Treating locally advanced or metastatic urothelial cancer with Anti-191p4d12 antibody drug conjugates in combination with pembrolizumab

Abstract

Provided herein are methods for treating cisplatin eligible and ineligible patients with unresectable locally advanced or metastatic urothelial cancer with antibody drug conjugates (ADC) that bind to 191P4D12 proteins in combination with pembrolizumab, wherein the anti-191P4D12 antibody is conjugated to one or more units of monomethyl auristatin E (MMAE).

Description

METHODS FOR TREATING PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CANCER WITH ANTIBODY DRUG CONJUGATES (ADC) THAT BIND 191P4D12 PROTEINS IN COMBINATION WITH PEMBROLIZUMABCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application No. 63 / 584,480, filed September 21, 2023, U.S. Application No. 63 / 620,610, filed January 12, 2024, U.S. Application No. 63 / 650,806, filed May 22, 2024, U.S. Application No. 63 / 672,135, filed July 16, 2024, and U.S. Application No. 63 / 694,044, filed on September 12, 2024 , the disclosure of each of which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14369-311-228 SEQ LI STING. xml”, was created on September 17, 2024, and is 62,860 bytes in size.1. Field

[0003] Provided herein are methods for treating cancers with antibody drug conjugates (ADC) that bind to 191P4D12 protein (Nectin-4). In particular, provided herein are methods for treating cisplatin eligible and ineligible patients with unresectable locally advanced or metastatic urothelial cancer with antibody drug conjugates (ADC) that bind to 191P4D12 proteins in combination with pembrolizumab.2. Background

[0004] Cancer is the leading cause of death in the US for people 35 to 65 years of age and it is the second leading cause of death worldwide. It was estimated in 2019 that there would be approximately 1.7 million new cancer cases and approximately 610000 deaths from cancer in the US (National Cancer Institute. 2019. Cancer Stat Facts: Cancer of Any Site. seer.cancer.gov / statfacts / html / all.html. Accessed 5 Jun 2019). Globally there were an estimated 18.1 million new cancer cases in 2018 and approximately 9.6 million deaths attributed to cancer in 2018 (World Health Organization. Press Release. Sept 2018. who.int / cancer / PRGlobocanFinal.pdf. Accessed 5 Jun 2019). Most deaths now occur inpatients with metastatic cancers. In fact, in the last 20 years, advances in treatment, including surgery, radiotherapy and adjuvant chemotherapy cured most patients with localized cancer. Patients whose cancer presented or recurred as metastatic disease obtained only modest benefit from conventional therapies in terms of overall survival (OS) and were rarely cured.

[0005] New therapeutic strategies for advanced and / or metastatic cancers include targeting molecular pathways important for cancer cell survival and novel cytotoxic compounds. The benefit of these novel drugs is reflected in prolonged survival; however, the outcome for most patients with distant metastases is still poor and novel therapies are needed.

[0006] 191P4D12 (which is also known as Nectin-4) is a 66 kDa type I transmembrane protein that belongs to the nectin family of adhesion molecules. It is composed of an extracellular domain (ECD) containing 3 immunoglobulin (Ig)-like subdomains, a transmembrane helix, and an intracellular region (Takai et al., Annu Rev Cell Dev Biol (2008); 24: 309-42). Nectins are thought to mediate Ca2+-independent cell-cell adhesion via both homophilic and heterophilic trans-interactions at adherens junctions where they can recruit cadherins and modulate cytoskeletal rearrangements (Rikitake et al., Cell Mol Life Sci (2008); 65(2): 253-63.). Sequence identity of Nectin-4 to other Nectin family members is low and ranges between 25%-30% in the ECD (Reymond et al., Biol Chem (2001); 276(46): 43205-15).

[0007] The 3 Ig-like subdomains in the ECD of Nectin-4 are designated V, Cl and C2. The Cl domain is responsible for cis-interaction (homodimerization), while V domains of most Nectin molecules contribute to trans-interaction 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 identified as markedly upregulated in urothelial cancer using suppression subtractive hybridization on a pool of urothelial cancer specimens. Characterization of expression in multiple tumor specimens, both at the ribonucleic acid (RNA) level and by immunohistochemistry (IHC), also demonstrated high levels of Nectin-4 in breast, pancreatic, lung, and other cancers (Challita-Eid et al., Cancer Res (2016); 76(10): 3003-13.).

[0009] Nectin-4 has been found to be expressed in multiple cancers, particularly urothelial, breast, lung, pancreatic, and ovarian cancers. 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 in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and up-regulated by T / B cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe, Arlene H. etal., 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 arising in various tissues. In large sample sets of e.g. ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective 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. CancerImmunol 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 on tumor infiltrating lymphocytes was found to mark 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). Thus, it has been proposed that PD-L1- expressing tumor cells interact with PD-1 -expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.

[0013] Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 have been approved for treating cancer. Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA) is a potent humanized immunoglobulin G4 (IgG4) mAb with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 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 and potent receptor blocking activity for PD-1. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of indications and is indicated for the first-line treatment of patients with unresectable or metastatic CRC that is microsatellite instability-high or mismatch repair deficient (MSI-H / dMMR). Pembrolizumab is the current standard of care for first line MSI- H / dMMR mCRC.

