirmation phase 3 trial failed to meet its primary endpoint, overall survival (OS) (Roche press release, “Roche provides update on phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer,” 10-May-2017). Many patients with locally advanced or metastatic urothelial carcinoma do not respond to CPIs, and many of those who do respond eventually experience disease progression (Rosenberg et al., Lancet (2016); 387(10031): 1909-20). Novel therapies remain particularly necessary for patients who do not respond to CPIs or whose disease progresses after CPI therapy.

[0024] bladder cancer

[0025] Among all new cancer cases in the United States, bladder cancer accounts for approximately 5 percent (the fifth most common neoplasm) in men and 3 percent (the eighth most common neoplasm) in women. The prevalence is gradually increasing with the growth of the elderly population. According to estimates from the American Cancer Society (cancer.org), there are 81,400 new cases annually, consisting of 62,100 men and 19,300 women, accounting for 4.5% of all cancer cases. The age-adjusted prevalence in the United States is 20 per 100,000 people for both men and women combined. The estimated annual number of deaths from bladder cancer is 17,980 (13,050 men and 4,930 women), accounting for 3% of all cancer-related deaths. The morbidity and mortality rates of bladder cancer increase significantly with age, and the problem is growing along with population aging. Globally, it is reported that approximately 580,000 people were diagnosed with bladder cancer in 2020, and bladder cancer causes approximately 210,000 deaths worldwide.

[0026] Most bladder cancers recur in the bladder. Bladder cancer is managed by a combination of transurethral resection of the bladder (TUR) and intravesical chemotherapy or intravesical immunotherapy. Multifocal and recurrent bladder cancer demonstrate the limitations of TUR. Most muscle-invasive cancers cannot be cured by TUR alone. Radical cystectomy and urinary diversion are the most effective means to eliminate cancer, but their impacts on urinary function and sexual function are unavoidable. There remains a strong demand for beneficial therapeutic methods for bladder cancer patients.

[0027] There is a strong need for further therapeutic methods for urothelial carcinoma and bladder cancer. These include the use of antibodies and antibody-drug conjugates, including in combination with other agents, as therapeutic modalities. [Summary of the Invention]

[0028] 3. Summary Provided herein are methods for the treatment of various cancers in a subject, such as a human subject, including methods of treating cisplatin-eligible and cisplatin-ineligible patients having unresectable locally advanced or metastatic urothelial carcinoma, using an antibody-drug conjugate (ADC) that binds to the 191P4D12 protein in combination with pembrolizumab.

[0029] In certain embodiments, the subject (e.g., a human subject) to be treated by the methods provided herein has not previously received treatment (e.g., treatment for unresectable locally advanced or metastatic urothelial carcinoma (UC)). In certain embodiments, the subject (e.g., a human subject) to be treated by the methods provided herein has not previously received treatment with a PD-(L)-1 inhibitor (e.g., a PD-1 inhibitor or a PD-L1 inhibitor, including but not limited to atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).

[0030] Embodiment 1. A method of treating cancer in a subject, comprising administering to the said subject, (a) an effective amount of an antibody-drug conjugate (ADC) comprising an anti-191P4D12 antibody or an antigen-binding fragment thereof, and (b) an effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof wherein the anti-191P4D12 antibody or antigen-binding fragment thereof binds to 191P4D12 and is conjugated to one or more units of monomethyl auristatin E (MMAE), wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising complementarity determining region (CDR) amino acid sequences of the heavy chain variable region set forth in SEQ ID NO: 32, and a light chain variable region comprising CDR amino acid sequences of the light chain variable region set forth in SEQ ID NO: 27, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDR amino acid sequences of the heavy chain variable region set forth in SEQ ID NO: 22, and a light chain variable region comprising CDR amino acid sequences of the light chain variable region set forth in SEQ ID NO: 23.​ The subject has urothelial carcinoma or bladder cancer, and The aforementioned subjects are eligible to receive cisplatin treatment (cisplatin eligible), The aforementioned method.

[0031] Embodiment 2. The method according to Embodiment 1, wherein the subject has not previously received a PD-(L)-1 inhibitor.

[0032] Embodiment 3. The method according to Embodiment 1 or 2, wherein the subject has a GFR of more than 60 mL / min.

[0033] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the subject has hearing loss on an audiometric test of NCI CTCAE grade 1 or lower.

[0034] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the subject does not have NYHA class III heart failure.

[0035] Embodiment 6.(a) The subject has a progression-free survival of at least 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months or approximately 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months after the treatment, and optionally, the subject has a progression-free survival of at least 14.6 months or approximately 14.6 months after the treatment, and optionally, the subject has a progression-free survival of 14 to 15 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months or approximately 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months, and optionally, the median progression-free survival in the treated population is at least 14.6 months or approximately 14.6 months, and optionally, the median progression-free survival in the treated population is 14 to 15 months, or (c) The median progression-free survival is at least 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months or approximately 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months for the population treated by the method, and optionally, the median progression-free survival is at least 14.6 months or approximately 14.6 months for the population treated by the method, and optionally, the median progression-free survival is 14 to 15 months for the population treated by the method. The method according to any one of Embodiments 1 to 5.

[0036] Embodiment 7.(a) The subject has an overall survival period of at least 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months or approximately 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months after the treatment, and optionally the subject has an overall survival period of at least 31.5 months or approximately 31.5 months after the treatment, and optionally the subject has an overall survival period of 31 to 32 months after the treatment, (b) The subject population is treated by the method, and the median overall survival in the treated population is at least 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months or approximately 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months, and optionally, the median overall survival in the treated population is at least 31.5 months or approximately 31.5 months, and optionally, the median overall survival in the treated population is 31 to 32 months, or (c) The median overall survival for the population treated by the method is at least 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months or approximately 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months, and optionally, the median overall survival for the population treated by the method is at least 31.5 months or approximately 31.5 months, and optionally, the median overall survival for the population treated by the method is 31 to 32 months. The method according to any one of Embodiments 1 to 5.

[0037] Embodiment 8. A method for treating cancer in a subject, wherein the subject (a) an effective amount of antibody-drug conjugate (ADC) containing an anti-191P4D12 antibody or its antigen-binding fragment and (b) an effective amount of anti-PD-1 antibody or its antigen-binding fragment This includes administering, The anti-191P4D12 antibody or its antigen-binding fragment is bound to 191P4D12 and conjugated to one or more units of monomethyl auristatin E (MMAE), The anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region including a CDR containing the amino acid sequence of the complementarity-determining region (CDR) of the heavy chain variable region shown in SEQ ID NO: 32, and a light chain variable region including a CDR containing the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO: 27, The anti-191P4D12 antibody or its antigen-binding fragment comprises a heavy chain variable region including a complementarity-determining region (CDR) containing 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 including a CDR containing the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO: 23. The subject has urothelial carcinoma or bladder cancer, and (i) The subject has aspartate transferase (AST) and alanine transaminase (ALT) values ​​that are 2.5 times or less of the upper limit of normal (ULN), (ii) The subject has treated central nervous system (CNS) metastases that have been clinically stable for at least four weeks prior to the administration of the ADC and the anti-PD-1 antibody or its antigen-binding fragment, and / or (iii) The subject has not undergone major surgery within four weeks prior to the administration of the ADC and the anti-PD-1 antibody or its antigen-binding fragment. The aforementioned method.

[0038] Embodiment 9.(a) The subject has treated central nervous system (CNS) metastases that have been clinically stable for at least 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody, and (b) The subject has not undergone major surgery within four weeks prior to the administration of the ADC and the anti-PD-1 antibody. The method described in Embodiment 8.

[0039] Embodiment 10.(a) The subject has a progression-free survival period of at least 12.5 months or approximately 12.5 months after the treatment, and optionally, the subject has a progression-free survival period of 12 to 13 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 12.5 months or approximately 12.5 months, and, on a random selection basis, the median progression-free survival in the treated population is 12 to 13 months, or (c) The median progression-free survival is at least 12.5 months or approximately 12.5 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 12 to 13 months for the population treated by the method described above. The method according to Embodiment 8 or 9.

[0040] Embodiment 11.(a) The subject has an overall survival period of at least 31.5 months or approximately 31.5 months after the treatment, and optionally, the subject has an overall survival period of 31 to 32 months after the treatment. (b) The subject population is treated by the method, and the median overall survival in the treated population is at least 31.5 months or approximately 31.5 months, and optionally, the median overall survival in the treated population is 31 to 32 months, or (c) The median overall survival is at least 31.5 months or approximately 31.5 months for the population treated by the method described above, and, on an optional basis, the median overall survival is 31 to 32 months for the population treated by the method described above. The method according to Embodiment 8 or 9.

[0041] Embodiment 12. The subject is eligible to receive cisplatin treatment (cisplatin eligible), and (a) The subject has a progression-free survival of at least 14.6 months or approximately 14.6 months after the treatment, and the subject has a progression-free survival of 14 to 15 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 14.6 months or approximately 14.6 months, and, on a random selection basis, the median progression-free survival in the treated population is 14 to 15 months, or (c) The median progression-free survival is at least 14.6 months or approximately 14.6 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 14 to 15 months for the population treated by the method described above. The method according to Embodiment 8 or 9.

[0042] Embodiment 13. The subject is ineligible to receive cisplatin treatment (cisplatin eligible), and (a) The subject has a progression-free survival of at least 10.6 months or approximately 10.6 months after the treatment, and, at the discretion of the subject, has a progression-free survival of 10 to 11 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10.6 months or approximately 10.6 months, and, on a random selection basis, the median progression-free survival in the treated population is 10 to 11 months, or (c) The median progression-free survival is at least 10.6 months or approximately 10.6 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 10 to 11 months for the population treated by the method described above. The method according to Embodiment 8 or 9.

[0043] Embodiment 14. The subject has PD-L1 expression with a CPS of 10 or higher, and optionally, (a) The subject has a progression-free survival of at least 18.5 months or approximately 18.5 months after the treatment, and, at the discretion of the subject, has a progression-free survival of 18 to 19 months after the treatment, (b) The subject population is treated by the method described above, and the median progression-free survival in the treated population is at least 18.5 months or approximately 18.5 months, and, on a random selection basis, the median progression-free survival in the treated population is 18 to 19 months, or (c) The median progression-free survival is at least 18.5 months or approximately 18.5 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 18 to 19 months for the population treated by the method described above. The method according to any one of Embodiments 1 to 5, 8, or 9.

[0044] Embodiment 15. The subject has PD-L1 expression with a CPS of less than 10, and optionally, (a) The subject has a progression-free survival of at least 10.5 months or approximately 10.5 months after the treatment, and, at the discretion of the subject, has a progression-free survival of 10 to 11 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10.5 months or approximately 10.5 months, and, on a random selection basis, the median progression-free survival in the treated population is 10 to 11 months, or (c) The median progression-free survival is at least 10.5 months or approximately 10.5 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 10 to 11 months for the population treated by the method described above. The method according to any one of Embodiments 1 to 5, 8, or 9.

[0045] Embodiment 16. The subject does not have liver metastases, and optionally, (a) The subject has a progression-free survival of at least 16.4 months or approximately 16.4 months after the treatment, and, at the discretion of the subject, has a progression-free survival of 16 to 17 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 16.4 months or approximately 16.4 months, and, on a random selection basis, the median progression-free survival in the treated population is 16 to 17 months, or (c) The median progression-free survival is at least 16.4 months or approximately 16.4 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 16 to 17 months for the population treated by the method described above. The method according to any one of Embodiments 1 to 5, 8, or 9.

[0046] Embodiment 17. The subject has liver metastases, and optionally, (a) The subject has a progression-free survival of at least 8.2 months or approximately 8.2 months after the treatment, and, at the discretion of the subject, has a progression-free survival of 8 to 9 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 8.2 months or approximately 8.2 months, and, on a random selection basis, the median progression-free survival in the treated population is 8 to 9 months, or (c) The median progression-free survival is at least 8.2 months or approximately 8.2 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 8 to 9 months for the population treated by the method described above. The method according to any one of Embodiments 1 to 5, 8, or 9.

[0047] Embodiment 18. The subject race is white, and optionally, (a) The subject has a progression-free survival of at least 10.4 months or approximately 10.4 months, and, on an optional basis, the subject has a progression-free survival of 10 to 11 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10.4 months or approximately 10.4 months, and, on a random selection basis, the median progression-free survival in the treated population is 10 to 11 months, or (c) The median progression-free survival is at least 10.4 months or approximately 10.4 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 10 to 11 months for the population treated by the method described above. The method according to any one of Embodiments 1 to 5, 8, or 9.

[0048] Embodiment 19. The target race is not white, and is optional, (a) The subject has a progression-free survival of at least 22.3 months or approximately 22.3 months, and, on an optional basis, the subject has a progression-free survival of 22 to 23 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 22.3 months or approximately 22.3 months, and, on a random selection basis, the median progression-free survival in the treated population is 22 to 23 months, or (c) The median progression-free survival is at least 22.3 months or approximately 22.3 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 22 to 23 months for the population treated by the method described above. The method according to any one of Embodiments 1 to 5, 8, or 9.

[0049] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein the subject has visceral metastases.

[0050] Embodiment 21. The method according to any one of Embodiments 1 to 19, wherein the subject has a disease affecting only the lymph nodes.

[0051] Embodiment 22. The method according to any one of Embodiments 1 to 19, wherein the site of disease occurrence is the upper urinary tract.

[0052] Embodiment 23. The method according to any one of Embodiments 1 to 19, wherein the site of disease occurrence is the lower urinary tract.

[0053] Embodiment 24. The method according to any one of Embodiments 1 to 23, wherein the subject has a composite positive score (CPS) of 10 or more PD-L1 expression levels.

[0054] Embodiment 25. The method according to any one of Embodiments 1 to 23, wherein the subject has PD-L1 expression CPS of less than 10.

[0055] Embodiment 26. The method according to any one of Embodiments 1 to 19, wherein the subject has an H score of 0 to 300 for nectin-4.

[0056] Embodiment 27. The method according to any one of Embodiments 1 to 19, wherein the subject has an H score of 0 to 200 for Nectin-4.

[0057] Embodiment 28. The method according to any one of Embodiments 1 to 19, wherein the subject has an H score of 0 to 150 for Nectin-4.

[0058] Embodiment 29. The method according to any one of Embodiments 1 to 19, wherein the method does not include determining the expression of the target PD-L1 or determining the expression of the target nectin-4.

[0059] Embodiment 30. The method according to any one of Embodiments 1 to 29, wherein the subject has locally advanced or metastatic urothelial carcinoma.

[0060] Embodiment 31. The method according to any one of Embodiments 1 to 30, wherein the subject has locally advanced or metastatic bladder cancer.

[0061] Embodiment 32. The anti-PD-1 antibody or its antigen-binding fragment is (a) A light chain variable region comprising light chain CDR1 containing the amino acid sequence of SEQ ID NO: 24, light chain CDR2 containing the amino acid sequence of SEQ ID NO: 25, and light chain CDR3 containing the amino acid sequence of SEQ ID NO: 26, respectively, (b) The method according to any one of Embodiments 1 to 31, comprising a heavy chain variable region comprising a heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 29, a heavy chain CDR2 containing the amino acid sequence of SEQ ID NO: 30, and a heavy chain CDR3 containing the amino acid sequence of SEQ ID NO: 31.

[0062] Embodiment 33. The anti-PD-1 antibody or its antigen-binding fragment is (a) A light chain variable region comprising, respectively, light chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 24, light chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 25, and light chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 26, (b) A heavy chain variable region comprising heavy chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 29, heavy chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 30, and heavy chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 31, respectively, The method according to any one of embodiments 1 to 31, including the method described above.

[0063] Embodiment 34. The anti-PD-1 antibody or its antigen-binding fragment is (a) A heavy chain variable region including Sequence ID No. 32 or a variant thereof, (b) A light chain variable region including Sequence ID No. 27 or a variant thereof, The method according to any one of embodiments 1 to 33, including the method described above.

[0064] Embodiment 35. The anti-PD-1 antibody is (a) A heavy chain containing Sequence ID No. 33, (b) Light chain containing Sequence ID No. 28, The method according to any one of embodiments 1 to 33, including the method described above.

[0065] Embodiment 36. The anti-191P4D12 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, or The anti-191P4D12 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. The method according to any one of Embodiments 1 to 35.

[0066] Embodiment 37. The anti-191P4D12 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, or The anti-191P4D12 antibody or its antigen-binding fragment includes 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. The method according to any one of Embodiments 1 to 35.

[0067] Embodiment 38. The method according to any one of Embodiments 1 to 37, wherein the anti-191P4D12 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.

[0068] Embodiment 39. The method according to any one of Embodiments 1 to 38, wherein the anti-191P4D12 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.

[0069] Embodiment 40. The method according to any one of Embodiments 1 to 34, 36 and 37, wherein the anti-191P4D12 antigen binding fragment is Fab, F(ab')2, Fv, or scFv.

[0070] Embodiment 41. The method according to any one of Embodiments 1 to 35, wherein the anti-191P4D12 antibody is a fully human antibody.

[0071] Embodiment 42. The method according to any one of Embodiments 1 to 39 and 41, wherein the anti-191P4D12 antibody is IgG1 and the light chain is a kappa light chain.

[0072] Embodiment 43. The method according to any one of Embodiments 1 to 42, wherein the anti-191P4D12 antibody or its antigen-binding fragment is recombinantly produced.

[0073] Embodiment 44. The method according to any one of Embodiments 1 to 43, wherein the anti-191P4D12 antibody or antigen-binding fragment is conjugated to each unit of the MMAE via a linker.

[0074] Embodiment 45. The method according to Embodiment 44, 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.

[0075] Embodiment 46. The method according to Embodiment 44 or 45, wherein the linker has the formula -Aa-Ww-Yy-, where -A- is an extension unit, a is 0 or 1, -W- is an amino acid unit, w is an integer in the range of 0 to 12, and -Y- is a spacer unit, y is 0, 1, or 2.

[0076] Embodiment 47. The extension unit has the structure of the following formula (1), the amino acid unit is valine-citrulline, and the spacer unit is a PAB group containing the structure of the following formula (2): The method described in Embodiment 46 of TIFF2026534110000002.tif89165.

[0077] Embodiment 48. The method according to Embodiment 46 or 47, 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.

[0078] Embodiment 49. The method according to any one of Embodiments 1 to 48, wherein the ADC contains 1 to 20 units of MMAE per antibody or antigen-binding fragment.

[0079] Embodiment 50. The method according to any one of Embodiments 1 to 49, wherein the ADC contains 1 to 10 units of MMAE per antibody or antigen-binding fragment.

[0080] Embodiment 51. The method according to any one of Embodiments 1 to 50, wherein the ADC contains 2 to 8 units of MMAE per antibody or antigen-binding fragment.

[0081] Embodiment 52. The method according to any one of Embodiments 1 to 51, wherein the ADC contains 3 to 5 units of MMAE per antibody or antigen-binding fragment.

[0082] Embodiment 53. The ADC has the following structure: The method according to any one of Embodiments 1 to 52, wherein the formula has TIFF2026534110000003.tif47165, where L- represents the anti-191P4D12 antibody or its antigen-binding fragment, and p is 1 to 10.

[0083] The method according to Embodiment 53, wherein Embodiment 54.p is 2 to 8.

[0084] Embodiment 55. The method according to Embodiment 53 or 54, wherein p is 3 to 5.

[0085] Embodiment 56. The method according to any one of Embodiments 53 to 55, wherein p is 3 to 4.

[0086] Embodiment 57. The method according to any one of Embodiments 53 to 56, wherein p is approximately 4.

[0087] Embodiment 58. The method according to Embodiment 53 or 54, wherein the average value of p in the effective amount of the antibody-drug conjugate is approximately 3.8.

[0088] Embodiment 59. The method according to any one of Embodiments 1 to 58, wherein the ADC is administered to the subject at a dose of approximately 1 to approximately 10 mg / kg of body weight, approximately 1 to approximately 5 mg / kg of body weight, approximately 1 to approximately 2.5 mg / kg of body weight, or approximately 1 to approximately 1.25 mg / kg of body weight.