[0014] Urothelial Cancer

[0015] According to the International Agency for Research on Cancer (IARC), urothelial cancer kills more than 165000 patients annually and is the ninth most common cancer overall worldwide. Approximately 151000 new cases of urothelial cancer are diagnosed annually in Europe, with 52000 deaths per year. Over 22000 new cases are diagnosed annually in Japan, with 7600 deaths per year (Cancer Fact Sheets: All cancers excluding Non-Melanoma Skin. International Agency for Research on Cancer 2017. Retrieved from gco.iarc.fr / today / fact- sheets- cancers?cancer=29&type=0&sex=0. Accessed 19 Dec 2017). In the U.S., theNational Cancer Institute estimates more than 79,000 new cases of bladder cancer were diagnosed in 2017, and more than 16,800 people died from the disease (National Cancer Institute 2018).

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

[0017] Urothelial cancer is the most common type of bladder cancer (90 percent of cases), and can also be found in the urothelial cells that line the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.

[0018] First-line therapy for metastatic urothelial cancer in patients with sufficient renal function consists of cis-diamminedichloroplatinum (II) (cisplatin)-based combinations, like methotrexate, vinblastine, doxorubicin, and cisplatin (MV AC) or gemcitabine plus cisplatin, which demonstrate an objective response rate (ORR) up to 55%, including approximately 12% complete responses (CRs) (von der Maase 2000). Despite initial chemosensitivity, patients are not cured and the outcome of metastatic urothelial cancer after these regimens is poor: median time to progression is 7 months and median overall survival (OS) is 14 months. Long-term survival is poor (approximately 15%) and the prognosis is particularly grim for patients with visceral metastases, for whom the five year survival rate is 7% (von der Maase 2005; Bellmunt 2011).

[0019] Almost half of urothelial cancer patients are unfit for cisplatin-containing chemotherapy due to impaired renal function, poor performance status, or comorbidity (Dash et al. Cancer (2006); 107(3): 506-13). In these patients, no standard first-line treatment has been defined, but current options typically include cis-Diammine (cyclobutane 1,1 dicarboxylato) platinum (carboplatin)-based regimens or single-agent taxane or gemcitabine (Cathomas 2015). In this setting, long term survival is even lower (De Santis et al. J Clin Oncol (2009); 27(33): 5634-9). In April 2017, the Food and Drug Administration (FDA) approved the anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (CPI) atezolizumab (TECENTRIQ®) as first line treatment for locally advanced or metastatic urothelial carcinoma (la / mUC) patients ineligible for cisplatin. The accelerated approval was based on an open-label single arm study that showed long durations of response, indicating activity in this difficult-to-treat population, with an objective response rate (ORR) of 23% that was similar across varying levels of target expression (Balar 2017). The median OS for these patients was 15.9 months, although this is a single arm study and any OS benefit will 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 first line treatment for patients with la / mUC ineligible for cisplatin. The study on which approval was based resulted in an ORR of 29% and median response duration not reached at the time of the analysis (median follow-up time of 7.8 months) (Pembrolizumab Prescribing Information, Merck Sharp and Dohme Corp., 2017). In May 2018, the FDA issued an alert regarding decreased survival of patients with low expression of PD-L1 being treated in the first line setting with pembrolizumab or atezolizumab, compared with platinumbased chemotherapy. Subsequently prescribing information for these two CPIs were revised to require high PD-L1 expression in first-line metastatic urothelial cancer patients who are eligible for platinum-containing chemotherapy. This development has further limited the options for metastatic urothelial cancer patients with low expression of PD-L1.

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

[0022] Few options are available for second-line treatment of metastatic disease. In the European Union, the small-molecule tubulin inhibitor vinflunine (Javlor®) was authorized in 2009 based on modest activity (overall response rate 9%), moderate survival benefit of 2 months (6.9 months for vinflunine + best supportive care (BSC) vs 4.6 months for BSC alone, hazard ratio 0.88), and a favorable safety profile (Bellmunt et al. Clin Oncol (2009); 27(27): 4454-61). In May 2016, the FDA provided accelerated approval of atezolizumab as the first salvage therapy following platinum agents for la / mUC in the US, followed by EU approval in September 2017. In February 2017, nivolumab (Opdivo®) became the second immunotherapy granted accelerated approval by the FDA, which was followed by EU approval in June 2017. In March and May 2017, the FDA granted accelerated approval for avelumab (Bavencio®) and durvalumab (Imfinzi™), respectively, both PD-L1 blocking antibodies indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Pembrolizumab received regular approval from the FDA in May 2017 as second-line treatment (Keytruda Prescribing Information, Merck, May 2017). The approval was based on the first randomized experience reported for a CPI in the locally advanced or metastatic post-platinum urothelial cancer setting, a phase 3 study in 542 patients showing an OS of 10.3 months as compared to 7.4 months with taxane chemotherapy or vinflunine. Additionally, ORR was 21% for pembrolizumab and 11% forchemotherapy. No statistically significant difference in progression-free survival (PFS) between the two arms was observed (Bellmunt etal., N Engl J Med (2017);376(l 1): 1015- 26). EU approval for the same indication was granted in September 2017 and Japanese approval in January 2018. Other programmed cell death protein 1 (PD-1) and PD-L1 inhibitors are currently being evaluated in clinical trials for urothelial cancer, as first and second-line therapy (Mullane et cd.. Curr Opin Urol (2016);26(6): 556-63).