[0089] Embodiment 60. The method according to any one of Embodiments 1 to 59, wherein the ADC is administered to the subject at a dose of approximately 0.25 mg / kg of body weight, approximately 0.5 mg / kg of body weight, approximately 0.75 mg / kg of body weight, approximately 1.0 mg / kg of body weight, approximately 1.25 mg / kg of body weight, approximately 1.5 mg / kg of body weight, approximately 1.75 mg / kg of body weight, approximately 2.0 mg / kg of body weight, approximately 2.25 mg / kg of body weight, or approximately 2.5 mg / kg of body weight.

[0090] Embodiment 61. The method according to any one of Embodiments 1 to 60, wherein the ADC is administered to the subject at a dose of approximately 1 mg / kg of the subject's body weight.

[0091] Embodiment 62. The method according to any one of Embodiments 1 to 60, wherein the ADC is administered to the subject at a dose of approximately 1.25 mg / kg of body weight.

[0092] Embodiment 63. The method according to any one of Embodiments 1 to 62, wherein the ADC is administered to the subject by intravenous (IV) injection or infusion.

[0093] Embodiment 64. The method according to any one of Embodiments 1 to 63, wherein the ADC is administered to the subject by IV injection or infusion for up to two days of a 21-day treatment cycle.

[0094] Embodiment 65. The method according to any one of Embodiments 1 to 64, wherein the ADC is administered to the subject by IV injection or infusion on the 1st and 8th days of a 21-day treatment cycle.

[0095] Embodiment 66. The method according to any one of Embodiments 1 to 65, wherein the ADC is administered to the subject by IV injection or infusion over approximately 30 minutes for up to 2 days of a 21-day treatment cycle.

[0096] Embodiment 67. The method according to any one of Embodiments 1 to 66, wherein the ADC is administered by IV injection or infusion over approximately 30 minutes on days 1 and 8 of a 21-day treatment cycle.

[0097] Embodiment 68. The method according to any one of Embodiments 1 to 67, wherein the ADC is formulated into a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN-20), and trehalose dehydrate.

[0098] Embodiment 69. The method according to any one of Embodiments 1 to 68, 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, and the pH of the pharmaceutical composition is about 6.0 at 25°C.

[0099] Embodiment 70. The method according to any one of Embodiments 1 to 68, 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, and the pH of the pharmaceutical composition is about 6.0 at 25°C.

[0100] Embodiment 71. The ADC has the following structure: It has TIFF2026534110000004.tif47165, and in the formula, L- represents the antibody or its antigen-binding fragment, and p is approximately 3 to approximately 4. The anti-191P4D12 antibody comprises a heavy chain containing an amino acid sequence ranging 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 ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO: 8. The aforementioned ADC is administered at a dose of approximately 1.25 mg / kg of body weight, and The aforementioned dose is administered by IV injection or infusion over approximately 30 minutes on days 1 and 8 of a 21-day treatment cycle. The method according to any one of Embodiments 1 to 70.

[0101] Embodiment 72. The method according to any one of Embodiments 1 to 70, wherein the anti-PD-1 antibody is administered to the subject in a dose of approximately 100 mg to approximately 400 mg.

[0102] Embodiment 73. The method according to any one of Embodiments 1 to 70, wherein the anti-PD-1 antibody is administered to the subject at a dose of approximately 200 mg.

[0103] Embodiment 74.(a) The anti-PD-1 antibody is administered to the subject at a dose of approximately 200 mg, and (b) After step (a), the anti-PD-1 antibody is administered to the subject at a dose of approximately 400 mg every 42 days. The method according to Embodiment 71.

[0104] Embodiment 75. The method according to any one of Embodiments 1 to 74, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on one day of the 21-day treatment cycle.

[0105] Embodiment 76. The method according to any one of Embodiments 1 to 75, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on the first day of each 21-day treatment cycle.

[0106] Embodiment 77. The method according to any one of Embodiments 1 to 76, wherein the anti-PD-1 antibody is administered to the subject by IV infusion for approximately 30 minutes on one day of the 21-day treatment cycle.

[0107] Embodiment 78. The method according to any one of Embodiments 1 to 75, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over approximately 30 minutes on the first day of each 21-day treatment cycle.

[0108] Embodiment 79. The method according to any one of Embodiments 1 to 76, wherein the subject shows a complete response after the treatment.

[0109] Embodiment 80. The method according to any one of Embodiments 1 to 77, wherein the subject shows a partial response after the treatment.

[0110] Embodiment 81. The method according to any one of Embodiments 1 to 78, wherein the subject shows disease stabilization after the treatment.

[0111] Embodiment 82. The method according to any one of Embodiments 1 to 81, wherein, before administration of the ADC to the subject, the subject has a maximum pain score of approximately zero (0) on the Reduced Brief Pain Inventory (BPI-SF), and after administration of the ADC to the subject, the subject has an improved maximum pain score on the BPI-SF.

[0112] Embodiment 83. The method according to any one of Embodiments 1 to 81, wherein before administration of the ADC to the subject, the subject has a BPI-SF maximum pain baseline score of approximately zero (0), and after administration of the ADC to the subject, the subject shows a change of approximately -0.3 to approximately -1.2 from the maximum pain baseline score.

[0113] Embodiment 84. The method according to any one of Embodiments 1 to 81, wherein before administration of the ADC to the subject, the subject has a BPI-SF maximum pain baseline score of approximately zero (0), and after administration of the ADC to the subject, the subject shows a change of approximately -0.61 from the maximum pain baseline score.

[0114] The method according to any one of Embodiments 1 to 81, wherein, before administration of the ADC to the subject, the subject has a baseline quality of life (QoL) score of approximately zero (0) on the Quality of Life Questionnaire in Cancer Treatment - Core Questionnaire (EORTC QLQ-C30), and after administration of the ADC to the subject, the subject has an improved QoL score on the EORTC QLQ-C30.

[0115] The method according to any one of Embodiments 1 to 81, wherein, before administration of the ADC to the subject, the subject has a QoL baseline score of approximately zero (0) on the EORTC QLQ-C30, and after administration of the ADC to the subject, the subject shows a change of approximately 10.0 to approximately 15.0 from the QoL baseline score on the EORTC QLQ-C30.

[0116] Embodiment 85. The method according to any one of Embodiments 1 to 81, wherein, before administration of the ADC to the subject, the subject has a QoL baseline score of approximately zero (0) on the EORTC QLQ-C30, and after administration of the ADC to the subject, the subject shows a change of approximately 13.0 from the QoL baseline score on the EORTC QLQ-C30.

[0117] Embodiment 86. The method according to any one of Embodiments 1 to 85, wherein the subject is a human. [Brief explanation of the drawing]

[0118] 4. Brief explanation of the drawing [Figure 1A-1] The nucleotide and amino acid sequences of the nectin-4 protein are shown. [Figure 1A-2] The nucleotide and amino acid sequences of the nectin-4 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 indicates the research stage of the clinical study, which is a Phase 3 study of enfortumab vedotin in combination with pembrolizumab as a first-line treatment in patients with unresectable locally advanced or metastatic urothelial carcinoma (la / mUC), as described in Section 6.1. [Figure 3A] This shows RECIST criteria version 1.1. This figure shows Table 2, which shows the effect at each time point: patients with targeted (+ / - non-targeted) disease. [Figure 3B] This shows RECIST criteria version 1.1. This figure shows Table 2, which shows the effect at each time point: patients with only non-targeted diseases. [Figure 3C] This shows RECIST criteria version 1.1. This figure shows Table 3, which shows the best overall effect when confirmation of CR and PR is required. [Figure 4-1] Section 6.1 shows the European Organization for Research and Therapy (EORTC) Core Quality of Life (QLQ-C-30) assessment (EORTC-QLQ-C-30, current version, version 3). [Figure 4-2] Section 6.1 shows the European Organization for Research and Therapy (EORTC) Core Quality of Life (QLQ-C-30) assessment (EORTC-QLQ-C-30, current version, version 3). [Figure 5-1] The EuroQol-5 items (EQ-5D-5L) described in Section 6.1 are shown below. [Figure 5-2] The EuroQol-5 items (EQ-5D-5L) described in Section 6.1 are shown below. [Figure 6] The initial graph adjusted for multiplicity (two-sided FWER = 5%) is shown. ε is a positive number close to 0, indicating the possibility of shifting alpha to ORR only when both PFS and OS are statistically significant. FWER = Family-Wise Error Rate. [Figure 7]This section outlines the overall research design for the clinical studies described in Section 6.1. [Figure 8A] Section 6.1 shows the statistical testing methods used in the clinical studies. A indicates the efficacy boundary for PFS analysis. B indicates the efficacy boundary for OS analysis. [Figure 8B] See the explanation in Figure 8A. [Figure 9] This table shows an overview of the breakdown of subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 10] This table shows the stratification factors at the time of randomization for subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 11] This table summarizes the patient characteristics of the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. * indicates individuals including Native Americans or Alaskans, Native Hawaiians or other Pacific Islanders, and those of multiple ethnicities. [Figure 12] This table summarizes the baseline characteristics of the subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 13] This table summarizes the disease characteristics of the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 14] This table summarizes the prior anticancer therapies of the subjects in the EV+Pembro and Plat+Gem groups in the clinical study described in Section 6.1. [Figure 15] This table shows the treatment duration for the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 16] This table summarizes the subsequent anticancer therapies for the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 17A]This section shows progression-free survival (PFS) based on blinded, independent central review of subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. This figure shows a graph of PFS (%) against time (months). [Figure 17B] Section 6.1 shows the progression-free survival (PFS) of the EV+Pembro and Plat+Gem groups in the clinical studies described therein, based on blinded, independent central review. This figure is a table showing the PFS data for the EV+Pembro and Plat+Gem groups. [Figure 18A] This section presents subgroup analyses of progression-free survival (PFS) based on blinded independent central review (BICR). The table shows subgroup analyses of PFS for the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. "-" indicates that PFS was not achieved. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from stratified Cox proportional hazards regression models are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 18B] This figure presents a subgroup analysis of progression-free survival (PFS) based on blinded independent central review (BICR). The graph shows PFS (%) against observed time (months) in subjects with liver metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 18C] This figure presents a subgroup analysis of progression-free survival (PFS) based on blinded independent central review (BICR). The graph shows PFS (%) against observed time (months) in subjects without liver metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 18D]This figure presents a subgroup analysis of progression-free survival (PFS) based on blinded independent central review (BICR). The graph shows PFS (%) against observed time (months) in subjects with visceral metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 18E] This figure presents a subgroup analysis of progression-free survival (PFS) based on blinded independent central review (BICR). The graph shows PFS (%) against observed time (months) in subjects with lymph node-only metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 19A] This section shows progression-free survival (PFS) based on blinded, independent central review in clinical studies described in Section 6.1 for the cisplatin-eligible subgroup. [Figure 19B] This section shows progression-free survival (PFS) based on blinded, independent central review in clinical studies described in Section 6.1 for the cisplatin-ineligible subgroup. [Figure 20A] This section shows progression-free survival (PFS) based on blinded, independent central review in clinical studies described in Section 6.1 for the PD-L1 high-expression (CPS≧10) subgroup. [Figure 20B] This section shows progression-free survival (PFS) based on blinded, independent central review in clinical studies described in Section 6.1 for the PD-L1 low-expression (CPS<10) subgroup. [Figure 21A] Section 6.1 shows the overall survival (OS)-ITT for the EV+Pembro and Plat+Gem groups in the clinical studies described. This figure shows a graph of OS (%) against time (months). [Figure 21B] Section 6.1 shows the overall survival (OS)-ITT for the EV+Pembro and Plat+Gem groups in the clinical studies described. The median f / u = median follow-up period. This figure is a table showing the OS data for the EV+Pembro and Plat+Gem groups. [Figure 22A] This section presents subgroup analyses of overall survival (OS). The table shows subgroup analyses of overall survival (OS) for subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. "-" indicates that OS was not achieved. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from stratified Cox proportional hazards regression models are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 22B] This section presents a subgroup analysis of overall survival (OS). The graph shows OS (%) against observed time (months) in subjects with liver metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 22C] This section presents a subgroup analysis of overall survival (OS). The graph shows OS (%) against observed time (months) in subjects without liver metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 22D] This section presents a subgroup analysis of overall survival (OS). The graph shows OS (%) against observed time (months) in subjects with visceral metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 22E] This section presents a subgroup analysis of overall survival (OS). The graph shows OS (%) against observed time (months) in subjects with lymph node-only metastases. Estimated hazard ratios (HRs) and corresponding 95% confidence intervals from a stratified Cox proportional hazards regression model are also shown. A hazard ratio less than 1 supports the EV+P group. [Figure 23A] This section shows overall survival (OS) based on blinded, independent central review in clinical studies described in Section 6.1 for the cisplatin-eligible subgroup. [Figure 23B]This section shows overall survival (OS) based on blinded, independent central review in the clinical studies described in Section 6.1 for the cisplatin-ineligible subgroup. [Figure 24A] This section shows overall survival (OS) based on blinded, independent central review in clinical studies described in Section 6.1 for the PD-L1 high-expression (CPS≧10) subgroup. [Figure 24B] This section shows overall survival (OS) based on blinded, independent central review in the clinical studies described in Section 6.1 for the PD-L1 low-expression (CPS<10) subgroup. [Figure 25] This table shows the objective response rate (ORR) based on blinded, independent central review of subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. [Figure 26] This table shows subgroup analyses of objective response rates (ORR) for the EV+Pembro and Plat+Gem groups in the clinical studies described in Section 6.1. "-" indicates that the ORR was not achieved. [Figure 27A] Section 6.1 shows the duration of response (DOR) based on blinded, independent central review of subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described. This figure shows a graph of responders (%) with no disease progression or death over time (months). [Figure 27B] Section 6.1 shows the duration of response (DOR) based on blinded, independent central review of subjects in the EV+Pembro and Plat+Gem groups in the clinical studies described. This figure is a table showing the DOR data for the EV+Pembro and Plat+Gem groups. [Figure 28] This table provides an overall summary of the treatment-related adverse events (TEAEs) that occurred in the EV+Pembro and Plat+Gem groups of the clinical studies described in Section 6.1. [Figure 29] This table shows the TEAEs (by basic term) that occurred in 20% or more of the subjects in the EV+Pembro and Plat+Gem groups of the clinical studies described in Section 6.1. [Figure 30]Section 6.1 shows the TEAEs (by basic term) that occurred in 15% or more of the subjects in the EV+Pembro and Plat+Gem groups of the clinical studies described therein. [Figure 31] This table shows Grade 3 or higher TEAEs (categorized by basic term) that occurred in 5% or more of the subjects in the EV+Pembro and Plat+Gem groups of the clinical studies described in Section 6.1. [Figure 32] Section 6.1 shows Grade 3 or higher TEAEs (categorized by basic term) that occurred in 5% or more of the subjects in the EV+Pembro and Plat+Gem groups of the clinical studies described therein. [Figure 33] This table shows the number of serious TEAEs (categorized by basic term) that occurred in 2% or more of the subjects in the EV+Pembro and Plat+Gem groups of the clinical studies described in Section 6.1. [Figure 34] This table shows the TEAEs (by basic term) that led to death in the EV+Pembro and Plat+Gem groups of the clinical studies described in Section 6.1. [Figure 35] This table, categorized by basic term, shows the number of TEAEs (Triaded Endocrine Emissions) that resulted in discontinuation of any research drug in 1% or more of the subjects in the EV+Pembro and Plat+Gem groups of the clinical studies described in Section 6.1. [Figure 36] This table shows particularly noteworthy adverse events (AESIs) related to enfortumab vedotin (EV) in subjects in the EV+Pembro group and Plat+Gem group (and EV monotherapy) of the clinical studies described in Section 6.1. [Figure 37] This table shows particularly noteworthy adverse events (AEOSI) of pembrolizumab that occurred in more than two subjects in the EV+Pembro group of the clinical studies described in Section 6.1. [Figure 38]This table shows key patient characteristics and baseline traits of subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 3, which relates to cisplatin-ineligible subjects. In this figure, the superscript "a" indicates: a includes the renal pelvis, ureter, and kidney. In this figure, the superscript "b" indicates: b includes the bladder, urethra, and others. In this figure, the superscript "c" indicates: c the patient may have metastatic disease in two or more sites. In this figure, the superscript "d" indicates: d the patient had locally progressive disease with no metastasis to lymph nodes or distant organs. In this figure, the superscript "e" indicates: e CPS status was determined by Neogenomics and Labcorp using the validated PD-(L)1 IHC 22C3 pharmDx assay, and two patients in the EV+P group and one patient in the chemotherapy group had tissue quality samples insufficient for analysis. [Figure 39] This table summarizes the breakdown of subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 3, which relates to cisplatin-ineligible subjects. In this figure, the superscript "a" indicates the following: a. Patients in the EV+P group received EV until disease progression or toxicity (in accordance with the protocol, there was no maximum number of EV cycles) or completion of the maximum number of cycles (35 cycles for P), and chemotherapy could be administered for up to 6 cycles. In this figure, the superscript "b" indicates the following: b. Patients completed 35 cycles of P and discontinued EV before P. In this figure, the superscript "c" indicates the following: c. Six patients in EV+P: death (2), grade 3 asthenia outside the protocol reporting period (1), unable to follow up (1), chronic lymphocytic leukemia (1), deterioration of general condition (1); one patient in chemotherapy: patient's insurance did not cover chemotherapy treatment in the clinical trial (1). [Figure 40] This table shows the reasons for cisplatin ineligibility for patients related to the clinical study described in Example 3. In this figure, the superscript "a" indicates the following: a patient may be counted in two or more categories regarding cisplatin ineligibility. [Figure 41A] This figure shows the best overall response rate (ORR) according to RECIST, based on blinded independent central review (BICR), for subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 3, which relates to cisplatin-ineligible subjects. In this figure, the superscript "a" indicates the following: a Best overall response according to RECIST v1.1. CR or PR was confirmed by repeat scanning at least 28 days after the initial response. In this figure, the superscript "b" indicates the following: b The patient's best overall response was determined to be unassessable according to RECIST v1.1, or the patient did not undergo response assessment after baseline. [Figure 41B] This figure shows the time to objective response in the EV+P group and chemotherapy group related to cisplatin-ineligible patients. In this figure, the superscript "a" indicates: a Any objective response defined as a confirmed CR or PR. In this figure, the superscript "b" indicates: b The time from randomization to the first recorded confirmed CR or PR. [Figure 42] This shows the objective duration of response (DOR) based on blinded independent central review (BICR) for subjects in the EV+Pembro and chemotherapy groups of the clinical study described in Example 3, which relates to cisplatin-ineligible subjects. In detail, a graph of responders (%) with no disease progression or death per unit of time (months) is shown. [Figure 43] This table outlines the subsequent therapies for subjects in the EV+Pembro and chemotherapy groups of the clinical study described in Example 3, which relates to cisplatin-ineligible subjects. In this figure, the superscript "a" indicates the following: a 62 patients (31.3%) in the EV+P group were still receiving treatment at the DCO (Disability Occurrence) time, and all patients in the chemotherapy group were not receiving study treatment. In this figure, the superscript "b" indicates the following: b When platinum-based therapy and PD-1 / L1 agents were administered in the same therapy line, the therapy was classified as platinum-based therapy. [Figure 44]This table shows the treatment-related adverse events in the EV+Pembro and chemotherapy groups of the clinical study described in Example 3, which relates to patients ineligible for cisplatin. The TRAEs shown are all grades by basic term, observed in 20% or more patients across all grades in either group. [Figure 45] This table shows particularly noteworthy adverse events (AESIs) related to EV treatment for subjects in the EV+Pembro group and chemotherapy group of the clinical study described in Example 3, which relates to subjects ineligible for cisplatin. [Figure 46] This table shows particularly noteworthy adverse events (AEOSIs) that occurred under pembrolizumab treatment in patients ineligible for cisplatin. In this figure, an asterisk "*" indicates the following: *There are differences in the reported proportions of skin reactions for AESIs associated with EV treatment and particularly noteworthy TEAEs with P, because these adverse events were reported using different methods developed for EV monotherapy and P monotherapy, respectively. [Figure 47] This table shows key patient characteristics and baseline features of subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 4, which relates to cisplatin-eligible subjects. In this figure, the superscript "a" indicates: a includes the renal pelvis, ureter, and kidney. In this figure, the superscript "b" indicates: b includes the bladder, urethra, and others. In this figure, the superscript "c" indicates: c the patient may have metastatic disease in two or more sites. In this figure, the superscript "d" indicates: d the patient had locally progressive disease with no metastasis to lymph nodes or distant organs. In this figure, the superscript "e" indicates: e CPS status was determined by Neogenomics and Labcorp using the validated PD-(L)1 IHC 22C3 pharmDx assay, and two patients in the EV+P group and four patients in the chemotherapy group had tissue quality samples insufficient for analysis. [Figure 48]This table summarizes the breakdown of subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 4, which relates to cisplatin-eligible subjects. In this figure, the superscript "a" indicates the following: a Patients in the EV+P group received EV until disease progression or toxicity (according to the protocol, there was no maximum number of EV cycles) or completion of the maximum number of cycles (35 cycles for P), and chemotherapy could be administered for up to 6 cycles. In this figure, the superscript "b" indicates the following: b Patients completed 35 cycles of P and discontinued EV before P. In this figure, the superscript "c" indicates the following: c One patient in EV+P: death; one patient in chemotherapy: respiratory failure. [Figure 49A] This figure shows the best overall response rate (ORR) according to RECIST, based on blinded independent central review (BICR), for subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 4, which relates to cisplatin-eligible subjects. In this figure, the superscript "a" indicates: a Best overall response according to RECIST v1.1. CR or PR was confirmed by repeat scanning at least 28 days after the initial response. In this figure, the superscript "b" indicates: b The patient's best overall response was determined to be unassessable according to RECIST v1.1, or the patient did not undergo response assessment after baseline. [Figure 49B] This figure shows the time to objective response in the EV+P group and chemotherapy group of the clinical study described in Example 4 related to cisplatin-eligible subjects. In this figure, the superscript "a" indicates: a Any objective response defined as a confirmed CR or PR. In this figure, the superscript "b" indicates: b The time from randomization to the first recorded confirmed CR or PR. [Figure 50] This shows the objective duration of response (DOR) based on blinded independent central review (BICR) for subjects in the EV+Pembro and chemotherapy groups of the clinical study described in Example 4, which relates to cisplatin-eligible subjects. In detail, a graph of responders (%) with no disease progression or death per unit of time (months) is shown. [Figure 51]This table outlines the subsequent therapies for subjects in the EV+Pembro and chemotherapy groups in the clinical study described in Example 4, which relates to cisplatin-eligible subjects. In this figure, the superscript "a" indicates the following: a. 82 patients (33.6%) in the EV+P group were still receiving treatment at DCO, and all patients in the chemotherapy group were not receiving study treatment. In this figure, the superscript "b" indicates the following: b. When platinum-based therapy and PD-1 / L1 agents were administered in the same therapy line, the therapy was classified as platinum-based therapy. [Figure 52] This table shows the treatment-related adverse events in the EV+Pembro and chemotherapy groups of the clinical study described in Example 4, which relates to cisplatin-eligible subjects. In this figure, the superscript "a" indicates the following: The TRAEs shown are all grades by basic word observed in 20% or more patients across all grades in either group. [Figure 53] This table shows particularly noteworthy adverse events (AESIs) related to cisplatin treatment for subjects in the EV+Pembro group and chemotherapy group of the clinical study described in Example 4, which relates to eligible subjects for cisplatin. [Figure 54] This table shows particularly noteworthy adverse events (AEOSIs) that occurred under pembrolizumab treatment in cisplatin-eligible patients. In this figure, an asterisk "*" indicates the following: *There are differences in the reported proportions of skin reactions for AESIs associated with EV treatment and particularly noteworthy TEAEs with P, because these adverse events were reported using different methods developed for EV monotherapy and P monotherapy, respectively. [Figure 55] The following shows progression-free survival (PFS) based on blinded, independent central review in clinical studies described in Section 6.5 concerning the Pan-Asian subgroup. EV, enfortumab vedotin; Gem, gemcitabine; HR, hazard ratio; ITT, intention to treat; Pembro, pembrolizumab; PFS, progression-free survival; Plat, platinum. [Figure 56]Overall survival (OS) is shown based on blinded, independent central review in clinical studies described in Section 6.5 concerning the Pan-Asian subgroup. EV: Enfortumab vedotin; Gem: Gemcitabine; HR: Hazard ratio; ITT: Intended treatment; OS: Overall survival; Pembro: Pembrolizumab; Plat: Platinum. [Figure 57A] This shows the time to pain progression (TTPP) in subjects treated with enfortumab vedotin (EV+P) in combination with pembrolizumab, compared to subjects treated with Plat+Gem. [Figure 57B] This section presents data on TTPP in subjects treated with EV+P compared to subjects treated with Plat+Gem. [Figure 58] This shows the compliance rate for the EORTC-QLQ C30. PRO FAS analysis. EORTC QLQ-C30, European Organisation for Research and Therapy of Cancer Quality of Life Questionnaire - Core Questionnaire; EV+P, enfortumab vedotin and pembrolizumab; PRO FAS, the largest analysis population for patient-reported outcomes. [Figure 59] This shows the overall mean change from baseline in the maximum pain score on the Reduced Brief Pain Inventory (BPI-SF) at week 26. BPI-SF, Reduced Brief Pain Inventory; EV+P, enfortumab vedotin and pembrolizumab; PBC, platinum-based chemotherapy. [Figure 60] The mean change in LS from baseline in the BPI-SF scale score up to week 26 is shown. BPI-SF, shortened simplified pain questionnaire; CI, confidence interval; EV+P, enfortumab vedotin and pembrolizumab; LS, least squares; SE, standard error. [Figure 61] This shows the overall mean change from baseline in BPI-SF score up to week 26 in subjects with moderate to severe pain at baseline. BPI-SF: Reduced version of the Brief Pain Questionnaire; EV+P: Enfortumab vedotin and pembrolizumab; PBC: Platinum-based chemotherapy; PRO: Patient-reported outcome. [Figure 62]This shows the mean change in LS (Least Score) from baseline in the BPI-SF scale score up to week 26 in subjects with moderate to severe pain at baseline. BPI-SF, shortened simplified pain questionnaire; CI, confidence interval; EV+P, enfortumab vedotin and pembrolizumab; LS, least squares; SE, standard error. [Figure 63A] This shows the overall mean change from baseline in EORTC QLQ-C30 GHS / QoL up to week 26. EORTC QLQ-C30, European Organisation for Research and Therapy of Cancer Quality of Life Questionnaire - Core Questionnaire; EV+P, enfortumab vedotin and pembrolizumab; GHS, general health status; LS, least squares; QoL, quality of life. [Figure 63B] The overall mean change from baseline in functional status scale scores and GHS / QoL up to week 26 is shown. EV+P, enfortumab vedotin and pembrolizumab; GHS, general health status; LS, least squares; QoL, quality of life; SE, standard error. [Figure 64A] The overall mean change from baseline in EORTC QLQ-C30 GHS / QoL up to 26 weeks in cisplatin-eligible sex patients: cisplatin-eligible. EORTC QLQ-C30, European Organisation for Research and Therapy of Cancer Quality of Life Questionnaire - Core Questionnaire; GHS, General Health Status; LS, Least Squares; QoL, Quality of Life. [Figure 64B] The overall mean change from baseline in EORTC QLQ-C30 GHS / QoL up to 26 weeks in cisplatin-eligible sexes: cisplatin-ineligible sexes. EORTC QLQ-C30, European Organisation for Research and Therapy of Cancer Quality of Life Questionnaire - Core Questionnaire; GHS, General Health Status; LS, Least Squares; QoL, Quality of Life. [Figure 65] The EORTC QLQ-C30 indicates the time to definitive deterioration of QoL and functional status scales. CI: Confidence interval; EORTC QLQ-C30: European Organisation for Cancer Research and Therapy Quality of Life Questionnaire - Core Questionnaire; EV+P: Enfortumab vedotin and pembrolizumab; LS: Least squares; mTTCD: Median time to definitive deterioration; PBC: Platinum-based chemotherapy; QoL: Quality of life; SD: Standard deviation. [Figure 66A]This shows the overall mean change from baseline in EORTC QLQ-C30 GHS / QoL up to week 26. [Figure 66B] This shows the overall mean change from baseline in functional status scale scores up to week 26 in patients with moderate / severe pain at baseline. [Figure 67] The H-score for nectin-4 expression is shown for each biopsy sample source (i.e., primary tissue or metastatic tissue). [Figure 68A] The H-scores for nectin-4 expression in both groups as a whole (N=800) are shown. The y-axis represents baseline nectin-4 expression (H-score), and the x-axis represents individual patients. [Figure 68B] The following data regarding the H-score of nectin-4 expression in the EV+P group and the chemotherapy group are shown for each of the following subgroups: <150, 150 to <225, and ≥225. [Figure 69A] The Kaplan-Meier plot of PFS for the subgroup with a Nectin-4 H score of less than 275 is shown. [Figure 69B] The Kaplan-Meier plot of PFS for the subgroup with a Nectin-4 H score of 275 or higher is shown. [Figure 70A] The Kaplan-Meier plot shows the OS of the subgroup with a Nectin-4 H score of less than 275. [Figure 70B] The Kaplan-Meier plot shows the OS of the subgroup with a Nectin-4 H score of 275 or higher. [Figure 71A] This shows a subgroup analysis of PFS by Nectin-4 H score. [Figure 71B] This shows the OS subgroup analysis by Nectin-4 H score. [Figure 72] The ORR (percentage of patients with an ORR) is shown for the subgroups with a Nectin-4 H score of less than 275 and the subgroup with a Nectin-4 H score of 275 or higher (where the median Nectin-4 H score was 275 for all patients in both groups), as well as for the subgroups with a Nectin-4 H score of less than 150, the subgroup with a Nectin-4 H score of 150 to less than 225, and the subgroup with a Nectin-4 H score of 225 or higher. [Figure 73] The expression distribution of nectin-4 and PD-L1 in the EV+P (N=442) group and the chemotherapy (N=444) group, specifically in subgroups with a nectin-4 H score of less than 275 and subgroups with a nectin-4 H score of 275 or higher (where the median nectin-4 H score was 275 for all patients in both groups), as well as in subjects without nectin-4 results, is shown. [Figure 74A] The following Kaplan-Meier plots of PFS (%) for each group are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 74B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 74D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 74B] The following Kaplan-Meier plots of PFS (%) for each group are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 74B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 74D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 74C]The following Kaplan-Meier plots of PFS (%) for each group are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 74B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 74D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 74D] The following Kaplan-Meier plots of PFS (%) for each group are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 74B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 74C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 74D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 75A]The Kaplan-Meier plots for OS (%) in each of the following groups are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 75B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 75D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 75B] The Kaplan-Meier plots for OS (%) in each of the following groups are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 75B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 75D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 75C]The Kaplan-Meier plots for OS (%) in each of the following groups are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 75B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 75D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Figure 75D] The Kaplan-Meier plots for OS (%) in each of the following groups are shown: (1) a subgroup with a nectin-4 H score less than 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75A), (2) a subgroup with a nectin-4 H score less than 275 and high levels of PD-L1 expression (CPS ≥ 10) (see Figure 75B), (3) a subgroup with a nectin-4 H score of ≥ 275 and low levels of PD-L1 expression (CPS < 10) (see Figure 75C), and (4) a subgroup with a nectin-4 H score of ≥ 275 and high levels of PD-L1 expression (see Figure 75D) (Note that for (1) to (4), the median nectin-4 H score was 275 for all patients in both groups) (CPS ≥ 10). [Modes for carrying out the invention]

[0119] 5. Detailed explanation In describing this disclosure in detail, 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.

[0120] 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).

[0121] 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.

[0122] The terms “antibody,” “immunoglobulin,” or “Ig” are used interchangeably herein and in their broadest sense, specifically, as described below, 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. 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., 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.

[0123] 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.

[0124] An "antigen" is a structure to which an antibody can selectively bind. Target antigens may be polypeptides, carbohydrates, nucleic acids, lipids, haptens, or other natural or synthetic compounds. 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.

[0125] 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.

[0126] 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.) See, al., 2003, Nat. Med. 9:129-34, WO93 / 11161, and U.S. Patents 5,837,242 and 6,492,123); single-chain antibody molecules (see, for example, U.S. Patents 4,946,778, 5,260,203, 5,482,858, and 5,476,786); bivariable domain antibodies (see, for example, U.S. Patent 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.

[0127] The terms “binding” or “joining” refer to intermolecular interactions, including, for example, the formation of a complex. Interactions can be non-covalent interactions, including, for example, hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. Complexes can also involve the binding 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 on a target molecule such as an antigen is the affinity of the antibody or functional fragment to that epitope. The ratio (koff / kon) of the dissociation rate (koff) to the association rate (kon) of a binding molecule (e.g., an antibody) to a monovalent antigen is the dissociation constant KD, which is inversely proportional to affinity. A lower KD value indicates higher antibody affinity. The KD value differs for different antibody-antigen complexes and depends on both kon and koff. The dissociation constant KD of antibodies provided herein can be determined using any method provided herein or any other method well known to those skilled in the art. Affinity at a single 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, comes into contact with an antibody containing multiple binding sites, the interaction between the antibody and antigen at one site increases the probability of a reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity.

[0128] 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 be cross-reactive 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, as 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 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 comparing the binding of a molecule to the binding of a control molecule, which is a similarly structured molecule that generally does not have 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 antibody or antigen-binding fragment has a dissociation constant (KD) of less than 0.3 nM, less than 0.2 nM, or less than 0.1 nM, or 1000 nM, 800 nM, 500 nM, 250 nM, 100 nM, 50 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. 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 humans and cynomolgus monkeys).

[0129] "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, "binding affinity" as used herein 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 to its binding partner Y can generally be expressed by a dissociation constant (KD). 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 rapidly to antigens and remain bound for longer. 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, "KD" or "KD value" can be measured by an assay known in the art, such as a binding assay. KD can be measured, for example, in a RIA performed using the Fab version of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). KD or KD value 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 "kon" can also be determined using the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, for example by Octet® QK384, Biacore® TM-2000, or Biacore® TM-3000 system.

[0130] In certain embodiments, an antibody or antigen-binding fragment may contain a “chimeric” sequence in which a portion 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, and the remainder of the chain 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 an antibody, 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).

[0131] 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 that is a chimeric antibody containing human immunoglobulin (e.g., recipient antibody) in which the native CDR residues are replaced with residues derived from the corresponding CDRs of a non-human species (e.g., donor antibody) such as mouse, rat, rabbit, or non-human primate, having desired specificity, affinity, and ability. 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, where all or substantially all of the CDRs correspond to the CDRs of the non-human immunoglobulin and all or substantially all of the FRs are 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.

[0132] In certain embodiments, an antibody or antigen-binding fragment may include a “fully human antibody” or a portion of a “human antibody,” these terms 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, a “fully human” antibody may also include an antibody that binds to a polypeptide and is 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). A “human antibody” is an antibody having an amino acid sequence corresponding to an antibody produced by a human, and / or an antibody 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.

[0133] 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 may not be naturally present in the human antibody germline repertoire in vivo.

[0134] In certain embodiments, the 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, the individual antibodies constituting the population being 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 by using recombinant DNA methods in bacterial, eukaryotic, or plant cells (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies may 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).

[0135] 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 structures 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., 5th ed. 2001).

[0136] 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 regions 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 regions 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 described in more detail in the following sections.

[0137] 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, typically having a length of approximately 120 to 130 amino acids in the heavy chain and approximately 100 to 110 amino acids 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 is sometimes referred to as "VH." The variable region of the light chain is sometimes referred to as "VL." The term "variable" refers to the fact that the sequence of a particular segment of the variable region differs significantly between antibodies. The V region mediates antigen binding and determines 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 (FRs) of about 15-30 amino acids, separated by shorter regions of greater variability (e.g., extreme variability) called "hypervariable regions" of about 9-12 amino acids each. 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 region differs significantly between different antibodies. In a specific embodiment, the variable region is the human variable region.

[0138] 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, a 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 when referring to residues in the variable domain (approximately light chain residues 1-107 and heavy chain residues 1-113) (e.g., Kabat et al., cited above). The "EU numbering system" or "EU index" is generally used when referring 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 are described, for example, by AbM, Chothia, Contact, IMGT, and AHon.

[0139] 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 different 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.

[0140] 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).

[0141] 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) VHβ sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of an antibody VLβ sheet framework. Therefore, a CDR is a variable region sequence scattered within a framework region sequence.

[0142] CDR regions are well known to those skilled in the art and are 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). Herein, 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, for example, the Kabat numbering system and the IMGT-specific numbering system, 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 of each of these hypervariable regions or CDRs are shown in Table 1 below.

[0143] [Table 1]

[0144] The boundaries of a given CDR may differ 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.

[0145] 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.

[0146] 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 and the CL region of the light chain.

[0147] 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.

[0148] 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 recombinant processing of 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 in the native Fc region or the Fc region of the parent polypeptide, or about 1 to about 5 amino acid substitutions. 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.

[0149] 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). Generally, 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.

[0150] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may 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.

[0151] As used herein, the term “pharmaceutically acceptable” means that it is approved by a federal or state regulatory agency, or that it is listed in the United States Pharmacopeia, the European Pharmacopeia, or any other generally accepted pharmacopoeia for use in animals, more specifically in humans.

[0152] "Excipients" means pharmaceutically acceptable materials, compositions, or vehicles, such as liquid or solid fillers, diluents, solvents, or encapsulating materials. Excipients include encapsulating materials or additives such as absorption enhancers, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizers, sweeteners, solubilizers, wetting agents, and mixtures thereof. The term "excipients" may also refer to diluents, adjuvants (e.g., Freund's adjuvants (complete or incomplete)) or vehicles.

[0153] In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, 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 embodiments, a pharmaceutically acceptable excipient is nontoxic to cells or mammals to which it is exposed at the dosage and concentration used. In some embodiments, the pharmaceutically acceptable excipient is a pH-buffered aqueous solution.

[0154] The abbreviation "MMAE" refers to monomethyl auristatin E.

[0155] Unless otherwise specified in the context, a hyphen (-) indicates the attachment point to the pendant molecule.

[0156] 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.

[0157] 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 recognize that single amino acid substitutions in non-essential regions of polypeptides generally do not substantially alter the 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 specific 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 interchangeable at positions where the different pKs of these two amino acid residues are not important, as their charge is a key characteristic of the amino acid residue. In certain environments, other changes may be considered "conservative" (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, and 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.

[0158] [Table 2]

[0159] [Table 3]

[0160] 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.

[0161] 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.

[0162] 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, PSI BLAST can be used to perform iterative searches 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.

[0163] 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.

[0164] 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, but are not limited to, 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, dihydroxyanthracinedione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modesine A chain, alpha-sarcin, geronin, mitogenin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, and saponaria. Examples include officinalis inhibitors, glucocorticoids and other chemotherapeutic agents, and radioisotopes such as At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212 or Bi213, P32, and radioisotopes of Lu, including Lu177. Antibodies may also be conjugated to anticancer prodrug activating enzymes that can convert prodrugs into their active form.

[0165] 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.

[0166] The terms “subject” and “patient” may be used synonymously. As used herein, in certain embodiments, the subject is a mammal such as a non-primate (e.g., cattle, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkeys and humans). 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.

[0167] "Administer" or "Deliver" 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.

[0168] 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.

[0169] 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).

[0170] The terms “cancer” or “cancer cell” are used herein to refer to 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.

[0171] As used herein, “locally advanced” cancer refers to cancer that has spread from its place of origin to nearby tissues or lymph nodes.

[0172] As used herein, “metastatic” cancer refers to cancer that has spread from its original site to other parts of the body.

[0173] As used herein, the term “major surgery” may refer to any surgical procedure that involves cutting one of the major body cavities, such as the abdomen (i.e., laparotomy), the chest (i.e., thoracotomy), or the skull (i.e., craniotomy).

[0174] The terms "about" and "approximately" mean within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than 20% of a given value or range.

[0175] 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.

[0176] Wherever an embodiment is described herein using the term “including,” it should be understood that it is also provided in other similar embodiments described in terms of “consisting of” and / or “essentially consisting of.” Similarly, wherever an embodiment is described herein using the phrase “essentially consisting of,” it should be understood that other similar embodiments described in terms of “consisting of” are also provided.

[0177] 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).

[0178] 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 1A). Analogues are an example of a variant protein. Splice isoforms and single nucleotide polymorphisms (SNPs) are further examples of variants.