[0023] While CPIs offer a new approach to treatment of metastatic urothelial cancer, tumor responses have occurred in a minority of patients and the improvement in long-term survival is only a few months. For example, in May 2017, Roche announced that a confirmatory phase 3 trial of second-line atezolizumab had failed to meet its primary endpoint of 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). Most patients with locally advanced or metastatic urothelial cancer do not respond to CPIs and many who do respond ultimately develop disease progression (Rosenberg etal., Lancet (2016); 387(10031): 1909-20). Novel treatments are still needed, particularly for patients who have not responded to CPIs or who have progressed following CPI therapy.

[0024] Bladder Cancer

[0025] Of all new cases of cancer in the United States, bladder cancer represents approximately 5 percent in men (fifth most common neoplasm) and 3 percent in women (eighth most common neoplasm). The incidence is increasing slowly, concurrent with an increasing older population. American Cancer Society (cancer.org) estimates that there are 81,400 new cases annually, including 62,100 in men and 19,300 in women, which accounts for 4.5% of all cancer cases. The age-adjusted incidence in the United States is 20 per 100,000 for men and women. There are an estimated 17,980 deaths from bladder cancer in annually (13,050 in men and 4,930 in women), which accounts for 3% of cancer related deaths. Bladder cancer incidence and mortality strongly increase with age and will be an increasing problem as the population becomes more elderly. Globally, approximately 580,000 people will be diagnosed with bladder cancer in 2020, and bladder cancer will be attributed to approximately 210,000 deaths worldwide.

[0026] Most bladder cancers recur in the bladder. Bladder cancer is managed with a combination of transurethral resection of the bladder (TUR) and intravesical chemotherapy or immunotherapy. The multifocal and recurrent nature of bladder cancer points out the limitations of TUR. Most muscle-invasive cancers are not cured by TUR alone. Radical cystectomy and urinary diversion is the most effective means to eliminate the cancer butcarry an undeniable impact on urinary and sexual function. There continues to be a significant need for treatment modalities that are beneficial for bladder cancer patients.

[0027] There is a significant need for additional therapeutic methods for urothelial and bladder cancers. These include the use of antibodies and antibody drug conjugates, including in combination with other agents, as treatment modalities.3. Summary

[0028] Provided herein are methods for the treatment of various cancers in subjects, such as human subjects, including methods for treating cisplatin eligible and ineligible patients with unresectable locally advanced or metastatic urothelial cancer with antibody drug conjugates (ADC) that bind to 191P4D12 proteins in combination with pembrolizumab.

[0029] In certain embodiments, the subject (e.g., a human subject) treated with the methods provided herein has not received previous treatment (e.g., treatment for unresectable, locally advanced or metastatic urothelial cancer (UC)). In certain embodiments, the subject (e.g., a human subject) treated with the methods provided herein has not received previous treatment with a PD-(L)-1 inhibitor (e.g., a PD-1 inhibitor or 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 subject:(a) an effective amount of an antibody drug conjugate (ADC) comprising an anti- 191P4D12 antibody or antigen binding fragment thereof, and(b) an effective amount of an anti -PD-1 antibody or 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 regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:32 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs 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 complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region setforth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject has urothelial or bladder cancer; and wherein the subject is eligible to receive cisplatin treatment (cisplatin eligible).

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

[0032] Embodiment 3. The method of embodiment 1 or 2, wherein the subject has a GFR >60 mL / min.

[0033] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the subject has NCI CTCAE Grade <1 audiometric hearing loss.

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

[0035] Embodiment 6. The method of any one of embodiments 1 to 5, wherein:(a) the subject has a progression free survival of at least or about 10, 11, 12, 13,14, 14.6, 15, 16, 17, 18, or 19 months following the treatment, optionally wherein the subject has a progression free survival of at least or about 14.6 months following the treatment, further optionally wherein the subject has a progression free survival of 14 to 15 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10, 11, 12, 13, 14, 14.6,15, 16, 17, 18, or 19 months, optionally wherein median progression free survival in the treated population is at least or about 14.6 months, further optionally wherein median progression free survival in the treated population is 14 to 15 months; or(c) median progression free survival is at least or about 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months for a population of subjects treated with the method, optionally wherein median progression free survival is at least or about 14.6 months for a population of subjects treated with the method, further optionally wherein median progression free survival is 14 to 15 months for a population of subjects treated with the method.

[0036] Embodiment 7. The method of any one of embodiments 1 to 5, wherein:(a) the subject has an overall survival of at least or about 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months following the treatment, optionally wherein the subject has an overall survival of at least or about 31.5 months following the treatment, further optionally wherein the subject has an overall survival of 31 to 32 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 27, 28, 29, 30, 31, 31.5, 32, 33,34, 35, or 36 months, optionally wherein median overall survival in the treated population is at least or about 31.5 months, further optionally wherein median overall survival in the treated population is 31 to 32 months; or(c) median overall survival is at least or about 27, 28, 29, 30, 31, 31.5, 32, 33, 34,35, or 36 months for a population of subjects treated with the method, optionally whererin median overall survival is at least or about 31.5 months for a population of subjects treated with the method, further optionally wherein median overall survival is 31 to 32 months for a population of subjects treated with the method.