[0179] The “191P4D12 protein” and / or “191P4D12-related protein” in this disclosure include those specifically identified herein (see Figure 1A), as well as allele variants, conserved substitution variants, analogs, and homologs that can be isolated / produced and characterized without excessive experimentation by following 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, proteins of this disclosure, or 191P4D12. The term "191P4D12-related protein" refers to more than 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 25 amino acids, or at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 105 amino acids. This refers to polypeptide fragments or the 191P4D12 protein sequence with 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 330, 335, 339 amino acids or more. The term "191P4D12" is used interchangeably with Nectin-4.

[0180] 5.2 Cancer Treatment Methods Urothelial carcinoma (UC), a cancerous tumor encompassing both the lower and upper urinary tracts, is a malignant tumor with a high degree of unmet medical need. The global incidence of UC is increasing, driven by overall population growth and aging. The prognosis for patients with locally advanced or metastatic urothelial carcinoma (la / mUC) is poor, with a relatively low 5-year survival rate (approximately 5%).

[0181] For decades, platinum-based chemotherapy has been the standard of care (SOC) for first-line treatment of la / mUC. Despite the survival benefit, treatment outcomes remain poor. While most patients initially respond to cisplatin- or carboplatin-based chemotherapy, many patients progress within 7 months, highlighting the need for new therapies in the first-line treatment setting. Treatment guidelines recommend avelumab maintenance therapy as an option for a subset of patients with la / mUC that has not progressed on platinum-containing chemotherapy, but the majority of patients cannot or do not receive maintenance therapy, primarily due to disease progression or death during initial therapy (including appropriate references).

[0182] Accordingly, the present disclosure provides proven and effective methods for treating patients (e.g., cisplatin-eligible and cisplatin-ineligible patients) (e.g., patients who have not previously received any treatment for cancer) having urothelial cancer and / or bladder cancer (including locally advanced urothelial cancer, metastatic urothelial cancer, locally advanced metastatic urothelial cancer, locally advanced bladder cancer, and metastatic bladder cancer).

[0183] In embodiments referring to the treatment methods described herein, such embodiments are also further embodiments for the use of an antibody-drug conjugate (ADC) and / or anti-PD-1 antibody for use in combination therapy, or the use of an ADC and / or anti-PD-1 antibody in the manufacture of a medicament for use in combination therapy.

[0184] 5.2.1 General and Selected Patient Cancer Treatment Methods Provided herein are methods for treatment as first-line and second-line therapy for various cancers in subjects, including subjects having unresectable locally advanced or metastatic urothelial cancer (la / mUC) who are cisplatin-eligible and cisplatin-ineligible, wherein an antibody-drug conjugate (ADC) that binds 191P4D12 is used in combination with an anti-PD-1 antibody (e.g., pembrolizumab).

[0185] In one embodiment, a method for treating cancer in a subject using an ADC conjugating to 191P4D12 and an anti-PD-1 antibody (e.g., pembrolizumab) is provided herein. In some embodiments, the human subject treated by the method provided herein has not previously received any cancer treatment other than an ADC conjugating to 191P4D12. In certain embodiments, the human subject treated by the method provided herein has not previously received treatment including or consisting of an immune checkpoint inhibitor (CPI). In some embodiments, the CPI is an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the CPI is a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In certain embodiments, the CPI is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subjects treated by the methods provided herein have not previously received treatment including or consisting of a PD-(L)-1 inhibitor. A PD-(L)-1 inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-(L)-1 inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the PD-(L)-1 inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. In certain embodiments, the PD-(L)-1 inhibitor is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subjects treated by the methods provided herein have never been administered any agent targeting another stimulating or co-inhibitory T cell receptor (including, but not limited to, CD137 agonists, CTLA4 inhibitors, or OX-40 agonists). In certain embodiments, the agent targeting another stimulating or co-inhibitory T cell receptor is a CD137 agonist, a CTLA4 inhibitor, or an OX-40 agonist. In some embodiments, the human subjects treated by the methods provided herein are ineligible to receive cisplatin treatment.In other embodiments, human subjects treated by the methods provided herein are ineligible to receive cisplatin treatment and have not previously received treatment including or comprising CPI. In certain embodiments, human subjects treated by the methods provided herein are ineligible to receive cisplatin treatment and have not previously received treatment including or comprising CPI, and have not previously received systemic therapy except for neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments, human subjects treated by the methods provided herein are eligible to receive cisplatin treatment. In other embodiments, human subjects treated by the methods provided herein are eligible to receive cisplatin treatment and have not previously received treatment including or comprising CPI. In certain embodiments, human subjects treated by the methods provided herein are eligible to receive cisplatin treatment and have not previously received treatment including or comprising CPI, and have not previously received systemic therapy except for neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In certain embodiments, the human subjects treated by the methods provided herein are eligible to receive cisplatin therapy, have not previously received treatment including or comprising CPI, and have received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments, the human subjects treated by the methods provided herein are eligible to receive carboplatin therapy. In other embodiments, the human subjects treated by the methods provided herein are eligible to receive carboplatin therapy and have not previously received treatment including or comprising CPI. In certain embodiments, the human subjects treated by the methods provided herein are eligible to receive carboplatin therapy, have not previously received treatment including or comprising CPI, and have not previously received systemic therapy other than neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy.In certain embodiments, human subjects treated by the methods provided herein are eligible to receive carboplatin therapy, have not previously received treatment including or comprising CPI, and have received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments, human subjects treated by the methods provided herein are ineligible or eligible to receive cisplatin therapy. In other embodiments, human subjects treated by the methods provided herein are ineligible or eligible to receive cisplatin therapy and have not previously received treatment including or comprising CPI. In certain embodiments, human subjects treated by the methods provided herein are ineligible or eligible to receive cisplatin therapy, have not previously received treatment including or comprising CPI, and have not previously received systemic therapy other than neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In certain embodiments, the human subjects treated by the methods provided herein are ineligible or ineligible for cisplatin treatment, have not previously received treatment including or consisting of CPI, and have received neoadjuvant chemotherapy or adjuvant chemotherapy after cystectomy with recurrence more than 12 months after completion of therapy. In some embodiments, the cancer is urothelial carcinoma. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is renal pelvis cancer. In certain embodiments, the cancer is ureteral cancer. In certain embodiments, the cancer is urethral cancer. In one embodiment, the cancer is locally advanced cancer. In another embodiment, the cancer is metastatic cancer. In yet another embodiment, the cancer is locally advanced urothelial carcinoma. In yet another embodiment, the cancer is unresectable locally advanced urothelial carcinoma. In yet another embodiment, the cancer is metastatic urothelial carcinoma. In one embodiment, the cancer is locally advanced bladder cancer. In another embodiment, the cancer is metastatic bladder cancer.

[0186] 5.2.1.1 Patients ineligible for cisplatin and patients eligible for cisplatin Cisplatin-ineligible patients: Various conditions may be used to determine cisplatin ineligibility in human subjects for the methods provided herein, including but not limited to the methods described in the preceding paragraph. In one embodiment, the conditions for determining cisplatin ineligibility include, or consist of, an ECOG Performance Status score of 2. In some embodiments, the conditions for determining cisplatin ineligibility include, or consist of, renal impairment (e.g., glomerular filtration rate (GFR) less than 60 mL / min but greater than 30 mL / min or creatinine clearance (estimated by the Cockcroft-Gault formula, modification of diet in renal disease [MDRD], or 24-hour urine collection)). In certain embodiments, the conditions for determining cisplatin ineligibility include, or consist of, grade 2 or higher hearing loss (e.g., grade 2 or higher hearing loss in NCI CTCAE version 4.03). In certain embodiments, the conditions for determining cisplatin ineligibility include, or consist of, NYHA class III heart failure. In one embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and renal impairment. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and hearing loss of grade 2 or higher. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, renal impairment and hearing loss of grade 2 or higher. In even further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, renal impairment and NYHA class III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, renal impairment, and hearing loss of grade 2 or higher.In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, renal impairment, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, any one of renal impairment and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any one of renal impairment, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the ECOG performance status score of 2, renal impairment, and grade 2 or higher hearing loss in any combination or permutation. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the renal impairment, grade 2 or higher hearing loss, and NYHA class III heart failure in any combination or permutation. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: an ECOG performance status score of 2, renal impairment, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: renal impairment, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided herein, the subjects had not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, the subjects had received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject has (i) hemoglobin of 10 g / dL or higher, (ii) a GFR of 50 mL / min or higher, and (iii) no NYHA class III heart failure.

[0187] Renal impairment can be determined by a variety of means known and available in the art. Various embodiments for determining renal impairment in human subjects are provided herein for methods provided herein, including but not limited to the methods described in the preceding paragraph. In one embodiment, renal impairment is determined by a glomerular filtration rate (GFR) of less than 60 mL / min. In some embodiments, renal impairment is determined by a GFR of less than 60 mL / min but greater than or equal to 30 mL / min. In certain embodiments, renal impairment is determined by a GFR of less than 30 mL / min but greater than or equal to 15 mL / min. In some embodiments of the methods provided herein, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided herein, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided herein, GFR is measured by dietary adjustments in renal disease [MDRD].

[0188] In further embodiments, renal impairment is determined by a creatinine clearance (CrCl) of less than 60 mL / min. In some embodiments, renal impairment is determined by a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min. In certain embodiments, renal impairment is determined by a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria.

[0189] Accordingly, for methods provided herein, including but not limited to the methods described in the preceding paragraph, several specific conditions based on GFR or creatinine clearance may be used to determine cisplatin ineligibility in human subjects. In some embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min. In one embodiment, the conditions for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and a CrCl of less than 60 mL / min. In further embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min and hearing loss of grade 2 or higher. In further embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min and NYHA class III heart failure. In yet another embodiment, the conditions for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, a GFR of less than 60 mL / min, and hearing loss of grade 2 or higher. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, a GFR of less than 60 mL / min, and any one of grade 2 or higher hearing loss. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any one of a GFR of less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: an ECOG performance status score of 2, a GFR of less than 60 mL / min, and grade 2 or higher hearing loss.In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: a GFR of less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: an ECOG performance status score of 2, a GFR of less than 60 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: a GFR of less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by dietary adjustments in renal disease [MDRD]. In some embodiments of the methods provided herein, subjects had not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, subjects had received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has a hemoglobin of ≥10 g / dL, (ii) has a GFR of ≥50 mL / min, and (iii) does not have NYHA class III heart failure.

[0190] In further embodiments, the criteria for determining cisplatin ineligibility include or consist of a CrCl level of less than 60 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a CrCl level of less than 60 mL / min. In further embodiments, the criteria for determining cisplatin ineligibility include or consist of a CrCl level of less than 60 mL / min and hearing loss of grade 2 or higher. In further embodiments, the criteria for determining cisplatin ineligibility include or consist of a CrCl level of less than 60 mL / min and NYHA class III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a CrCl level of less than 60 mL / min, and hearing loss of grade 2 or higher. In yet another embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl level of less than 60 mL / min, hearing loss of grade 2 or higher, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, one of the following: an ECOG performance status score of 2, CrCl less than 60 mL / min, and grade 2 or higher hearing loss. In yet other embodiments, the criteria for determining cisplatin ineligibility include, or consist of, one of the following: CrCl less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following: an ECOG performance status score of 2, CrCl less than 60 mL / min, and grade 2 or higher hearing loss, in any combination or permutation. In yet other embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following: CrCl less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure, in any combination or permutation.In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: an ECOG performance status score of 2, CrCl < 60 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: CrCl < 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subjects had not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, the subjects had received neoadjuvant chemotherapy or adjuvant chemotherapy after cystectomy with relapse more than 12 months after completion of therapy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has a hemoglobin of 10 g / dL or higher, (ii) has a GFR of 50 mL / min or higher, and (iii) does not have NYHA class III heart failure.

[0191] Alternatively, for methods provided herein, including but not limited to the methods described in the preceding paragraph, other specific conditions based on GFR or creatinine clearance may be used to determine cisplatin ineligibility in human subjects. In some embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min. In one embodiment, the conditions for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and a GFR of less than 60 mL / min but greater than or equal to 30 mL / min. In further embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min and grade 2 or higher hearing loss. In further embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min and NYHA class III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, a GFR of 30 mL / min or more but less than 60 mL / min, and hearing loss of grade 2 or higher. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, a GFR of 30 mL / min or more but less than 60 mL / min, hearing loss of grade 2 or higher, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any one of the following: an ECOG performance status score of 2, a GFR of 30 mL / min or more but less than 60 mL / min, and hearing loss of grade 2 or higher. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any one of the following: a GFR of 30 mL / min or more but less than 60 mL / min, hearing loss of grade 2 or higher, and NYHA class III heart failure.In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: an ECOG performance status score of 2, a GFR of 30 mL / min or more but less than 60 mL / min, and hearing loss of grade 2 or higher. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: a GFR of 30 mL / min or more but less than 60 mL / min, hearing loss of grade 2 or higher, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: an ECOG performance status score of 2, a GFR of 30 mL / min or more but less than 60 mL / min, and hearing loss of grade 2 or higher. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: GFR less than 60 mL / min but greater than 30 mL / min, grade 2 or greater hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by dietary adjustments in renal disease [MDRD]. In some embodiments of the methods provided herein, subjects had not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, subjects had received neoadjuvant chemotherapy or adjuvant chemotherapy after cystectomy with relapse more than 12 months after completion of therapy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has a hemoglobin of 10 g / dL or higher, (ii) has a GFR of 50 mL / min or higher, and (iii) does not have NYHA class III heart failure.

[0192] In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a CrCl level of less than 60 mL / min but greater than 30 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and a CrCl level of less than 60 mL / min but greater than 30 mL / min. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a CrCl level of less than 60 mL / min but greater than 30 mL / min and grade 2 or higher hearing loss. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a CrCl level of less than 60 mL / min but greater than 30 mL / min and NYHA class III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, a CrCl level of less than 60 mL / min but greater than 30 mL / min, and grade 2 or higher hearing loss. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, CrCl levels of 30 mL / min or higher but less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, CrCl levels of 30 mL / min or higher but less than 60 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, CrCl levels of 30 mL / min or higher but less than 60 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: an ECOG performance status score of 2, CrCl levels of 30 mL / min or higher but less than 60 mL / min, and grade 2 or higher hearing loss.In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: CrCl of less than 60 mL / min but greater than 30 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, CrCl of less than 60 mL / min but greater than 30 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: CrCl of less than 60 mL / min but greater than 30 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, subjects had not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, subjects had received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has a hemoglobin of ≥10 g / dL, (ii) has a GFR of ≥50 mL / min, and (iii) does not have NYHA class III heart failure.

[0193] Similarly, for methods provided herein, including but not limited to the methods described in the preceding paragraph, further specific conditions based on GFR or creatinine clearance may be used to determine cisplatin ineligibility in human subjects. In some embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min. In one embodiment, the conditions for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and a GFR of less than 30 mL / min but greater than or equal to 15 mL / min. In further embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, and grade 2 or higher hearing loss. In further embodiments, the conditions for determining cisplatin ineligibility include, or consist of, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, and NYHA class III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, a GFR of 15 mL / min or higher but less than 30 mL / min, and hearing loss of grade 2 or higher. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, a GFR of 15 mL / min or higher but less than 30 mL / min, hearing loss of grade 2 or higher, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any one of the following: an ECOG performance status score of 2, a GFR of 15 mL / min or higher but less than 30 mL / min, and hearing loss of grade 2 or higher. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any one of the following: a GFR of 15 mL / min or higher but less than 30 mL / min, hearing loss of grade 2 or higher, and NYHA class III heart failure.In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: an ECOG performance status score of 2, a GFR of 15 mL / min or more but less than 30 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: a GFR of 15 mL / min or more but less than 30 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: an ECOG performance status score of 2, a GFR of 15 mL / min or more but less than 30 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: GFR less than 30 mL / min but greater than 15 mL / min, grade 2 or greater hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by dietary adjustments in renal disease [MDRD]. In some embodiments of the methods provided herein, subjects have not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, subjects have received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has a hemoglobin of 10 g / dL or higher, (ii) has a GFR of 50 mL / min or higher, and (iii) does not have NYHA class III heart failure.

[0194] In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a CrCl level of less than 30 mL / min but greater than 15 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2 and a CrCl level of less than 30 mL / min but greater than 15 mL / min. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a CrCl level of less than 30 mL / min but greater than 15 mL / min and grade 2 or higher hearing loss. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, a CrCl level of less than 30 mL / min but greater than 15 mL / min and NYHA class III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, a CrCl level of less than 30 mL / min but greater than 15 mL / min, and grade 2 or higher hearing loss. In further embodiments, the criteria for determining cisplatin ineligibility include, or consist of, CrCl levels of 15 mL / min or higher but less than 30 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, CrCl levels of 15 mL / min or higher but less than 30 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, CrCl levels of 15 mL / min or higher but less than 30 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: an ECOG performance status score of 2, CrCl levels of 15 mL / min or higher but less than 30 mL / min, and grade 2 or higher hearing loss.In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, any two of the following in any combination or permutation: CrCl of less than 30 mL / min but greater than 15 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, an ECOG performance status score of 2, CrCl of less than 30 mL / min but greater than 15 mL / min, and grade 2 or higher hearing loss. In some embodiments, the criteria for determining cisplatin ineligibility include, or consist of, all three of the following: CrCl of less than 30 mL / min but greater than 15 mL / min, grade 2 or higher hearing loss, and NYHA class III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, subjects had not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, subjects had received neoadjuvant chemotherapy with relapse more than 12 months after completion of therapy or adjuvant chemotherapy after cystectomy. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has a hemoglobin of ≥10 g / dL, (ii) has a GFR of ≥50 mL / min, and (iii) does not have NYHA class III heart failure.

[0195] Cisplatin-eligible patients: For the methods provided herein, including but not limited to the methods described in the preceding paragraph, various conditions may be used to determine cisplatin ineligibility (e.g., cisplatin eligibility) in human subjects. In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) greater than 60 mL / min or creatinine clearance (estimated by the Cockcroft-Gault formula, dietary adjustments in renal disease [MDRD], or 24-hour urine collection). In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, hearing loss on an audiometric test of NCI CTCAE grade 1 or less. In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, the absence of NYHA grade III heart failure. In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) greater than 60 mL / min or creatinine clearance and hearing loss on an audiometric test of NCI CTCAE grade 1 or less. In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) or creatinine clearance greater than 60 mL / min and the absence of NYHA class III heart failure. In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, NCI CTCAE grade 1 or lower hearing loss on a hearing test and the absence of NYHA class III heart failure. In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) or creatinine clearance greater than 60 mL / min, NCI CTCAE grade 1 or lower hearing loss on a hearing test and the absence of NYHA class III heart failure.

[0196] In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) greater than 60 mL / min and hearing loss on an audiometric test of NCI CTCAE grade 1 or lower. In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) greater than 60 mL / min and the absence of NYHA class III heart failure. In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, hearing loss on an audiometric test of NCI CTCAE grade 1 or lower and the absence of NYHA class III heart failure. In one embodiment, the criteria for determining cisplatin eligibility include, or consist of, a glomerular filtration rate (GFR) greater than 60 mL / min, hearing loss on an audiometric test of NCI CTCAE grade 1 or lower and the absence of NYHA class III heart failure.

[0197] In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, a creatinine clearance greater than 60 mL / min and hearing loss on an audiometric test of NCI CTCAE grade 1 or lower. In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, a creatinine clearance greater than 60 mL / min and the absence of NYHA class III heart failure. In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, hearing loss on an audiometric test of NCI CTCAE grade 1 or lower and the absence of NYHA class III heart failure. In one embodiment, the conditions for determining cisplatin eligibility include, or consist of, a creatinine clearance greater than 60 mL / min, hearing loss on an audiometric test of NCI CTCAE grade 1 or lower and the absence of NYHA class III heart failure.

[0198] 5.2.1.2 Additional patient characteristics In addition, the human subjects to whom the methods provided herein may be used are human subjects having a variety of other conditions. In some embodiments, the human subjects are cisplatin-eligible or cisplatin-ineligible. In one embodiment, the human subjects to whom the methods provided herein may be used may have histologically confirmed locally advanced or metastatic urothelial (conventionally known as transitional cell) cancer (e.g., cancer of the bladder, renal pelvis, ureter, or urethra). In some embodiments, the human subjects to whom the methods provided herein may be used may be eligible for CPI therapy. In certain embodiments, the human subjects to whom the methods provided herein may be used may have a disease measurable by RECIST version 1.1. In certain embodiments, the human subjects to whom the methods provided herein may be used may have a disease measurable by RECIST version 1.1 that is outside the radiation field or has demonstrated evident progression since the completion of radiotherapy. In certain embodiments, the human subjects to whom the methods provided herein may be used may not have previously received systemic therapy for locally advanced or metastatic cancer. In yet another embodiment, the human subjects to whom the methods provided herein may be used may have an ECOG performance status score of 0. In yet another embodiment, a human subject to which the method provided herein can be used may have an ECOG performance status score of 1. In yet another embodiment, a human subject to which the method provided herein can be used may have an ECOG performance status score of 2. In yet another embodiment, a human subject to which the method provided herein can be used may have an ECOG performance status score of 1 to 2. In yet another embodiment, a human subject to which the method provided herein can be used may have an ECOG performance status score of 1 or 2. In yet another embodiment, a human subject to which the method provided herein can be used may have an ECOG performance status score of 0 to 1. In yet another embodiment, a human subject to which the method provided herein can be used may have an ECOG performance status score of 0 or 1.In yet another embodiment, a human subject to whom the method provided herein may be used may have an ECOG performance status score of 0 to 2. In yet another embodiment, a human subject to whom the method provided herein may be used may have an ECOG performance status score of 0 or 2. In yet another embodiment, a human subject to whom the method provided herein may be used may have an ECOG performance status score of 0, 1, or 2. In one embodiment, a human subject to whom the method provided herein may be used may have an expected mean life expectancy of 12 weeks or more. Some embodiments of the method provided in this paragraph may have any combination or permutation of any of the embodiments described above.

[0199] In further embodiments of the methods provided herein, including the methods described in the preceding paragraph, the human subjects to which the methods provided herein can be used are human subjects having a variety of other conditions. In some embodiments, the human subjects to which the methods provided herein can be used also have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) states of 2.5 times or less the ULN. In some embodiments, the human subjects to which the methods provided herein can be used also have treated central nervous system (CNS) metastases that have been clinically stable for at least four weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to which the methods provided herein can be used also have not undergone major surgery within four weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to whom the methods provided herein may be used also have (i) an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) state of 2.5 times or less the ULN, or (ii) a treated central nervous system (CNS) metastasis state that has been clinically stable for at least four weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to whom the methods provided herein may be used also have (i) an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) state of 2.5 times or less the ULN, or (ii) have not undergone major surgery within four weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to whom the methods provided herein may be used also (i) have a treated central nervous system (CNS) metastasis state that has been clinically stable for at least four weeks prior to administration of the ADC and anti-PD-1 antibody or its antigen-binding fragment, or (ii) have not undergone major surgery within four weeks prior to administration of the ADC and anti-PD-1 antibody or its antigen-binding fragment.In some embodiments, human subjects to whom the methods provided herein may be used also have (i) an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) state of 2.5 times or less the ULN, (ii) a treated central nervous system (CNS) metastasis state that is clinically stable for at least 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment, or (iii) not undergone major surgery within 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, human subjects to whom the methods provided herein may be used also have (i) an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) state of 2.5 times or less the ULN, and (ii) a treated central nervous system (CNS) metastasis state that is clinically stable for at least 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to whom the methods provided herein may be used also (i) have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) states of 2.5 times or less ULN, and (ii) have not undergone major surgery within 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to whom the methods provided herein may be used also (i) have a treated central nervous system (CNS) metastasis state that has been clinically stable for at least 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment, and (ii) have not undergone major surgery within 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the human subjects to whom the methods provided herein may be used also (i) have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) state of 2.5 times or less ULN, (ii) have a treated central nervous system (CNS) metastasis state that has been clinically stable for at least 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment, and (iii) have not undergone major surgery within 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment.In some embodiments, the human subjects to whom the methods provided herein may be used also (i) have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) state of 2.5 times or less ULN, (ii) have a treated central nervous system (CNS) metastasis state that has been clinically stable for at least 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment, and / or (iii) have not undergone major surgery within 4 weeks prior to administration of ADC and anti-PD-1 antibody or its antigen-binding fragment.

[0200] In further embodiments of the methods provided herein, including the methods described in the preceding paragraph, the human subjects to which the methods provided herein can be used are human subjects having a variety of other conditions. In one embodiment, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count (ANC) of 1500 / μL or higher. In some embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have a hemoglobin state of 9 g / dL or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have a hemoglobin state of 9 g / dL or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have a hemoglobin state of 5.6 mmol / L or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have a hemoglobin state of 5.6 mmol / L or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have a hemoglobin state of 9 g / dL or 5.6 mmol / L or higher. In other embodiments, the human subjects to which the methods provided herein may be used also have a total bilirubin level of 1.5 times or less above the upper limit of normal (ULN), a direct bilirubin level of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, a total bilirubin level of 3 times or less above ULN. In yet another embodiment, the human subjects to which the methods provided herein may be used also have a CrCl level of 30 mL / min or more. In yet another embodiment, the human subjects to which the methods provided herein may be used also have a GFR level of 30 mL / min or more. In yet another embodiment, the human subjects to which the methods provided herein may be used also have a CrCl level of 30 mL / min or more, where the subject has a total bilirubin level greater than 1.5 × facility ULN and / or 1.5 ULN or less.In further embodiments, the human subjects to which the methods provided herein may be used also have a GFR of 30 mL / min or higher, where the subjects have a total bilirubin level greater than 1.5 × facility ULN and / or less than or equal to 1.5 ULN. In another embodiment, the human subjects to which the methods provided herein may be used also have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of 2.5 times ULN or less. In one embodiment, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher and a platelet count of 100,000 / μL or higher. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher and a hemoglobin level of 9 g / dL or 5.6 mmol / L or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, and a total bilirubin level of 1.5 times or less than or equal to ULN, or direct bilirubin level of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, a total bilirubin level of 3 times or less than or equal to ULN. In other embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, and a CrCl or GFR level of 30 mL / min or more. In other embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, and a CrCl level of 30 mL / min or more (wherein the subjects have a total bilirubin level greater than 1.5 × institutional ULN and / or less than or equal to 1.5 ULN). In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more and ALT and AST status of 2.5 times or less the ULN. In further embodiments, the human subjects to which the methods provided herein may be used also have a platelet count of 100,000 / μL or more and a hemoglobin status of 9 g / dL or 5.6 mmol / L or more.In one embodiment, a human subject to which the method provided herein can be used also has a platelet count of 100,000 / μL or more, and a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than ULN. In some embodiments, a human subject to which the method provided herein can be used also has a platelet count of 100,000 / μL or more and a CrCl or GFR level of 30 mL / min or more. In a particular embodiment, a human subject to which the method provided herein can be used also has a platelet count of 100,000 / μL or more, and ALT and AST levels of 2.5 times or less than ULN. In other embodiments, the human subjects to which the methods provided herein can be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, and either total bilirubin levels of 1.5 times or less than ULN, or direct bilirubin levels of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of Gilbert's disease patients, total bilirubin levels of 3 times or less than ULN. In yet another embodiment, the human subjects to which the methods provided herein can be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher and CrCl or GFR levels of 30 mL / min or higher. In some embodiments, the human subjects to which the methods provided herein can be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, and ALT and AST levels of 2.5 times or less than ULN. In one embodiment, a human subject to which the method provided herein may be used also has a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than ULN, and a CrCl level of 30 mL / min or more.In another embodiment, a human subject to which the methods provided herein may be used also has a total bilirubin level of 1.5 times or less than or equal to the ULN, or direct bilirubin level of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than or equal to the ULN, as well as ALT and AST levels of 2.5 times or less than or equal to the ULN. In yet another embodiment, a human subject to which the methods provided herein may be used also has a CrCl or GFR of 30 mL / min or more, as well as ALT and AST levels of 2.5 times or less than or equal to the ULN. In yet another embodiment, a human subject to which the methods provided herein may be used also has an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a hemoglobin level of 9 g / dL or 5.6 mmol / L or more. In further embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a total bilirubin level of 1.5 times or less than or equal to ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than or equal to ULN. In further embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a CrCl or GFR level of 30 mL / min or more. In some embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater, a hemoglobin level of 9 g / dL or 5.6 mmol / L or greater, and a total bilirubin level not exceeding 1.5 times the ULN or, in the case of patients with Gilbert's disease, 3 times the ULN.In certain embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or higher, hemoglobin of 9 g / dL or 5.6 mmol / L or higher, and a CrCl or GFR of 30 mL / min or higher. In some embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or higher, hemoglobin of 9 g / dL or 5.6 mmol / L or higher, and ALT and AST levels of 2.5 times or less than ULN. In yet other embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or higher, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 3 times or less than ULN in the case of patients with Gilbert's disease, and a CrCl or GFR of 30 mL / min or higher. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, total bilirubin of 1.5 times or less than or equal to ULN, or direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, CrCl or GFR of 30 mL / min or more, as well as ALT and AST states of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than ULN.In certain embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a CrCl or GFR state of 30 mL / min or more. In some embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and ALT and AST states of 2.5 times or less the ULN. In other embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less the ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 30 mL / min or less in the case of a patient with Gilbert's disease, and a CrCl or GFR state of 30 mL / min or more. In further embodiments, the human subjects to which the methods provided herein may be used also have a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times ULN or less, or direct bilirubin of ULN or less (wherein the human subjects are 1.5 × ULN). In some embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, a CrCl or GFR of 30 mL / min or more, and an ALT and AST of 2.5 mL / min or less, as well as a total bilirubin level greater than 1.5 × ULN (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or a total bilirubin level of 30 mL / min or less, as well as an ALT and AST level of 2.5 mL / min or less. In yet other embodiments, the human subjects to which the methods provided herein can be used also have a hemoglobin level of 9 g / dL or 5.6 mmol / L or more, a total bilirubin level of 1.5 mL / min or less, or a direct bilirubin level of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or a total bilirubin level of 30 mL / min or less, as well as a CrCl or GFR of 30 mL / min or more. In other embodiments, the human subjects to whom the methods provided herein may be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, total bilirubin levels of 1.5 times or less than or equal to ULN, direct bilirubin levels of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin levels of 3 times or less than ULN, as well as ALT and AST levels of 2.5 times or less than ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, CrCl or GFR of 30 mL / min or higher, and ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, a total bilirubin level of 3 times or less than ULN, a CrCl or GFR of 30 mL / min or more, and ALT and AST levels of 2.5 times or less than ULN.In other embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a total bilirubin of 1.5 times ULN or less, or direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times ULN or less. In further embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a CrCl or GFR of 30 mL / min or more. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and ALT and AST levels of 2.5 times or less of ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a total bilirubin level of 1.5 times or less of ULN, or direct bilirubin level of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less of ULN, and a CrCl or GFR level of 30 mL / min or more. In some embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST levels of 2.5 times or less than ULN.In some embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, a platelet count of 100,000 / μL or higher, a CrCl or GFR of 30 mL / min or higher, and ALT and AST levels of 2.5 times or less than or equal to ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, a hemoglobin of 9 g / dL or 5.6 mmol / L or higher, a total bilirubin level of 1.5 times or less than or equal to ULN, or direct bilirubin level of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 30 mL / min or less, and a CrCl or GFR level of 30 mL / min or higher. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, hemoglobin of 9 g / dL or 5.6 mmol / L or higher, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, hemoglobin of 9 g / dL or 5.6 mmol / L or higher, CrCl or GFR of 30 mL / min or higher, as well as ALT and AST states of 2.5 times or less than ULN. In further embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than or equal to ULN, CrCl or GFR of 30 mL / min or more, and ALT and AST levels of 2.5 times or less than or equal to ULN.In further embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times ULN or less, and a CrCl or GFR of 30 mL / min or more. In some embodiments, the human subjects to which the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In further embodiments, the human subjects to which the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, CrCl or GFR of 30 mL / min or more, as well as ALT and AST states of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less than ULN, direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, CrCl or GFR of 30 mL / min or more, and ALT and AST conditions of 2.5 times or less than ULN.In some embodiments, the human subjects to whom the methods provided herein may be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, total bilirubin levels of 1.5 times or less than ULN, direct bilirubin levels of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin levels of 3 times or less than ULN, CrCl or GFR of 30 mL / min or higher, and ALT and AST levels of 2.5 times or less than ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, a total bilirubin of 1.5 times or less than or equal to the ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times or less than or equal to the ULN, and a CrCl or GFR of 30 mL / min or more. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, a platelet count of 100,000 / μL or higher, a hemoglobin of 9 g / dL or 5.6 mmol / L or higher, a total bilirubin level of 1.5 times ULN or less, or a direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level of 1.5 × ULN or less), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times ULN or less, as well as ALT and AST levels of 2.5 times ULN or less. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, a platelet count of 100,000 / μL or higher, a hemoglobin level of 9 g / dL or 5.6 mmol / L or higher, a CrCl or GFR of 30 mL / min or higher, as well as ALT and AST levels of 2.5 times ULN or less.In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times ULN or less, CrCl or GFR of 30 mL / min or more, and ALT and AST levels of 2.5 times ULN or less. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, CrCl or GFR of 30 mL / min or more, and ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times ULN or less, CrCl or GFR of 30 mL / min or more, and ALT and AST states of 2.5 times ULN or less. In some embodiments, the human subjects to whom the methods provided herein may be used also have 15. The patient has an absolute neutrophil count of 00 / μL or higher, a platelet count of 100,000 / μL or higher, a hemoglobin of 9 g / dL or 5.6 mmol / L or higher, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (wherein human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of Gilbert's disease patients, total bilirubin of 3 times or less than ULN, CrCl or GFR of 30 mL / min or higher, and ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, a total bilirubin of 1.5 times or less than or equal to ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times or less than or equal to ULN, a CrCl or GFR of 30 mL / min or more, and one of the following conditions: ALT and AST of 2.5 times or less than or equal to ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have, in any combination or permutation, an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, a total bilirubin of 1.5 times or less than or equal to ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 30 mL / min or more, and any two of the following states of ALT and AST of 2.5 times or less than or equal to ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have, in any combination or permutation, any three of the following conditions: an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less the ULN or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less the ULN, CrCl or GFR of 30 mL / min or more, and any three of the ALT and AST of 2.5 times or less the ULN.In some embodiments, the human subjects to which the methods provided herein may be used also have, in any combination or permutation, any four of the following conditions: an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level of 1.5 × ULN or less), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times or less than or equal to ULN, CrCl or GFR of 30 mL / min or more, and any four of the following conditions of ALT and AST of 2.5 times or less than or equal to ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have, in any combination or permutation, any five of the following conditions: absolute neutrophil count of 1500 / μL or more, platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level of 1.5 × ULN or less), or total bilirubin of 3 times or less than or equal to ULN in the case of patients with Gilbert's disease, CrCl or GFR of 30 mL / min or more, and any five of the following conditions of ALT and AST of 2.5 times or less than or equal to ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 3 times ULN or less in the case of a patient with Gilbert's disease, CrCl or GFR of 30 mL / min or more, and all six of the following states of ALT and AST of 2.5 times ULN or less.

[0201] In yet another embodiment, a human subject to which the methods provided herein may be used also has a CrCl state greater than 60 mL / min, where the subject has a total bilirubin level greater than 1.5 × facility ULN and / or 1.5 ULN or less. In yet another embodiment, a human subject to which the methods provided herein may be used also has a GFR state greater than 60 mL / min, where the subject has a total bilirubin level greater than 1.5 × facility ULN and / or 1.5 ULN or less. In yet another embodiment, a human subject to which the methods provided herein may be used also has alanine aminotransferase (ALT) and aspartate aminotransferase (AST) states of 2.5 times ULN or less. In one embodiment, a human subject to which the methods provided herein may be used also has an absolute neutrophil count of 1500 / μL or more and a platelet count of 100,000 / μL or more. In some embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or higher and a hemoglobin state of 9 g / dL or 5.6 mmol / L or higher. In certain embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or higher and a total bilirubin state of 1.5 times or less than ULN, or direct bilirubin less than or equal to ULN (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, a total bilirubin state of 3 times or less than ULN. In other embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or higher and a CrCl or GFR state greater than 60 mL / min. In other embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more and a CrCl level greater than 60 mL / min (where the subject has a total bilirubin level greater than 1.5 × facility ULN and / or less than or equal to 1.5 ULN). In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more and ALT and AST levels of 2.5 times ULN or less.In further embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more and a hemoglobin state of 9 g / dL or 5.6 mmol / L or more. In one embodiment, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more and a total bilirubin state of 1.5 times or less the ULN, or direct bilirubin less than or equal to the ULN (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin state of 3 times or less the ULN. In some embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more and a CrCl or GFR state greater than 60 mL / min. In a particular embodiment, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more and ALT and AST states of 2.5 times or less the ULN. In other embodiments, the human subjects to which the methods provided herein can be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, and either total bilirubin levels of 1.5 times or less than ULN, or direct bilirubin levels of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin levels of 3 times or less than ULN. In yet another embodiment, the human subjects to which the methods provided herein can be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher and CrCl or GFR levels greater than 60 mL / min. In some embodiments, the human subjects to which the methods provided herein can be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, and ALT and AST levels of 2.5 times or less than ULN. In one embodiment, a human subject to which the method provided herein may be used also has a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than ULN, and a CrCl level greater than 60 mL / min.In another embodiment, a human subject to which the methods provided herein may be used also has a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than ULN, as well as ALT and AST levels of 2.5 times or less than ULN. In yet another embodiment, a human subject to which the methods provided herein may be used also has a CrCl or GFR greater than 60 mL / min, as well as ALT and AST levels of 2.5 times or less than ULN. In yet another embodiment, a human subject to which the methods provided herein may be used also has an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a hemoglobin level of 9 g / dL or 5.6 mmol / L or more. In further embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a total bilirubin level of 1.5 times or less than or equal to ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than or equal to ULN. In further embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a CrCl or GFR level greater than 60 mL / min. In some embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and ALT and AST levels of 2.5 times or less than or equal to ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater, a hemoglobin level of 9 g / dL or 5.6 mmol / L or greater, and a total bilirubin level not exceeding 1.5 times the ULN or, in the case of patients with Gilbert's disease, 3 times the ULN.In certain embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a CrCl or GFR of greater than 60 mL / min. In some embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, and ALT and AST of 2.5 times or less the ULN. In yet other embodiments, the human subjects to which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or more, total bilirubin of 1.5 times or less the ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 3 times or less the ULN in the case of patients with Gilbert's disease, and a CrCl or GFR of greater than 60 mL / min. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, total bilirubin of 1.5 times or less than or equal to ULN, or direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a total bilirubin level of 1.5 times or less than ULN, or direct bilirubin level of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin level of 3 times or less than ULN.In certain embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a CrCl or GFR of greater than 60 mL / min. In some embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, and ALT and AST of 2.5 times or less the ULN. In other embodiments, the human subjects to which the methods provided herein can be used also have a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less the ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 3 times or less the ULN in the case of Gilbert's disease patients, and a CrCl or GFR of greater than 60 mL / min. In further embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, CrCl or GFR greater than 60 mL / min, and ALT and AST states of 2.5 times or less than ULN. In further embodiments, the human subjects to whom the methods provided herein may be used also have a hemoglobin of 9 g / dL or 5.6 mmol / L or higher, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times or less than ULN, and a CrCl or GFR greater than 60 mL / min.In other embodiments, the human subjects to whom the methods provided herein may be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, total bilirubin levels of 1.5 times or less than ULN, direct bilirubin levels of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin levels of 3 times or less than ULN, as well as ALT and AST levels of 2.5 times or less than ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times or less than ULN. In some embodiments, the methods provided herein may be used on human subjects who have either total bilirubin of 1.5 times or less ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 3 times or less ULN in the case of patients with Gilbert's disease, with CrCl or GF greater than 60 mL / min. In other embodiments, the human subject to which the methods provided herein may be used also has an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a total bilirubin of 1.5 times the ULN or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times the ULN. In further embodiments, the human subject to which the methods provided herein may be used also has an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and a CrCl or GFR of greater than 60 mL / min. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, and ALT and AST states of 2.5 times or less the ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a total bilirubin of 1.5 times or less the ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times or less the ULN, and a CrCl or GFR state greater than 60 mL / min. In some embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST levels of 2.5 times or less than ULN.In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a CrCl or GFR greater than 60 mL / min, and ALT and AST status of 2.5 times or less of ULN. In certain embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, a total bilirubin of 1.5 times or less of ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times or less of ULN, and a CrCl or GFR greater than 60 mL / min. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, hemoglobin of 9 g / dL or 5.6 mmol / L or higher, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or higher, hemoglobin of 9 g / dL or 5.6 mmol / L or higher, CrCl or GFR greater than 60 mL / min, as well as ALT and AST states of 2.5 times or less than ULN. In further embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, total bilirubin of 1.5 times or less than ULN, direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times or less than ULN.In further embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times ULN or less, and a CrCl or GFR of 60 mL / min or more. In some embodiments, the human subjects to which the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In further embodiments, the human subjects to which the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, CrCl or GFR greater than 60 mL / min, as well as ALT and AST states of 2.5 times or less than ULN. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times or less than or equal to ULN, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times or less than or equal to ULN.In some embodiments, the human subjects to whom the methods provided herein may be used also have hemoglobin levels of 9 g / dL or 5.6 mmol / L or higher, total bilirubin levels of 1.5 times or less than ULN, direct bilirubin levels of ULN or less (wherein the human subjects have a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin levels of 3 times or less than ULN, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times or less than ULN. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times ULN or less, and a CrCl or GFR of 60 mL / min or more. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than ULN, or direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times or less than ULN, as well as ALT and AST states of 2.5 times or less than ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, CrCl or GFR greater than 60 mL / min, as well as ALT and AST states of 2.5 times or less than ULN.In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times ULN or less, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times ULN or less. In certain embodiments, the human subjects to whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times ULN or less, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times ULN or less. In some embodiments, the human subjects to whom the methods provided herein may be used also have a platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of patients with Gilbert's disease, total bilirubin of 3 times ULN or less, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times ULN or less. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times or less than or equal to ULN, CrCl or GFR greater than 60 mL / min, and ALT and AST levels of 2.5 times or less than or equal to ULN.In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, a total bilirubin of 1.5 times or less than or equal to the ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times or less than or equal to the ULN, a CrCl or GFR greater than 60 mL / min, and one of the following conditions: ALT and AST of 2.5 times or less than or equal to the ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have, in any combination or permutation, an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, a total bilirubin of 1.5 times or less than or equal to ULN, or direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, a total bilirubin of 3 times or less than or equal to ULN, a CrCl or GFR greater than 60 mL / min, and any two of the following states of ALT and AST of 2.5 times or less than or equal to ULN. In some embodiments, the methods provided herein may be used in human subjects with an absolute neutrophil count of 1500 / μL or higher, a platelet count of 100,000 / μL or higher, a hemoglobin of 9 g / dL or 5.6 mmol / L or higher, a total bilirubin of 1.5 times the ULN or lower, or in patients with Gilbert's disease. The subject has any combination or permutation of three of the following conditions: total bilirubin up to 3 times the ULN, CrCl or GFR greater than 60 mL / min, and ALT and AST up to 2.5 times the ULN. In some embodiments, the human subject to which the methods provided herein may be used also has any combination or permutation of four of the following conditions: absolute neutrophil count of 1500 / μL or more, platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin up to 1.5 times the ULN, direct bilirubin below the ULN (where the human subject has a total bilirubin level of 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin up to 3 times the ULN, CrCl or GFR greater than 60 mL / min, and ALT and AST up to 2.5 times the ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have, in any combination or permutation, any five of the following conditions: absolute neutrophil count of 1500 / μL or more, platelet count of 100,000 / μL or more, hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times or less than or equal to ULN, direct bilirubin of ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 × ULN), or total bilirubin of 3 times or less than or equal to ULN in patients with Gilbert's disease, CrCl or GFR greater than 60 mL / min, and any five of the following conditions of ALT and AST of 2.5 times or less than or equal to ULN. In some embodiments, the human subjects to which the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, a hemoglobin of 9 g / dL or 5.6 mmol / L or more, total bilirubin of 1.5 times ULN or less, direct bilirubin of ULN or less (where the human subject has a total bilirubin level greater than 1.5 × ULN), or, in the case of a patient with Gilbert's disease, total bilirubin of 3 times ULN or less, CrCl or GFR greater than 60 mL / min, and all six of the following states of ALT and AST of 2.5 times ULN or less.