[0037] Embodiment 8. A method of treating cancer in a subject, comprising administering to the subject:(a) an effective amount of an antibody drug conjugate (ADC) comprising an anti- 191P4D12 antibody or antigen binding fragment thereof, and(b) an effective amount of an anti-PD-1 antibody or 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 regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:32 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs 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 complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject has urothelial or bladder cancer; and wherein:(i) the subject has aspartate transferase (AST) and alanine transaminase (ALT) no more than 2.5 fold of upper limit of normal (ULN),(ii) 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 or antigen binding fragment thereof, and / or(iii) the subject has not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof.

[0038] Embodiment 9. The method of embodiment 8, wherein:(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 received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody.

[0039] Embodiment 10. The method of embodiment 8 or 9, wherein:(a) the subject has a progression free survival of at least or about 12.5 months following the treatment, optionally wherein the subject has a progression free survival of 12 to 13 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 12.5 months, optionally wherein median progression free survival in the treated population is 12 to 13 months; or(c) median progression free survival is at least or about 12.5 months for a population of subjects treated with the method, optionally wherein median progression free survival is 12 to 13 months for a population of subjects treated with the method.

[0040] Embodiment 11. The method of embodiment 8 or 9, wherein:(a) the subject has an overall survival of at least or about 31.5 months following the treatment, optionally wherein the subject has an overall survival of 31 to 32 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 31.5 months, optionally wherein median overall survival in the treated population is 31 to 32 months; or(c) median overall survival is at least or about 31.5 months for a population of subjects treated with the method, optionally wherein median overall survival is 31 to 32 months for a population of subjects treated with the method.

[0041] Embodiment 12. The method of embodiment 8 or 9, wherein the subject is eligible to receive cisplatin treatment (cisplatin eligible), and wherein:(a) the subject has a progression free survival of at least or about 14.6 months following the treatment, optionally wherein the subject has a progression free survival of 14 to 15 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 14.6 months, optionally wherein median progression free survival in the treated population is 14 to 15 months; or(c) median progression free survival is at least or about 14.6 months for a population of subjects treated with the method, optionally wherein median progression free survival is 14 to 15 months for a population of subjects treated with the method.

[0042] Embodiment 13. The method of embodiment 8 or 9, wherein the subject is ineligible to receive cisplatin treatment (cisplatin eligible), and wherein:(a) the subject has a progression free survival of at least or about 10.6 months following the treatment, optionally wherein the subject has a progression free survival of 10 to 11 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10.6 months, optionally wherein median progression free survival in the treated population is 10 to 11 months; or(c) median progression free survival is at least or about 10.6 months for a population of subjects treated with the method, optionally wherein median progression free survival is 10 to 11 months for a population of subjects treated with the method.

[0043] Embodiment 14. The method of any one of embodiments 1 to 5, 8 or 9, wherein the subject has expression of PD-L1 no less than CPS of 10, and optionally wherein:(a) the subject has a progression free survival of at least or about 18.5 months following the treatment, optionally wherein the subject has a progression free survival of 18 to 19 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 18.5 months, optionally wherein median progression free survival in the treated population is 18 to 19 months; or(c) median progression free survival is at least or about 18.5 months for a population of subjects treated with the method, optionally wherein median progression free survival is 18 to 19 months for a population of subjects treated with the method.

[0044] Embodiment 15. The method of any one of embodiments 1 to 5, 8 or 9, wherein the subject has expression of PD-L1 less than CPS of 10, and optionally wherein:(a) the subject has a progression free survival of at least or about 10.5 months following the treatment, optionally wherein the subject has a progression free survival of 10 to 11 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10.5 months, optionally wherein median progression free survival in the treated population is 10 to 11 months; or(c) median progression free survival is at least or about 10.5 months for a population of subjects treated with the method, optionally wherein median progression free survival is 10 to 11 months for a population of subjects treated with the method.

[0045] Embodiment 16. The method of any one of embodiments 1 to 5, 8 or 9, wherein the subject does not have liver metastases, and optionally wherein:(a) the subject has a progression free survival of at least or about 16.4 months following the treatment, optionally wherein the subject has a progression free survival of 16 to 17 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 16.4 months, optionally wherein median progression free survival in the treated population is 16 to 17 months; or(c) median progression free survival is at least or about 16.4 months for a population of subjects treated with the method, optionally wherein median progression free survival is 16 to 17 months for a population of subjects treated with the method.

[0046] Embodiment 17. The method of any one of embodiments 1 to 5, 8 or 9, wherein the subject has liver metastases, and optionally wherein:(a) the subject has a progression free survival of at least or about 8.2 months following the treatment, optionally wherein the subject has a progression free survival of 8 to 9 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 8.2 months, optionally wherein median progression free survival in the treated population is 8 to 9 months; or(c) median progression free survival is at least or about 8.2 months for a population of subjects treated with the method, optionally wherein median progression free survival is 8 to 9 months for a population of subjects treated with the method.

[0047] Embodiment 18. The method of any one of embodiments 1 to 5, 8 or 9, wherein the race of the subject is white, and optionally wherein:(a) the subject has a progression free survival of at least or about 10.4 months, optionally wherein the subject has a progression free survival of 10 to 11 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10.4 months, optionally wherein median progression free survival in the treated population is 10 to 11 months; or(c) median progression free survival is at least or about 10.4 months for a population of subjects treated with the method, optionally wherein median progression free survival is 10 to 11 months for a population of subjects treated with the method.

[0048] Embodiment 19. The method of any one of embodiments 1 to 5, 8 or 9, wherein the race of the subject is not white, and optionally wherein:(a) the subject has a progression free survival of at least or about 22.3 months, optionally wherein the subject has a progression free survival of 22 to 23 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 22.3 months, optionally wherein median progression free survival in the treated population is 22 to 23 months; or(c) median progression free survival is at least or about 22.3 months for a population of subjects treated with the method, optionally wherein median progression free survival is 22 to 23 months for a population of subjects treated with the method.

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

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

[0051] Embodiment 22. The method of any one of embodiments 1 to 19, wherein the disease site of origin is in the upper tract.

[0052] Embodiment 23. The method of any one of embodiments 1 to 19, wherein the disease site of origin is in the lower tract.

[0053] Embodiment 24. The method of any one of embodiments 1 to 23, wherein the subject has a PD-L1 expression combined positive score (CPS) greater than or equal to 10.

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

[0055] Embodiment 26. The method of any one of embodiments 1 to 19, wherein the subject has a Nectin-4 H-score between 0 and 300.

[0056] Embodiment 27. The method of any one of embodiments 1 to 19, wherein the subject has a Nectin-4 H-score between 0 and 200.

[0057] Embodiment 28. The method of any one of embodiments 1 to 19, wherein the subject has a Nectin-4 H-score between 0 and 150.

[0058] Embodiment 29. The method of any one of embodiments 1 to 19, wherein the method does not comprise determining PD-L1 expression or Nectin-4 expression of the subject.

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

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

[0061] Embodiment 32. The method of any one of embodiments 1 to 31, wherein the anti-PD-1 antibody or antigen binding fragment thereof comprises: (a) a light chain variable region comprising 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 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 heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:31, respectively.

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

[0063] Embodiment 34. The method of any one of embodiments 1 to 33, wherein the anti-PD-1 antibody or antigen binding fragment thereof 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.

[0064] Embodiment 35. The method of any one of embodiments 1 to 33, wherein the anti-PD-1 antibody comprises (a) a heavy chain comprising SEQ ID NO: 33 and (b) a light chain comprising SEQ ID NO:28.

[0065] Embodiment 36. The method of any one of embodiments 1 to 35, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14, or wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 16, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 17, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 19, CDR-L2 comprising the amino acid sequence of SEQ ID NO:20, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

[0066] Embodiment 37. The method of any one of embodiments 1 to 35, wherein the anti-191P4D12 antibody or antigen binding fragment thereof 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 wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO: 16, CDR-H2 consisting of the amino acid sequence of SEQ ID NO: 17, CDR-H3 consisting of the amino acid sequence of SEQ ID NO: 18; CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 19, CDR-L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO:21.

[0067] Embodiment 38. The method of any one of embodiments 1 to 37, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.

[0068] Embodiment 39. The method of any one of embodiments 1 to 38, wherein the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ IDNO:7 and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.

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

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

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

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

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

[0074] Embodiment 45. The method of embodiment 44, wherein the linker is an enzyme-cleavable linker, and wherein the linker forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof.

[0075] Embodiment 46. The method of embodiment 44 or 45, wherein the linker has a formula of: -Aa-Ww-Yy-; wherein -A- is a stretcher unit, a is 0 or 1; -W- is an amino acid unit, w is an integer ranging from 0 to 12; and -Y- is a spacer unit, y is 0, 1, or 2.

[0076] Embodiment 47. The method of embodiment 46, wherein the stretcher unit has the structure of Formula (1) below; the amino acid unit is valine-citrulline; and the spacer unit is a PAB group comprising the structure of Formula (2) below:Formula (2).

[0077] Embodiment 48. The method of embodiment 46 or 47, wherein the stretcher unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof; and wherein the spacer unit is linked to MMAE via a carbamate group.

[0078] Embodiment 49. The method of any one of embodiments 1 to 48, wherein the ADC comprises from 1 to 20 units of MMAE per antibody or antigen binding fragment thereof.

[0079] Embodiment 50. The method of any one of embodiments 1 to 49, wherein the ADC comprises from 1 to 10 units of MMAE per antibody or antigen binding fragment thereof.

[0080] Embodiment 51. The method of any one of embodiments 1 to 50, wherein the ADC comprises from 2 to 8 units of MMAE per antibody or antigen binding fragment thereof.

[0081] Embodiment 52. The method of any one of embodiments 1 to 51, wherein the ADC comprises from 3 to 5 units of MMAE per antibody or antigen binding fragment thereof.

[0082] Embodiment 53. The method of any one of embodiments 1 to 52, wherein the ADC has the following structure:wherein L- represents the anti-191P4D12 antibody or antigen binding fragment thereof and p is from 1 to 10.

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

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

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

[0086] Embodiment 57. The method of any one of embodiments 53 to 56, wherein p is about 4.

[0087] Embodiment 58. The method of any one of embodiments 53 to 54, wherein the average p value of the effective amount of the antibody drug conjugates is about 3.8.

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

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

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

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

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

[0093] Embodiment 64. The method of any one of embodiments 1 to 63, wherein the ADC is administered to the subject by an IV injection or infusion up to 2 days of a 21 -day treatment cycle.