[0202] In certain embodiments, including any of the embodiments disclosed herein, such as any of the above embodiments, a human subject to whom the methods provided herein may be used may have treated central nervous system (CNS) metastases that are clinically stable for at least 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof. In certain embodiments, the human subject (1) may have treated central nervous system (CNS) metastases that are clinically stable for at least 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof, and (2) has an ALT and AST level of no more than 2.5 times the ULN. In certain embodiments, the human subject (1) may have treated central nervous system (CNS) metastases that are clinically stable for at least 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof, (2) has an ALT and AST level of no more than 2.5 times the ULN, and (3) has not undergone major surgery within 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0203] In certain embodiments, including any of the embodiments disclosed herein, such as any of the above embodiments, a human subject to whom the methods provided herein may be used is not permitted to have undergone major surgery within 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof. In certain embodiments, the human subject (1) may have treated central nervous system (CNS) metastases that are clinically stable for at least 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof, and (2) is not permitted to have undergone major surgery within 4 weeks prior to administration of the ADC and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0204] In certain embodiments, a human subject to whom the methods provided herein may be used may have previously been treated for prostate cancer surgically or by radiotherapy at least one year prior to treatment by any of the methods provided herein, wherein the subject does not have prostate cancer and (i) if has undergone or received radical prostatectomy, has had undetectable PSA for more than one year prior to treatment by any of the methods provided herein, and (ii) if received radiotherapy, has a PSA doubling time of more than one year (based on at least three values ​​determined at intervals of more than one month) and a total PSA value that does not meet the Phoenix criteria for biochemical recurrence (e.g., increase from the lowest point less than 2.0 ng / mL). In certain embodiments, a human subject to whom the methods provided herein are applied may have untreated low-risk prostate cancer, wherein the subject has a Gleason score of 6 or less and is under active surveillance for having a PSA doubling time of more than one year (based on at least three values ​​determined at intervals of more than one month).

[0205] In other embodiments of the methods provided herein, including the methods described in the preceding paragraph, the human subjects to whom the methods provided herein may be used are human subjects that are not in any particular condition. In one embodiment, the human subjects to whom the methods provided herein are applied have never previously received any treatment with a CPI. A CPI is defined as a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subjects to whom the methods provided herein are applied have never been administered a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor. In certain embodiments, the human subjects to whom the methods provided herein may be used have never been administered any of atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subjects treated by the methods provided herein have never previously received treatment including or consisting of a PD-(L)-1 inhibitor. A PD-(L)-1 inhibitor is either a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-(L)-1 inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the PD-(L)-1 inhibitor is either a PD-1 inhibitor or a PD-L1 inhibitor. In certain embodiments, the PD-(L)-1 inhibitor is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subjects to whom the methods provided herein may be used have not previously received any treatment with any agents targeting another stimulating or co-inhibitory T cell receptor (including, but not limited to, CD137 agonists, CTLA4 inhibitors, or OX-40 agonists). In certain embodiments, the human subjects to whom the methods provided herein may be used have not previously received any treatment with any CD137 agonists, CTLA4 inhibitors, or OX-40 agonists.In certain embodiments, the human subject is receiving anticancer treatment with chemotherapy, biologics, or investigational drugs, and the human subject has completed anticancer treatment at least four weeks prior to receiving the first dose of an antibody-drug conjugate (ADC) conjugating to 191P4D12 in combination with an anti-PD-1 antibody (e.g., pembrolizumab). In one embodiment, the human subject to whom the method provided herein may be used may have grade 2 or lower sensory or motor neuropathy. In one embodiment, the human subject to whom the method provided herein is applied may not have active metastases in the central nervous system. In one embodiment, the human subject to whom the method provided herein is applied may not have poorly controlled diabetes. In one embodiment, the human subject to whom the method provided herein is applied may have grade 2 or lower sensory or motor neuropathy and may not have active metastases in the central nervous system. In some embodiments, the human subject to whom the method provided herein is applied may have grade 2 or lower sensory or motor neuropathy and may not have poorly controlled diabetes. In further embodiments, human subjects to whom the methods provided herein are applied may have grade 2 or less sensory neuropathy or motor neuropathy, and may not have active central nervous system metastasis or poorly controlled diabetes. In some embodiments, human subjects to whom the methods provided herein are applied may have any one of the following: grade 2 or less sensory neuropathy or motor neuropathy, active central nervous system metastasis, or poorly controlled diabetes. In some embodiments, human subjects to whom the methods provided herein are applied may have any two of the following in any combination or permutation: grade 2 or less sensory neuropathy or motor neuropathy, active central nervous system metastasis, or poorly controlled diabetes. In some embodiments, human subjects to whom the methods provided herein are applied may have all three of the following: grade 2 or less sensory neuropathy or motor neuropathy, active central nervous system metastasis, or poorly controlled diabetes.In one embodiment of the method provided in this paragraph, poorly controlled diabetes is determined by a hemoglobin A1c (HbA1c) of 8% or higher. In some embodiments of the method provided in this paragraph, poorly controlled diabetes is determined by an HbA1c of 7-8% in conjunction with associated diabetic symptoms that cannot be explained by anything other than diabetes. In a further embodiment of the method provided in this paragraph, associated diabetic symptoms include or consist of polyuria. In some other embodiments of the method provided in this paragraph, associated diabetic symptoms include or consist of polydipsia. In yet another embodiment of the method provided in this paragraph, associated diabetic symptoms include or consist of both polyuria and polydipsia.

[0206] In certain embodiments, the human subjects to whom the method provided herein may be used do not have any persistent clinically significant toxicity associated with prior treatment that has not decreased to grade 1 or less or returned to baseline. In certain embodiments, the human subjects to whom the method provided herein may be used do not have any persistent clinically significant toxicity associated with prior treatment that has not decreased to grade 1 or less or returned to baseline, where prior treatment is radiotherapy or surgery. In certain embodiments, prior treatment is radiotherapy. In certain embodiments, prior treatment is surgery. In one embodiment, the human subjects to whom the method provided herein may be used do not have a condition requiring high doses of steroids (e.g., more than 10 mg / day of prednisone or an equivalent) or other immunosuppressants. In one embodiment, the human subjects to whom the method provided herein may be used do not have a condition requiring high doses of steroids or other immunosuppressants, where steroids or other immunosuppressants are neither inhaled steroids nor topical steroids. In certain embodiments, the human subjects to whom the method provided herein may be used do not have a history of another invasive malignancy within three years prior to treatment with the method provided herein. In certain embodiments, the human subjects to whom the methods provided herein may be used are free from evidence of residual disease of a previously diagnosed malignant tumor. In certain embodiments, the human subjects to whom the methods provided herein may be used are free from systemic antibiotic treatment for an active infection, which can be a viral, bacterial, or fungal infection. In certain embodiments, the human subjects to whom the methods provided herein may be used are free from active hepatitis B, which is HBsAg-responsive. In certain embodiments, the human subjects to whom the methods provided herein may be used are free from active hepatitis C infection and a history of human immunodeficiency virus (HIV) infection. In certain embodiments, the human subjects to whom the methods provided herein may be used are free from active tuberculosis.In certain embodiments, human subjects to whom the methods provided herein may be used shall have no recorded medical history of cerebrovascular events (e.g., stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac conditions equivalent to NYHA class IV. In certain embodiments, human subjects to whom the methods provided herein may be used shall have not undergone radiotherapy within two weeks prior to treatment with the methods provided herein, nor have undergone major surgery within four weeks prior to treatment with the methods provided herein. In certain embodiments, human subjects to whom the methods provided herein may be used shall have not undergone chemotherapy, biologics, or investigational drug treatments that were not completed four weeks prior to treatment with the methods provided herein. In certain embodiments, human subjects to whom the methods provided herein may be applied may not have known severe (grade 3 or higher) hypersensitivity to enfortumab vedotin or any excipients contained in enfortumab vedotin drug formulations (including histidine, trehalose dihydrate, and polysorbate 20). In certain embodiments, the human subjects to whom the methods provided herein may be used are not known to have severe (grade 3 or higher) hypersensitivity to pembrolizumab or any excipients contained in pembrolizumab drug formulations. In certain embodiments, the human subjects to whom the methods provided herein may be used are not known to have severe (grade 3 or higher) hypersensitivity to gemcitabine. In certain embodiments, the human subjects to whom the methods provided herein may be used are not having active keratitis or corneal ulcers. In certain embodiments, the human subjects to whom the methods provided herein may be applied may not have had an active autoimmune disease requiring systemic treatment (e.g., the use of disease modifiers, corticosteroids, or immunosuppressants) in the past two years. In certain embodiments, the human subjects to whom the methods provided herein may not have had an active autoimmune disease requiring systemic treatment (e.g., the use of disease modifiers, corticosteroids, or immunosuppressants) in the past two years.In some embodiments, the systemic treatment is not replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary dysfunction). In some embodiments, the systemic treatment is not thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary dysfunction. In some embodiments, the systemic treatment is not a corticosteroid administered for less than 7 days. In some embodiments, the human subject has vitiligo, psoriasis, type 1 diabetes, hypothyroidism, or cleared childhood asthma / atopic dermatitis. In some embodiments, the systemic treatment is not a bronchodilator, inhaled corticosteroid, or topical corticosteroid administered by injection. In some embodiments, the human subject has hypothyroidism, which is stabilized by hormone replacement therapy. In some embodiments, the human subject has Sjögren's syndrome. In certain embodiments, the human subjects to whom the methods provided herein may be used shall not have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis by screening chest CT scans. In certain embodiments, the human subjects to whom the methods provided herein may be applied may not have previously undergone allogeneic stem cell transplantation or solid organ transplantation. In certain embodiments, the human subjects to whom the methods provided herein may be used shall not be found to have received an attenuated live vaccine within 30 days prior to treatment by the methods provided herein. In certain embodiments, the live vaccine may be a measles vaccine, mumps vaccine, rubella vaccine, varicella / zoster (chickenpox) vaccine, yellow fever vaccine, rabies vaccine, Calmette-Guérins bacillus (BCG) vaccine, or typhoid vaccine. In certain embodiments, the attenuated live vaccine may be a nasal influenza vaccine. In certain embodiments, the human subjects to whom the methods provided herein are applied may not have any underlying medical conditions that would impair their ability to receive or tolerate the methods provided herein.

[0207] In some embodiments of the methods provided herein, CrCl is measured by a 24-hour urine collection. In other embodiments of the methods provided herein, CrCl is estimated by the Cockcroft-Gault criterion.

[0208] In some embodiments of the methods provided herein, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided herein, GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by dietary adjustments in renal disease [MDRD].

[0209] In some embodiments of the methods provided herein, the subject is treated with one or more other cancer treatments. In certain embodiments of the methods provided herein, urothelial carcinoma, including locally advanced or metastatic urothelial carcinoma, is treated with one or more other cancer treatments.

[0210] In some embodiments, the CPI described herein may include, or consist of, any CPI as described in this section (Section 5.2.1).

[0211] In all methods provided herein, particularly those described in the preceding paragraph: ADCs that may be used are described in sections 3, 5.2, 5.3, 5.4, 5.5, and 6; patient selection for therapeutic purposes is described herein and exemplified in this section (section 5.2) and sections 3 and 6; dosing regimens and pharmaceutical compositions for administering therapeutic agents are described in this section (section 5.2), and subsequent sections 5.4, 5.6, 5.7, and 6; and biomarkers that may be used to identify therapeutic agents, to select patients, to determine the results of these methods and / or to serve as any criteria for these methods are described herein. As illustrated in this section (Section 5.2, including 5.2.1 and 5.2.2) and Section 6, biomarkers can be determined as described in Section 5.9 or as known in the art, the therapeutic outcomes of the methods provided herein are described in this section (Section 5.2, including 5.2.1.4) and Sections 3 and 6, and additional therapeutic outcomes of the methods provided herein may be improvements in biomarkers described herein, such as those described and illustrated in this section (Section 5.2, including 5.2.2) and Sections 3 and 6, and combination therapies including ADCs and other therapeutic agents are described in this section (Section 5.2) and Sections 5.5. Accordingly, those skilled in the art will understand that the methods provided herein include all permutations and combinations of patients, therapeutic agents, drug regimens, biomarkers, and therapeutic outcomes as described above and below.

[0212] In certain embodiments, the methods provided herein are used to treat subjects having urothelial carcinoma expressing 191P4D12 RNA, 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein.

[0213] In certain embodiments, the methods provided herein are used to treat subjects having locally advanced urothelial carcinoma expressing 191P4D12 RNA, 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat subjects having locally advanced urothelial carcinoma expressing 191P4D12 RNA, 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein, who have been previously treated with a CPI or PD-(L)-1 inhibitor.

[0214] In certain embodiments, the methods provided herein are used to treat subjects having metastatic cancer expressing 191P4D12 RNA, 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat subjects having metastatic urothelial carcinoma expressing 191P4D12 RNA, 191P4D12 protein, or both 191P4D12 RNA and 191P4D12 protein.

[0215] In some embodiments, 191P4D12 RNA expression in cancer is determined by polynucleotide hybridization, sequencing (assessment of relative abundance of sequences), 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 two or more methods. In some embodiments, 191P4D12 protein expression in cancer is determined by two methods of IHC.

[0216] 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.

[0217] In some embodiments, the subject has visceral metastases. In some embodiments, the subject has disease affecting only the lymph nodes. In some embodiments, the site of disease is the upper urinary tract. In some embodiments, the site of disease is the lower urinary tract.

[0218] In some embodiments, subjects have a combined PD-L1 expression positivity score (CPS) of 10 or more. PD-L1 protein expression is determined using a combined positivity score (CPS) obtained by dividing the number of PD-L1-positive cells (i.e., tumor cells, lymphocytes, and macrophages) by the total number of surviving tumor cells and then multiplying by 100. In some embodiments, subjects have a PD-L1 expression CPS of less than 10. The Nectin H score ranges from 0 to 300 based on the following calculation: H score = [(0 × negative cells%) + (1 × weakly positive cells%) + (2 × moderately positive cells%) + (3 × strongly positive cells%)]. Urothelial carcinoma generally has a median H score of 260 to 270. In some embodiments, subjects have an H score of 0 to 300 for Nectin-4. In some embodiments, subjects have an H score of 0 to 250, 0 to 200, 0 to 150, 0 to 100, or 0 to 50 for Nectin-4. In some embodiments, the subject has an H score of 0 to 200 for nectin-4. In some embodiments, the subject has an H score of 0 to 150 for nectin-4. In some embodiments, the method does not involve determining the subject's PD-L1 expression or the subject's nectin-4 expression. In some embodiments, the method does not involve determining the subject's PD-L1 expression or the subject's nectin-4 expression before treating the subject with an ADC. In some embodiments, the method does not involve determining the subject's PD-L1 expression. In some embodiments, the method does not involve determining the subject's PD-L1 expression before treating the subject with an ADC. In some embodiments, the method does not involve determining the subject's nectin-4 expression. In some embodiments, the method does not involve determining the subject's nectin-4 expression before treating the subject with an ADC.

[0219] 5.2.1.3 Combination therapy with checkpoint inhibitors and pembrolizumab Checkpoint inhibitors

[0220] In some embodiments, subjects that can be treated by the methods provided herein have certain phenotypic or genotypic characteristics. In some embodiments, subjects have any permutations or combinations of the phenotypic or genotypic characteristics described herein.

[0221] 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 carried out based on the most recently analyzed tissue, as described in the American Society of Clinical Oncology / College of American Pathologists (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.

[0222] In various aspects or embodiments of the methods provided herein, including the methods provided in this section (Section 5.2), such as the methods provided in this paragraph and the preceding paragraph, the human subjects to whom the methods provided herein have not previously received any treatment with CPIs. CPIs are defined as PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subjects to whom the methods provided herein may be used have not previously received treatment with PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors. In certain embodiments, the human subjects to whom the methods provided herein may be used have not previously received treatment with atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab.