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

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

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

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

[0098] Embodiment 69. The method of any one of embodiments 1 to 68, wherein the ADC is formulated in 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 wherein the pH of the pharmaceutical composition is about 6.0 at 25°C.

[0099] Embodiment 70. The method of any one of embodiments 1 to 68, wherein the ADC is formulated in 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 wherein the pH of the pharmaceutical composition is about 6.0 at 25°C.

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

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

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

[0103] Embodiment 74. The method of embodiment 71, wherein:(a) the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg; and(b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 400 mg every 42 days.

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

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

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

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

[0108] Embodiment 79. The method of any one of embodiments 1 to 76, whereby the subject has a complete response following the treatment.

[0109] Embodiment 80. The method of any one of embodiments 1 to 77, wherein the subject has a partial response following the treatment.

[0110] Embodiment 81. The method of any one of embodiments 1 to 78, wherein the subject has a stable disease following the treatment.

[0111] Embodiment 82. The method of any one of embodiments 1 to 81, wherein the subject has a Brief Pain Inventory Short Form (BPI-SF) worst pain score of about zero (0) prior to administration of the ADC to the subject, and wherein after administration of the ADC to the subject, the subject has an improved BPI-SF worst pain score.

[0112] Embodiment 83. The method of any one of embodiments 1 to 81, wherein the subject has a BPI-SF worst pain baseline score of about zero (0) prior to administration of the ADC to the subject, and wherein after administration of the ADC to the subject, the subject has a change from worst pain baseline score of about -0.3 to about -1.2.

[0113] Embodiment 84. The method of any one of embodiments 1 to 81, wherein the subject has a BPI-SF worst pain baseline score of about zero (0) prior to administration of the ADC to the subject, and wherein after administration of the ADC to the subject, the subject has a change from worst pain baseline score of about -0.61.

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

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

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

[0117] Embodiment 86. The method of any one of embodiments 1 to 85, wherein the subject is human.4. Brief Description of the Drawings

[0118] FIGS. 1A-1E depict the nucleotide and amino acid sequences of nectin-4 protein (FIG. 1A), the nucleotide and amino acid sequences of the heavy chain (FIG. IB) and light chain (FIG. 1C) of Ha22-2(2.4)6.1, and the amino acid sequences of the heavy chain (FIG. ID) and light chain of Ha22-2(2.4)6.1 (FIG. IE).

[0119] FIG. 2 depicts the study stages of the clinical study, which is a phase 3 study of enfortumab vedotin combined with pembrolizumab as first-line treatment in patients with unresectable locally advanced or metastatic urothelial cancer (la / mUC), as described in Section 6.1.

[0120] FIGS. 3A-3C depict RECIST Criteria, version 1.1. FIG. 3A shows Table 2, which provides time point response: patients with target (+ / - non-target) disease. FIG. 3B shows Table 2, which provides time point response: patients with non-target disease only. FIG. 3C shows Table 3, which provides best overall response when confirmation of CR and PR are required.

[0121] FIG. 4 depicts the European Organization for the Research and Treatment (EORTC) Core Quality of Life (QLQ-C-30) assessment (EORTC-QLQ-C-30, current version, Version 3), as described in Section 6.1.

[0122] FIG. 5 depicts the EuroQol-5 Dimensions (EQ-5D-5L) described in Section 6.1.

[0123] FIG. 6 depicts an initial graph of multiplicity adjustment (2 sided FWER=5%). a is a positive number close to zero, indicating the potential to pass alpha to ORR only if both PFS and OS are statistically significant. FWER=family wise error rate.

[0124] FIG. 7 depicts the overall study design of the clinical study described in Section 6.1.

[0125] FIGS. 8A and 8B show the statistical testing methods used in the clinical study described in Section 6.1. FIG. 8A shows the efficacy boundaries for PFS analysis. FIG. 8B shows the efficacy boundaries for OS analysis.

[0126] FIG. 9 is a table showing a Summary of Disposition of subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0127] FIG. 10 is a table showing Stratification Factors at Randomization for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0128] FIG. 11 is a table showing a Summary of Demographics for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. *Includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple races, and others.

[0129] FIG. 12 is a table showing a Summary of Baseline Characteristics for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0130] FIG. 13 is a table showing a Summary of Disease Characteristics for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0131] FIG. 14 is a table showing a Summary of Prior Anticancer Therapies for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0132] FIG. 15 is a table showing the Duration of Treatment for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0133] FIG. 16 is a table showing the Summary of Subsequent Anticancer Therapies for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0134] FIGS. 17A and 17B depict progression-free survival (PFS) per blinded independent central review for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. FIG. 17A shows a graph of PFS (in %) versus time (in months). FIG. 17B is a table that provides PFS data in the EV + Pembro and Plat + Gem arms.

[0135] FIGS. 18A, 18B, 18C, 18D, and 18E depict progression-free survival (PFS) subgroup analysis by blinded independent central review (BICR). FIG. 18A is a table showing the progression-free survival (PFS) subgroup analysis of subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. A indicates that the PFS has not been reached. FIG. 18B shows a graph of PFS (in %) versus time (inmonths) observed in subjects with liver metastases present. FIG. 18C shows a graph of PFS (in %) versus time (in months) observed in subjects with liver metastases absent. FIG. 18D shows a graph of PFS (in %) versus time (in months) observed in subjects with visceral metastases present. FIG. 18E shows a graph of PFS (in %) versus time (in months) observed in subjects with lymph node only metastases. The estimated HR and corresponding 95% confidence interval from the stratified Cox proportional hazards regression model is also presented. A hazard ratio <1 favors the EV+P arm.

[0136] FIGS. 19A and 19B depict progression-free survival (PFS) per blinded independent central review in the clinical study described in Section 6.1 for the cisplatin eligible (FIG. 19A) and ineligible (FIG. 19B) subgroups.

[0137] FIGS. 20A and 20B depict progression-free survival (PFS) per blinded independent central review in the clinical study described in Section 6.1 for the PD-L1 High Expression (CPS > 10) (FIG. 20A) and the PD-L1 Low Expression (CPS < 10) (FIG. 20B) subgroups.

[0138] FIGS. 21A and 21B depict overall survival (OS) - ITT for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. Median f / u = median follow-up time. FIG. 21A shows a graph of OS (in %) versus time (in months). FIG. 21B is a table that provides OS data in the EV + Pembro and Plat + Gem arms.

[0139] FIGS. 22A, 22B, 22C, 22D, and 22E depict subgroup analysis of overal survival (OS). FIG. 22A is a table showing the overall survival (OS) subgroup analysis of subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. A indicates that the OS has not been reached. FIG. 22B shows a graph of OS (in %) versus time (in months) observed in subjects with liver metastases present. FIG. 22C shows a graph of OS (in %) versus time (in months) observed in subjects with liver metastases absent. FIG. 22D shows a graph of OS (in %) versus time (in months) observed in subjects with visceral metastases present. FIG. 22E shows a graph of OS (in %) versus time (in months) observed in subjects with lymph node only metastases. The estimated HR and corresponding 95% confidence interval from the stratified Cox proportional hazards regression model is also presented. A hazard ratio <1 favors the EV+P arm.

[0140] FIGS. 23A and 23B depict overall survival (OS) per blinded independent central review in the clinical study described in Section 6.1 for the cisplatin eligible (FIG. 23A) and ineligible (FIG. 23B) subgroups.

[0141] FIGS. 24A and 24B depict overall survival (OS) per blinded independent central review in the clinical study described in Section 6.1 for the PD-L1 High Expression (CPS > 10) (FIG. 24A) and the PD-L1 Low Expression (CPS < 10) (FIG. 24B) subgroups.

[0142] FIG. 25 is a table showing the Objective Response Rate (ORR) per blinded independent central review for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0143] FIG. 26 is a table showing the Objective Response Rate (ORR) subgroup analysis of subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. A indicates that the ORR has not been reached.

[0144] FIGS. 27A and 27B depict duration of response (DOR) per blinded independent central review for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1. FIG. 27A shows a graph of responders without PD or Death (in %) versus time (in months). FIG. 27B is a table that provides DOR data in the EV + Pembro and Plat + Gem arms.

[0145] FIG. 28 is a table providing an overall summary of treatment-emergent adverse events (TEAEs) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0146] FIG. 29 is a table providing TEAEs occurring in >20% of subjects (by preferred term) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0147] FIG. 30 depicts TEAEs occurring in >15% of subjects (by preferred term) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0148] FIG. 31 is a table providing grade >3 TEAEs occurring in >5% of subjects (by preferred term) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0149] FIG. 32 depicts grade >3 TEAEs occurring in >5% of subjects (by preferred term) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0150] FIG. 33 is a table providing serious TEAEs Occurring in >2% of subjects (by preferred term) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0151] FIG. 34 is a table providing TEAEs leading to death (by preferred term) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0152] FIG. 35 is a table providing TEAEs leading to discontinuation of any study drugs occurring in >1% of subjects by preferred term for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1.

[0153] FIG. 36 is a table providing adverse events of special interest (AESI) for Enfortumab Vedotin (EV) for subjects in the EV + Pembro and Plat + Gem arms of the clinical study described in Section 6.1 (and EV Monotherapy).

[0154] FIG. 37 is a table providing pembrolizumab adverse events of special interest (AEOSI) occurring in >2 subjects in the EV+Pembro arm of the clinical study described in Section 6.1.

[0155] FIG. 38 is a table providing key demographics and baseline characteristics for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin-ineligible subjects. In FIG. 38, the superscript “a” indicates the following: includes renal pelvis, ureter, kidney. In FIG. 38, the superscript “b” indicates the following:bIncludes bladder, urethra, other. In FIG. 38, the superscript “c” indicates the following:CA patient may have metastatic disease in more than one location. In FIG. 38, the superscript “d” indicates the following:dPatients had locally advanced disease without metastasis to lymph nodes or distant organs. In FIG. 38, the superscript “e” indicates the following:eCPS status was determined using the validated PD-(L)1 IHC 22C3 pharmDx assay at Neogenomics and Labcorp; 2 patients in the EV+P arm and 1 patient in the chemotherapy arm had samples that were of inadequate tissue quality for analysis.