[0223] In various aspects or embodiments of the methods provided herein, including the methods provided in this section (Section 5.2), such as the methods provided in this paragraph and the preceding paragraph, the human subjects to whom the methods provided herein are provided have not previously received any treatment with PD-(L)-1 inhibitors. PD-(L)-1 inhibitors are defined as PD-1 inhibitors or PD-L1 inhibitors (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). Therefore, PD-(L)-1 inhibitors include CPI inhibitors that are PD-1 inhibitors or PD-L1 inhibitors. In some embodiments, the human subjects to whom the methods provided herein are used have not previously received treatment with PD-1 inhibitors or PD-L1 inhibitors. In certain embodiments, the human subjects to whom the methods provided herein are used have not previously received treatment with atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab.

[0224] As used herein, the terms “immune checkpoint inhibitor” or “checkpoint inhibitor” (CPI) refer to molecules that reduce, inhibit, interfere with, or modulate one or more checkpoint proteins, either entirely or partially. Many checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 and its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). Other exemplary checkpoint proteins include LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. These proteins appear to be involved in costimulatory or inhibitory interactions of the T cell response. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and magnitude of physiological immune responses. Immune checkpoint inhibitors contain or are derived from antibodies.

[0225] In certain embodiments, the checkpoint inhibitor for the methods provided herein may be an inhibitor or activator of checkpoint proteins that are upregulated in cancer. In some specific embodiments, the checkpoint inhibitor for the methods provided herein may be an inhibitor or activator of checkpoint proteins, including LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. In some embodiments, the checkpoint inhibitor for the methods provided herein may be an inhibitor or activator selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, B7 inhibitors, TIM3 (HAVCR2) inhibitors, OX40 (CD134) inhibitors, GITR agonists, CD137 agonists, or CD40 agonists, VTCN1 inhibitors, IDO1 inhibitors, CD276 inhibitors, PVRIG inhibitors, TIGIT inhibitors, CD25 (IL2RA) inhibitors, IFNAR2 inhibitors, IFNAR1 inhibitors, CSF1R inhibitors, VSIR (VISTA) inhibitors, or HLA-targeted therapeutic agents. Such inhibitors, activators, or therapeutic agents are further described below.

[0226] In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of CTLA-4 antibodies include, but are not limited to, those described in U.S. Patents 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; ​​6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein by reference in their entirety. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as tisilimumb or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the trade name Yervoy®.

[0227] In certain embodiments, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of PD-1 / 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 Patent Application Publications WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, all of which are incorporated herein by reference in their entirety.

[0228] A "PD-1 antagonist" refers to any chemical compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or natural killer T cells), and in specific embodiments, also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any of the therapeutic methods, pharmaceuticals, and uses of the present invention in which a human individual is treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and in specific embodiments, blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 can be found at NCBI locus number: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found at NCBI locus numbers: NP_054862 and NP_079515, respectively.

[0229] In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist. In one embodiment, the PD-1 inhibitor or antagonist 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, SCH900475, 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. CT-011 administered alone failed to elicit a response in the treatment of relapsed acute myeloid leukemia (AML). 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 specifically designed for binding to Fc gamma receptor I, possessing a unique binding signature to PD-1 with high affinity and excellent target specificity. In one embodiment, the PD-1 antibody is cemiplimab. In another embodiment, the PD-1 antibody is camrelizumab. In yet another embodiment, the PD-1 antibody is cintilimab. In some embodiments, the PD-1 antibody is tislerizumab. In certain embodiments, the PD-1 antibody is TSR-042. In yet another embodiment, the PD-1 antibody is PDR001. In yet another embodiment, the PD-1 antibody is tripalimab.

[0230] In certain embodiments, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). 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®). In yet another embodiment, the PD-L1 inhibitor is avelumab.

[0231] In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD-L2 antibody is rHIgM12B7A.

[0232] In one embodiment, the checkpoint inhibitor is a lymphocyte-activating gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is the soluble Ig fusion protein IMP321 (Brignone et al., J.Immunol., 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

[0233] In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).

[0234] In one embodiment, the checkpoint inhibitor is a TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J.Exp.Med., 2010, 207, 2175-86, Sakuishi et al., J.Exp.Med., 2010, 207, 2187-94).

[0235] In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In another embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In yet another embodiment, the anti-OX40 antibody is anti-OX-40.

[0236] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti-GITR antibody is TRX518.

[0237] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In another embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In yet another embodiment, the anti-CD137 antibody is urelumab.

[0238] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.

[0239] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

[0240] In one embodiment, the checkpoint inhibitor is a VTCN inhibitor. In one embodiment, the VTCN inhibitor is FPA150.

[0241] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod. In one embodiment, the IDO inhibitor is epacadostat. In another embodiment, the IDO inhibitor is BMS986205. In yet another embodiment, the IDO inhibitor is navoximod. In one embodiment, the IDO inhibitor is PF-06840003. In another embodiment, the IDO inhibitor is KHK2455. In yet another embodiment, the IDO inhibitor is RG70099. In one embodiment, the IDO inhibitor is IOM-E. In another embodiment, the IDO inhibitor is IOM-D.

[0242] In some embodiments, the checkpoint inhibitor is a TIGIT inhibitor. In certain embodiments, the TIGIT inhibitor is an anti-TIGIT antibody. In one embodiment, the TIGIT inhibitor is MTIG7192A. In another embodiment, the TIGIT inhibitor is BMS-986207. In yet another embodiment, the TIGIT inhibitor is OMP-313M32. In one embodiment, the TIGIT inhibitor is MK-7684. In another embodiment, the TIGIT inhibitor is AB154. In yet another embodiment, the TIGIT inhibitor is CGEN-15137. In one embodiment, the TIGIT inhibitor is SEA-TIGIT. In another embodiment, the TIGIT inhibitor is ASP8374. In yet another embodiment, the TIGIT inhibitor is AJUD008.

[0243] In some embodiments, the checkpoint inhibitor is a VSIR inhibitor. In certain embodiments, the VSIR inhibitor is an anti-VSIR antibody. In one embodiment, the VSIR inhibitor is MTIG7192A. In another embodiment, the VSIR inhibitor is CA-170. In yet another embodiment, the VSIR inhibitor is JNJ61610588. In one embodiment, the VSIR inhibitor is HMBD-002.

[0244] In some embodiments, the checkpoint inhibitor is a TIM3 inhibitor. In certain embodiments, the TIM3 inhibitor is an anti-TIM3 antibody. In one embodiment, the TIM3 inhibitor is AJUD009.

[0245] In some embodiments, the checkpoint inhibitor is a CD25(IL2RA) inhibitor. In certain embodiments, the CD25(IL2RA) inhibitor is an anti-CD25(IL2RA) antibody. In one embodiment, the CD25(IL2RA) inhibitor is daclizumab. In another embodiment, the CD25(IL2RA) inhibitor is basiliximab.

[0246] In some embodiments, the checkpoint inhibitor is an IFNAR1 inhibitor. In certain embodiments, the IFNAR1 inhibitor is an anti-IFNAR1 antibody. In one embodiment, the IFNAR1 inhibitor is aniflorumab. In another embodiment, the IFNAR1 inhibitor is cifalimumab.

[0247] In some embodiments, the checkpoint inhibitor is a CSF1R inhibitor. In certain embodiments, the CSF1R inhibitor is an anti-CSF1R antibody. In one embodiment, the CSF1R inhibitor is pexidartinib. In another embodiment, the CSF1R inhibitor is emuctuzumab. In yet another embodiment, the CSF1R inhibitor is kabilizumab. In one embodiment, the CSF1R inhibitor is ARRY-382. In another embodiment, the CSF1R inhibitor is BLZ945. In yet another embodiment, the CSF1R inhibitor is AJUD010. In one embodiment, the CSF1R inhibitor is AMG820. In another embodiment, the CSF1R inhibitor is IMC-CS4. In yet another embodiment, the CSF1R inhibitor is JNJ-40346527. In one embodiment, the CSF1R inhibitor is PLX5622. In another embodiment, the CSF1R inhibitor is FPA008.

[0248] In some embodiments, the checkpoint inhibitor is a therapeutic agent that targets HLA. In certain embodiments, the therapeutic agent that targets HLA is an anti-HLA antibody. In one embodiment, the therapeutic agent that targets HLA is GSK01. In another embodiment, the therapeutic agent that targets HLA is IMC-C103C. In yet another embodiment, the therapeutic agent that targets HLA is IMC-F106C. In one embodiment, the therapeutic agent that targets HLA is IMC-G107C. In yet another embodiment, the therapeutic agent that targets HLA is ABBV-184.

[0249] Where appropriate for the treatment of diseases described herein and understood in the art, the methods described herein may be used in combination with one or more second activators described herein.

[0250] PD-1 antagonists and pembrolizumab

[0251] This specification provides a method for treating various cancers in subjects, including those with unresectable locally advanced or metastatic urothelial carcinoma (LA / MUC) who are unable to receive cisplatin-based chemotherapy, using an antibody-drug conjugate (ADC) conjugated to 191P4D12 in combination with pembrolizumab. In certain embodiments, the treatment is a first-line treatment. In other embodiments, the treatment is a second-line treatment.

[0252] Pembrolizumab (formerly known as MK-3475, SCH900475, and lambrolizumab), also referred to herein as "pembro," is a humanized IgG4 mAb containing the heavy and light chain amino acid sequences and CDR described in Table 4, with its structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013). Pembrolizumab is approved by the U.S. FDA, as described in the Prescribing Information for KEYTRUDA® (Merck & Co., Inc., Rahway, NJ, USA; initial U.S. approval 2014, updated March 2021).

[0253] As used herein, “pembrolizumab variant” or “its variant” with respect to the pembrolizumab sequence means a monoclonal antibody containing a heavy and light chain sequence substantially identical to that of pembrolizumab, except that it has three, two, or one conservative amino acid substitutions located outside the light chain CDR and six, five, four, three, two, or one conservative amino acid substitutions located outside the heavy chain CDR, for example, the variant's position is located in the FR region or the constant region, and optionally, “pembrolizumab variant” or “its variant” has a deletion of a C-terminal lysine residue in the heavy chain. In other words, pembrolizumab and pembrolizumab variants contain the same CDR sequence, but their full-length light chain and full-length heavy chain sequences differ from each other due to the presence of three or fewer or six other conservative amino acid substitutions. The pembrolizumab variant is substantially identical to pembrolizumab in terms of the following properties: binding affinity to PD-1, and ability to block the binding of PD-L1 and PD-L2 to PD-1, respectively.

[0254] In one embodiment, a PD-1 antagonist useful for the treatment, pharmaceutical and use of the present invention comprises a monoclonal antibody (mAb) or its antigen-binding fragment, which specifically binds to PD-1 or PD-L1, preferably to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in some embodiments, the human constant region is IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0255] Examples of mAbs that bind to human PD-1 and are useful for the therapeutic methods, pharmaceuticals, and uses of the present invention are described in U.S. Patents US7488802, US7521051, US8008449, US8354509, and US8168757, as well as in International Publications WO2004 / 004771, WO2004 / 072286, WO2004 / 056875, U.S.2011 / 0271358, and WO2008 / 156712. As specific anti-human PD-1 mAbs useful as PD-1 antagonists in the therapeutic method, pharmaceutical and use of the present invention, the following are used: pembrolizumab (also known as MK-3475), a humanized IgG4 mAb whose structure is described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which contains the heavy chain and light chain amino acid sequences shown in Table 2; and human IgG4, whose structure is described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013) and which contains the heavy chain and light chain amino acid sequences shown in Table 2. Examples include the mAb nivolumab (BMS-936558); humanized antibodies h409A11, h409A16, and h409A17, as well as AMP-514, which is under development by MedImmune; semiprimab; camrelizumab; cintilimab; tislerizumab; and tripalimab. Further anti-PD-1 agents intended for use herein include MEDI0680 (U.S. Patent No. 8609089), BGB-A317 (U.S. Patent Publication No. 2015 / 0079109), INCSHR1210 (SHR-1210) (PCT International Application Publication No. WO2015 / 085847), REGN-2810 (PCT International Application Publication No. WO2015 / 112800), PDR001 (PCT International Application Publication No. WO2015 / 112900), TSR-042 (ANB011) (PCT International Application Publication No. WO2014 / 179664), and STI-1110 (PCT International Application Publication No. WO2014 / 194302).

[0256] Examples of mAbs that bind to human PD-L1 and are useful in the therapeutic methods, pharmaceuticals, and uses of the present invention are described in US8383796. Specific anti-human PD-L1 mAbs useful as PD-1 antagonists in the therapeutic methods, pharmaceuticals, and uses of the present invention include BMS-936559, MEDI4736, and MSB0010718C.

[0257] In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (TECENTRIQ®, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI®, AstraZeneca Pharmaceuticals LP, Wilmington, DE), semiprimab (LIBTAYO®, Regeneron Pharmaceuticals, Tarrytown, NY, USA), avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany), or dostallimab (JEMPERLI®, GlaxoSmithKline LLC, Philadelphia, PA). In other embodiments, the PD-1 antagonist is pizilizumab (U.S. Patent No. 7,332,582), AMP-514 (MedImmune LLC, Gaithersburg, MD, USA), PDR001 (U.S. Patent No. 9,683,048), BGB-A317 (U.S. Patent No. 8,735,553), or MGA012 (MacroGenics, Rockville, MD).

[0258] In one embodiment, a PD-1 antagonist useful in the method of the present invention is an anti-PD-1 antibody that blocks the binding of PD-1 to PD-L1 and PD-L2.

[0259] In some embodiments of the treatment method, the anti-PD-1 antibody comprises a heavy chain variable region containing a CDR that includes the amino acid sequence of the complementarity-determining region (CDR) of the heavy chain variable region shown in SEQ ID NO: 32, and a light chain variable region containing a CDR that includes the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO: 27.

[0260] In some embodiments of the therapeutic methods, pharmaceuticals, and uses of the present invention, the PD-1 antagonist is a monoclonal antibody or an antigen-binding fragment thereof comprising (a) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 of SEQ ID NOs. 24, 25, and 26, respectively, and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 of SEQ ID NOs. 29, 30, and 31, respectively.

[0261] In some embodiments of the therapeutic method, pharmaceutical and use of the present invention, the PD-1 antagonist is a monoclonal antibody or an antigen-binding fragment comprising (a) a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26, respectively, and (b) a heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 31, respectively.

[0262] In some embodiments of the therapeutic method, pharmaceutical and use of the present invention, the PD-1 antagonist is a monoclonal antibody or an antigen-binding fragment comprising (a) a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 24, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26, respectively, and (b) a heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 31, respectively.

[0263] In other embodiments of the therapeutic methods, pharmaceuticals, and uses of the present invention, the PD-1 antagonist is a monoclonal antibody or antigen-binding fragment that specifically binds to human PD-1 and comprises (a) a heavy chain variable region comprising SEQ ID NO: 32 or a variant thereof, and (b) a light chain variable region comprising SEQ ID NO: 27 or a variant thereof. The variant of the heavy chain variable region sequence is identical to the reference sequence except that it has up to six conserved amino acid substitutions in the framework region (i.e., outside the CDR). The variant of the light chain variable region sequence is identical to the reference sequence except that it has up to three conserved amino acid substitutions in the framework region (i.e., outside the CDR).

[0264] In another embodiment of the therapeutic method, pharmaceutical and use of the present invention, the PD-1 antagonist is a monoclonal antibody that specifically binds to human PD-1 and comprises (a) a heavy chain containing SEQ ID NO: 33 and (b) a light chain containing SEQ ID NO: 28. In one embodiment, the PD-1 antagonist is an anti-PD-1 antibody comprising two heavy chains and two light chains, where the heavy chain and light chain each contain the amino acid sequences of SEQ ID NO: 33 and SEQ ID NO: 28, respectively.

[0265] In all of the above-described therapeutic methods, pharmaceuticals, and uses, the PD-1 antagonist inhibits the binding of PD-L1 to PD-1, and in specific embodiments, also inhibits the binding of PD-L2 to PD-1. In some embodiments of the above-described therapeutic methods, pharmaceuticals, and uses, the PD-1 antagonist is a monoclonal antibody or its antigen-binding fragment that specifically binds to PD-1 or PD-L1 and blocks the binding of PD-L1 to PD-1.

[0266] Table 4 below lists the amino acid sequences of exemplary anti-PD-1 mAbs for use in the therapeutic methods, pharmaceuticals, and uses of the present invention.

[0267] [Table 4]

[0268] [Table 5] TIFF2026534110000010.tif194165TIFF2026534110000011.tif131165

[0269] In one embodiment, the anti-PD-1 antibody or its antigen-binding fragment includes a heavy chain constant region, e.g., a human constant region, e.g., g1, g2, g3, or g4 human heavy chain constant region, or a variant thereof. In another embodiment, the anti-PD-1 antibody or its antigen-binding fragment includes a light chain constant region, e.g., a human light chain constant region, e.g., a lambda or kappa human light chain region, or a variant thereof. For example, but not limited to, the human heavy chain constant region may be the g4 human heavy chain constant region, and the human light chain constant region may be the kappa human light chain constant region. In an alternative embodiment, the Fc region of the antibody is g4 with the Ser228Pro mutation (Schuurman, J et.al., Mol.Immunol.38:1-8, 2001). In some embodiments, different constant domains may be added to the humanized VL and VH regions derived from the CDR provided herein. For example, if a specific intended use of the antibody (or fragment) of the present invention requires a modification of effector function, a heavy chain constant domain other than human IgG1 may be used, or a hybrid IgG1 / IgG4 may be utilized. Human IgG1 antibodies provide a long half-life and effector functions such as complement activation and antibody-dependent cell-mediated cytotoxicity, but such activities may not be desirable for all uses of the antibody. In such cases, a human IgG4 constant domain may be used, for example. The present invention includes the use of an anti-PD-1 antibody or its antigen-binding fragment containing an IgG4 constant domain. In one embodiment, the IgG4 constant domain may differ from that of the natural human IgG4 constant domain (Swiss-Prot accession number P01861.1) at positions corresponding to position 228 in the EU system and position 241 in the KABAT system, where the natural Ser108 is replaced with Pro to prevent potential interchain disulfide bonding between Cys106 and Cys109 (corresponding to positions Cys226 and Cys229 in the EU system and positions Cys239 and Cys242 in the KABAT system), which may interfere with proper intrachain disulfide bond formation. See Angal et al. (1993) Mol. Imunol. 30:105. In other cases, modified IgG1 constant domains can be used that have been altered to extend the half-life or reduce effector function.

[0270] In another embodiment, the PD-1 antagonist is an antibody or antigen-binding protein having a variable light chain domain and / or a variable heavy chain domain having at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity with one of the variable light chain domains or variable heavy chain domains described above, and exhibiting specific binding to PD-1. In another embodiment of the th...

Claims

1. A method for treating cancer in the subject, wherein the subject (a) an effective amount of antibody-drug conjugate (ADC) containing an anti-191P4D12 antibody or its antigen-binding fragment, and (b) an effective amount of anti-PD-1 antibody or its antigen-binding fragment This includes administering, The anti-191P4D12 antibody or its antigen-binding fragment is bound to 191P4D12 and conjugated to one or more units of monomethyl auristatin E (MMAE), The anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region including a CDR containing the amino acid sequence of the complementarity-determining region (CDR) of the heavy chain variable region shown in SEQ ID NO: 32, and a light chain variable region including a CDR containing the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:

27. The anti-191P4D12 antibody or its antigen-binding fragment comprises a heavy chain variable region including a CDR containing the amino acid sequence of the complementarity-determining region (CDR) of the heavy chain variable region shown in SEQ ID NO: 22, and a light chain variable region including a CDR containing the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:

23. The subject has urothelial carcinoma or bladder cancer, and The subject is eligible to receive cisplatin treatment (cisplatin eligible), The aforementioned method.

2. The method according to claim 1, wherein the subject has not previously received a PD-(L)-1 inhibitor.

3. The method according to claim 1 or 2, wherein the subject has a GFR of more than 60 mL / min or a creatinine clearance of more than 60 mL / min.

4. The method according to any one of claims 1 to 3, wherein the subject has hearing loss on an audiometric test of NCI CTCAE grade 1 or lower.

5. The method according to any one of claims 1 to 4, wherein the subject does not have NYHA class III heart failure.

6. (a) The subject has a progression-free survival of at least 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months or approximately 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months after the treatment, and optionally, the subject has a progression-free survival of at least 14.6 months or approximately 14.6 months after the treatment, and optionally, the subject has a progression-free survival of 14 to 15 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months or approximately 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months, and optionally, the median progression-free survival in the treated population is at least 14.6 months or approximately 14.6 months, and optionally, the median progression-free survival in the treated population is 14 to 15 months, or (c) The median progression-free survival is at least 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months or approximately 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months for the population treated by the method, and optionally, the median progression-free survival is at least 14.6 months or approximately 14.6 months for the population treated by the method, and optionally, the median progression-free survival is 14 to 15 months for the population treated by the method. The method according to any one of claims 1 to 5.

7. (a) The subject has an overall survival period of at least 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months or approximately 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months after the treatment, and optionally, the subject has an overall survival period of at least 31.5 months or approximately 31.5 months after the treatment, and optionally, the subject has an overall survival period of 31 to 32 months after the treatment, (b) The subject population is treated by the method, and the median overall survival in the treated population is at least 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months or approximately 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months, and optionally, the median overall survival in the treated population is at least 31.5 months or approximately 31.5 months, and optionally, the median overall survival in the treated population is 31 to 32 months, or (c) The median overall survival for the population treated by the method is at least 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months or approximately 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months, and optionally, the median overall survival for the population treated by the method is at least 31.5 months or approximately 31.5 months, and optionally, the median overall survival for the population treated by the method is 31 to 32 months. The method according to any one of claims 1 to 5.

8. A method for treating cancer in the subject, wherein the subject (a) an effective amount of antibody-drug conjugate (ADC) containing an anti-191P4D12 antibody or its antigen-binding fragment, and (b) an effective amount of anti-PD-1 antibody or its antigen-binding fragment This includes administering, The anti-191P4D12 antibody or its antigen-binding fragment is bound to 191P4D12 and conjugated to one or more units of monomethyl auristatin E (MMAE), The anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region including a CDR containing the amino acid sequence of the complementarity-determining region (CDR) of the heavy chain variable region shown in SEQ ID NO: 32, and a light chain variable region including a CDR containing the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:

27. The anti-191P4D12 antibody or its antigen-binding fragment comprises a heavy chain variable region including a CDR containing the amino acid sequence of the complementarity-determining region (CDR) of the heavy chain variable region shown in SEQ ID NO: 22, and a light chain variable region including a CDR containing the amino acid sequence of the CDR of the light chain variable region shown in SEQ ID NO:

23. The subject has urothelial carcinoma or bladder cancer, and (i) The subject has aspartate transferase (AST) and alanine transaminase (ALT) at 2.5 times or less the upper limit of normal (ULN), (ii) The subject has treated central nervous system (CNS) metastases that have been clinically stable for at least four weeks prior to the administration of the ADC and the anti-PD-1 antibody or its antigen-binding fragment, and / or (iii) The subject has not undergone major surgery within four weeks prior to the administration of the ADC and the anti-PD-1 antibody or its antigen-binding fragment. The aforementioned method.

9. The subject has treated central nervous system (CNS) metastases that have been clinically stable for at least four weeks prior to the administration of the ADC and the anti-PD-1 antibody or its antigen-binding fragment, and The subject has not undergone major surgery within four weeks prior to the administration of the ADC and the anti-PD-1 antibody or its antigen-binding fragment. The method according to claim 8.

10. (a) The subject has a progression-free survival period of at least 12.5 months or approximately 12.5 months after the treatment, and optionally, the subject has a progression-free survival period of 12 to 13 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 12.5 months or approximately 12.5 months, and optionally, the median progression-free survival in the treated population is 12 to 13 months, or (c) The median progression-free survival is at least 12.5 months or approximately 12.5 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 12 to 13 months for the population treated by the method described above. The method according to claim 8 or 9.

11. (a) The subject has an overall survival of at least 31.5 months or approximately 31.5 months after the treatment, and optionally, the subject has an overall survival of 31 to 32 months after the treatment, (b) The subject population is treated by the method, and the median overall survival in the treated population is at least 31.5 months or approximately 31.5 months, and optionally, the median overall survival in the treated population is 31 to 32 months, or (c) The median overall survival is at least 31.5 months or approximately 31.5 months for the population treated by the method, and, on an optional basis, the median overall survival is 31 to 32 months for the population treated by the method. The method according to claim 8 or 9.

12. The subject is eligible to receive cisplatin treatment (cisplatin eligible), and (a) The subject has a progression-free survival of at least 14.6 months or approximately 14.6 months after the treatment, and, at the discretion of the subject, has a progression-free survival of 14 to 15 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 14.6 months or approximately 14.6 months, and, on a random selection basis, the median progression-free survival in the treated population is 14 to 15 months, or (c) The median progression-free survival is at least 14.6 months or approximately 14.6 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 14 to 15 months for the population treated by the method described above. The method according to claim 8 or 9.

13. The subject is ineligible to receive cisplatin treatment (cisplatin eligible), and (a) The subject has a progression-free survival period of at least 10.6 months or approximately 10.6 months after the treatment, and optionally, the subject has a progression-free survival period of 10 to 11 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10.6 months or about 10.6 months, and optionally the median progression-free survival in the treated population is 10 to 11 months, or (c) The median progression-free survival is at least 10.6 months or approximately 10.6 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 10 to 11 months for the population treated by the method described above. The method according to claim 8 or 9.

14. The aforementioned subjects have PD-L1 expression of CPS 10 or higher, and are selected at will. (a) The subject has a progression-free survival period of at least 18.5 months or approximately 18.5 months after the treatment, and optionally, the subject has a progression-free survival period of 18 to 19 months after the treatment, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 18.5 months or approximately 18.5 months, and, on a random selection basis, the median progression-free survival in the treated population is 18 to 19 months, or (c) The median progression-free survival is at least 18.5 months or approximately 18.5 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 18 to 19 months for the population treated by the method described above. The method according to any one of claims 1 to 5, 8, or 9.

15. The subjects mentioned above have PD-L1 expression with a CPS of less than 10, and are selected at will. (a) The subject has a progression-free survival period of at least 10.5 months or approximately 10.5 months after the treatment, and optionally, the subject has a progression-free survival period of 10 to 11 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10.5 months or about 10.5 months, and optionally, the median progression-free survival in the treated population is 10 to 11 months, or (c) The median progression-free survival is at least 10.5 months or approximately 10.5 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 10 to 11 months for the population treated by the method described above. The method according to any one of claims 1 to 5, 8, or 9.

16. The aforementioned subjects do not have liver metastases and are selected at will. (a) The subject has a progression-free survival of at least 16.4 months or approximately 16.4 months after the treatment, and optionally, the subject has a progression-free survival of 16 to 17 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 16.4 months or approximately 16.4 months, and, on a random selection basis, the median progression-free survival in the treated population is 16 to 17 months, or (c) The median progression-free survival is at least 16.4 months or approximately 16.4 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 16 to 17 months for the population treated by the method described above. The method according to any one of claims 1 to 5, 8, or 9.

17. The aforementioned subjects have liver metastases and are selected at will. (a) The subject has a progression-free survival of at least 8.2 months or approximately 8.2 months after the treatment, and optionally, the subject has a progression-free survival of 8 to 9 months, (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 8.2 months or approximately 8.2 months, and optionally, the median progression-free survival in the treated population is 8 to 9 months, or (c) The median progression-free survival is at least 8.2 months or approximately 8.2 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 8 to 9 months for the population treated by the method described above. The method according to any one of claims 1 to 5, 8, or 9.

18. The aforementioned subject is of white race and is of arbitrary choice, (a) The subject has a progression-free survival of at least 10.4 months or approximately 10.4 months, and the subject is optionally selected to have a progression-free survival of 10 to 11 months. (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 10.4 months or about 10.4 months, and, on a random selection basis, the median progression-free survival in the treated population is 10 to 11 months, or (c) The median progression-free survival is at least 10.4 months or approximately 10.4 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 10 to 11 months for the population treated by the method described above. The method according to any one of claims 1 to 5, 8, or 9.

19. The aforementioned subjects are not of white race, and are selected at will. (a) The subject has a progression-free survival of at least 22.3 months or approximately 22.3 months, and the subject is optionally selected to have a progression-free survival of 22 to 23 months. (b) The subject population is treated by the method, and the median progression-free survival in the treated population is at least 22.3 months or approximately 22.3 months, and optionally, the median progression-free survival in the treated population is 22 to 23 months, or (c) The median progression-free survival is at least 22.3 months or approximately 22.3 months for the population treated by the method described above, and, on an optional basis, the median progression-free survival is 22 to 23 months for the population treated by the method described above. The method according to any one of claims 1 to 5, 8, or 9.

20. The method according to any one of claims 1 to 19, wherein the subject has visceral metastasis.

21. The method according to any one of claims 1 to 19, wherein the subject has a disease affecting only the lymph nodes.

22. The method according to any one of claims 1 to 21, wherein the site of disease occurrence is the upper urinary tract.

23. The method according to any one of claims 1 to 21, wherein the site of disease occurrence is the lower urinary tract.

24. The method according to any one of claims 1 to 23, wherein the subject has 10 or more PD-L1 expression composite positive scores (CPS).

25. The method according to any one of claims 1 to 23, wherein the subject has PD-L1 expression CPS of less than 10.

26. The method according to any one of claims 1 to 19, wherein the subject has an H score of 0 to 300 for nectin-4.

27. The method according to any one of claims 1 to 19, wherein the subject has an H score of 0 to 200 for nectin-4.

28. The method according to any one of claims 1 to 19, wherein the subject has an H score of 0 to 150 for nectin-4.

29. The method according to any one of claims 1 to 19, wherein the method does not include determining the PD-L1 expression of the subject or determining the nectin-4 expression of the subject.

30. The method according to any one of claims 1 to 29, wherein the subject has locally advanced or metastatic urothelial carcinoma.

31. The method according to any one of claims 1 to 30, wherein the subject has locally advanced or metastatic bladder cancer.

32. The anti-PD-1 antibody or its antigen-binding fragment (a) A light chain variable region comprising light chain CDR1 containing the amino acid sequence of SEQ ID NO: 24, light chain CDR2 containing the amino acid sequence of SEQ ID NO: 25, and light chain CDR3 containing the amino acid sequence of SEQ ID NO: 26, (b) A heavy chain variable region comprising heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 29, heavy chain CDR2 containing the amino acid sequence of SEQ ID NO: 30, and heavy chain CDR3 containing the amino acid sequence of SEQ ID NO: 31, respectively, A method according to any one of claims 1 to 31, including the method described in any one of claims 1 to 31.

33. The anti-PD-1 antibody or its antigen-binding fragment (a) A light chain variable region comprising, respectively, light chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 24, light chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 25, and light chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 26, (b) A heavy chain variable region comprising heavy chain CDR1 consisting of the amino acid sequence of SEQ ID NO: 29, heavy chain CDR2 consisting of the amino acid sequence of SEQ ID NO: 30, and heavy chain CDR3 consisting of the amino acid sequence of SEQ ID NO: 31, A method according to any one of claims 1 to 31, including the method described in any one of claims 1 to 31.

34. The anti-PD-1 antibody or its antigen-binding fragment (a) A heavy chain variable region including sequence number 32 or a variant thereof, (b) A light chain variable region including Sequence ID No. 27 or a variant thereof, The method according to any one of claims 1 to 33, including the method described in any one of claims 1 to 33.

35. The aforementioned anti-PD-1 antibody, (a) A heavy chain containing Sequence ID No. 33, (b) A light chain containing Sequence ID No. 28, The method according to any one of claims 1 to 33, including the method described in any one of claims 1 to 33.

36. The anti-191P4D12 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, or The anti-191P4D12 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. The method according to any one of claims 1 to 35.

37. The anti-191P4D12 antibody or its antigen-binding fragment includes 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, or The anti-191P4D12 antibody or its antigen-binding fragment includes 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. The method according to any one of claims 1 to 35.

38. The method according to any one of claims 1 to 37, wherein the anti-191P4D12 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.

39. The method according to any one of claims 1 to 38, wherein the anti-191P4D12 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.

40. The method according to any one of claims 1 to 34 and 36 to 38, wherein the anti-191P4D12 antigen binding fragment is Fab, F(ab')2, Fv, or scFv.

41. The method according to any one of claims 1 to 35, wherein the anti-191P4D12 antibody is a fully human antibody.

42. The method according to any one of claims 1 to 39 and 41, wherein the anti-191P4D12 antibody is IgG1 and the light chain is a kappa light chain.

43. The method according to any one of claims 1 to 42, wherein the anti-191P4D12 antibody or its antigen-binding fragment is recombinantly produced.

44. The method according to any one of claims 1 to 43, wherein the anti-191P4D12 antibody or antigen-binding fragment is conjugated to each unit of the MMAE via a linker.

45. The method according to claim 44, 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.

46. The method according to claim 44 or 45, wherein the linker has the formula -Aa-Ww-Yy-, where -A- is an extension unit, a is 0 or 1, -W- is an amino acid unit, w is an integer in the range of 0 to 12, and -Y- is a spacer unit, y is 0, 1, or 2.

47. The extension unit has the structure of the following formula (1), the amino acid unit is valine-citrulline, and the spacer unit is a PAB group containing the structure of the following formula (2): The method according to claim 46.

48. The method according to claim 46 or 47, 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.

49. The method according to any one of claims 1 to 48, wherein the ADC comprises 1 to 20 units of MMAE per antibody or antigen-binding fragment.

50. The method according to any one of claims 1 to 49, wherein the ADC comprises 1 to 10 units of MMAE per antibody or antigen-binding fragment.

51. The method according to any one of claims 1 to 50, wherein the ADC comprises 2 to 8 units of MMAE per antibody or antigen-binding fragment.

52. The method according to any one of claims 1 to 51, wherein the ADC comprises 3 to 5 units of MMAE per antibody or antigen-binding fragment.

53. The ADC has the following structure: The method according to any one of claims 1 to 52, wherein L- represents the anti-191P4D12 antibody or its antigen-binding fragment, and p is 1 to 10.

54. The method according to claim 53, wherein p is 2 to 8.

55. The method according to claim 53 or 54, wherein p is 3 to 5.

56. The method according to any one of claims 53 to 55, wherein p is 3 to 4.

57. The method according to any one of claims 53 to 56, wherein p is approximately 4.

58. The method according to any one of claims 53 to 56, wherein the average value of p of the effective amount of the antibody-drug conjugate is approximately 3.

8.

59. The method according to any one of claims 1 to 58, wherein the ADC is administered to the subject at a dose of approximately 1 to approximately 10 mg / kg of body weight, approximately 1 to approximately 5 mg / kg of body weight, approximately 1 to approximately 2.5 mg / kg of body weight, or approximately 1 to approximately 1.25 mg / kg of body weight.

60. The method according to any one of claims 1 to 59, wherein the ADC is administered to the subject at a dose of approximately 0.25 mg / kg of body weight, approximately 0.5 mg / kg of body weight, approximately 0.75 mg / kg of body weight, approximately 1.0 mg / kg of body weight, approximately 1.25 mg / kg of body weight, approximately 1.5 mg / kg of body weight, approximately 1.75 mg / kg of body weight, approximately 2.0 mg / kg of body weight, approximately 2.25 mg / kg of body weight, or approximately 2.5 mg / kg of body weight.

61. The method according to any one of claims 1 to 60, wherein the ADC is administered to the subject at a dose of approximately 1 mg / kg of the subject's body weight.

62. The method according to any one of claims 1 to 60, wherein the ADC is administered to the subject at a dose of approximately 1.25 mg / kg of body weight.

63. The method according to any one of claims 1 to 62, wherein the ADC is administered to the subject by intravenous (IV) injection or infusion.

64. The method according to any one of claims 1 to 63, wherein the ADC is administered to the subject by IV injection or infusion for a maximum of two days within a 21-day treatment cycle.

65. The method according to any one of claims 1 to 64, wherein the ADC is administered to the subject by IV injection or infusion on the first and eighth days of a 21-day treatment cycle.

66. The method according to any one of claims 1 to 65, wherein the ADC is administered to the subject by IV injection or infusion over a period of approximately 30 minutes for up to two days of a 21-day treatment cycle.

67. The method according to any one of claims 1 to 66, wherein the ADC is administered by IV injection or infusion over approximately 30 minutes on the 1st and 8th days of a 21-day treatment cycle.

68. The method according to any one of claims 1 to 67, wherein the ADC is formulated into a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN-20), and trehalose dehydrate.

69. The method according to any one of claims 1 to 68, 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, and the pH of the pharmaceutical composition is about 6.0 at 25°C.

70. The method according to any one of claims 1 to 68, 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, and the pH of the pharmaceutical composition is about 6.0 at 25°C.

71. The ADC has the following structure: It has, in the formula, L- represents the antibody or its antigen-binding fragment, and p is approximately 3 to approximately 4. The anti-191P4D12 antibody comprises a heavy chain containing an amino acid sequence ranging 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 ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:

8. The aforementioned ADC is administered at a dose of approximately 1.25 mg / kg of body weight, and The aforementioned dose is administered by IV injection or infusion over approximately 30 minutes on days 1 and 8 of a 21-day treatment cycle. The method according to any one of claims 1 to 70.

72. The method according to any one of claims 1 to 70, wherein the anti-PD-1 antibody is administered to the subject in a dose of approximately 100 mg to approximately 400 mg.

73. The method according to any one of claims 1 to 70, wherein the anti-PD-1 antibody is administered to the subject in a dose of approximately 200 mg.

74. (a) The anti-PD-1 antibody is administered to the subject at a dose of approximately 200 mg, and (b) After step (a), the anti-PD-1 antibody is administered to the subject at a dose of approximately 400 mg every 42 days. The method according to claim 71.

75. The method according to any one of claims 1 to 74, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on one day of the 21-day treatment cycle.

76. The method according to any one of claims 1 to 75, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on the first day of each 21-day treatment cycle.

77. The method according to any one of claims 1 to 76, wherein the anti-PD-1 antibody is administered to the subject by IV infusion for approximately 30 minutes on one day of the 21-day treatment cycle.

78. The method according to any one of claims 1 to 75, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over approximately 30 minutes on the first day of each 21-day treatment cycle.

79. The method according to any one of claims 1 to 78, wherein the subject shows a complete response after the treatment.

80. The method according to any one of claims 1 to 78, wherein the subject exhibits a partial response after the treatment.

81. The method according to any one of claims 1 to 78, wherein the subject shows stable disease progression after the treatment.

82. The method according to any one of claims 1 to 81, wherein, before administration of the ADC to the subject, the subject has a maximum pain score of approximately zero (0) on the Reduced Pain Inventory-Science Form (BPI-SF), and after administration of the ADC to the subject, the subject has an improved maximum pain score on the BPI-SF.

83. The method according to any one of claims 1 to 81, wherein, before administration of the ADC to the subject, the subject has a BPI-SF maximum pain baseline score of about zero (0), and after administration of the ADC to the subject, the subject shows a change of about -0.3 to about -1.2 from the maximum pain baseline score.

84. The method according to any one of claims 1 to 81, wherein, before administration of the ADC to the subject, the subject has a BPI-SF maximum pain baseline score of approximately zero (0), and after administration of the ADC to the subject, the subject shows a change of approximately -0.61 from the maximum pain baseline score.

85. The method according to any one of claims 1 to 81, wherein, prior to administration of the ADC to the subject, the subject has a baseline quality of life (QoL) score of approximately zero (0) on the Quality of Life Questionnaire for Cancer Treatment – ​​Core Questionnaire (EORTC QLQ-C30), and, after administration of the ADC to the subject, the subject has an improved QoL score on the EORTC QLQ-C30.

86. The method according to any one of claims 1 to 81, wherein, prior to administration of the ADC to the subject, the subject has a QoL baseline score of approximately zero (0) on the EORTC QLQ-C30, and after administration of the ADC to the subject, the subject shows a change of approximately 10.0 to approximately 15.0 from the QoL baseline score on the EORTC QLQ-C30.

87. The method according to any one of claims 1 to 81, wherein, prior to administration of the ADC to the subject, the subject has a QoL baseline score of approximately zero (0) on the EORTC QLQ-C30, and after administration of the ADC to the subject, the subject shows a change of approximately 13.0 from the QoL baseline score on the EORTC QLQ-C30.

88. The method according to any one of claims 1 to 85, wherein the subject is a human.

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