[0156] FIG. 39 is a table showing a summary of disposition of subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin-ineligible subjects. In FIG. 39, the superscript “a” indicates the following:aPatients in EV+P arm received EV until disease progression or toxicity (per protocol, there was no maximum number of EV cycles) or completion of maximum cycles. (35 cycles for P); chemotherapy could be given for a maximum of 6 cycles. In FIG. 39, the superscript “b” indicates the following:bPatients completed 35 cycles of P and had discontinued EV prior to P. In FIG. 39, the superscript “c” indicates the following:c6 patients on EV+P: Death (2), Grade 3 Asthenia outside of protocol reporting period (1), Lost to follow-up (1), Chronic Lymphatic Leukemia (1), General Deterioration (1); 1 patient on Chemotherapy: Patient insurance would not cover chemotherapy treatment on clinical trial (1).

[0157] FIG. 40 is a table showing reasons for cisplatin ineligibility in connection with cisplatin-ineligible subjects in connection with the clinical study described in Example 3. In FIG. 40, the superscript “a” indicates the following:aPatients may be counted in more than one category for cisplatin-ineligibility.

[0158] FIG. 41A provides the best Overall Response Rate (ORR) per RECIST by blinded independent central review (BICR) for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin- ineligible subjects. In FIG. 41 A, the superscript “a” indicates the following:aBest overall response according to RECIST vl .1. CR or PR was confirmed with repeat scans >28 days after initial response. In FIG. 41A, the superscript “b” indicates the following:bPatients best overall response was determined to be not evaluable per RECIST vl .1 or patients had no response assessment post-baseline. FIG. 41B provides the time to objective response for the EV+P and chemotherapy arms in connection with cisplatin-ineligible subjects. In FIG. 41B, the superscript “a” indicates the following:aAny objective response defined as confirmed CR or PR. In FIG. 41B, the superscript “b” indicates the following:bTime from randomization to first documentation of CR or PR that is subsequently confirmed.

[0159] FIG. 42 depicts duration of objective response (DOR) per blinded independent central review (BICR) for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin-ineligible subjects. In particular, FIG. 42 shows a graph of responders without PD or Death (in %) versus time (in months).

[0160] FIG. 43 is a table showing the summary of subsequent therapies for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin-ineligible subjects. In FIG. 43, the superscript “a” indicates the following:a62 (31.3%) patients in the EV+P arm remained on treatment at DCO; all patients in chemotherapy arm were off study treatment. In FIG. 43, the superscript “b” indicates the following:bWhen platinum-based therapy and a PD-1 / L1 agent were given in the same line of therapy, the therapy was categorized under Platinum-based therapy.

[0161] FIG. 44 is a table showing the treatment-related adverse events for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin-ineligible subjects. TRAEs shown are any grade by preferred term in >20% of patients for any grade in either arm.

[0162] FIG. 45 is a table providing EV treatment-related adverse events of special interest (AESI) for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 3 in connection with cisplatin-ineligible subjects.

[0163] FIG. 46 is a table providing pembrolizumab treatment-emergent adverse events of special interest (AEOSI) in connection with cisplatin-ineligible subjects. In FIG. 46, the asterisk indicates the following: *There are differences in the rates of skin reactions reported for EV treatment-related AESIs and P TEAEs of special interest because these adverse events were reported via different methodologies developed for EV and P monotherapies, respectively.

[0164] FIG. 47 is a table providing key demographics and baseline characteristics for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects. In FIG. 47, the superscript “a” indicates the following: includes renal pelvis, ureter, kidney. In FIG. 47, the superscript “b” indicates the following:bIncludes bladder, urethra, other. In FIG. 47, the superscript “c” indicates the following:CA patient may have metastatic disease in more than one location. In FIG. 47, the superscript “d” indicates the following:dPatients had locally advanced disease without metastasis to lymph nodes or distant organs. In FIG. 47, the superscript “e” indicates the following:eCPS status was determined using the validated PD-(L)1 IHC 22C3 pharmDx assay at Neogenomics and Labcorp; 2 patients in the EV+P arm and 4 patients in the chemotherapy arm had samples that were of inadequate tissue quality for analysis.

[0165] FIG. 48 is a table showing a summary of disposition of subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects. In FIG. 48, the superscript “a” indicates the following:aPatients in EV+P arm received EV until disease progression or toxicity (per protocol, there was no maximum number of EV cycles) or completion of maximum cycles. (35 cycles for P); chemotherapy could be given for a maximum of 6 cycles. In FIG. 48, the superscript “b” indicates the following:bPatients completed 35 cycles of P and had discontinued EV prior to P. In FIG. 48, the superscript “c” indicates the following:C1 patient on EV+P: death; 1 patient on Chemotherapy: respiratory failure.

[0166] FIG. 49A provides the best Overall Response Rate (ORR) per RECIST by blinded independent central review (BICR) for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin- eligible subjects. In FIG. 49A, the superscript “a” indicates the following:aBest overall response according to RECIST vl .1. CR or PR was confirmed with repeat scans >28 daysafter initial response. In FIG. 49A, the superscript “b” indicates the following:bPatients best overall response was determined to be not evaluable per RECIST vl .1 or patients had no response assessment post-baseline. FIG. 49B provides the time to objective response for the EV+P and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects. In FIG. 49B, the superscript “a” indicates the following:aAny objective response defined as confirmed CR or PR. In FIG. 49B, the superscript “b” indicates the following:bTime from randomization to first documentation of CR or PR that is subsequently confirmed.

[0167] FIG. 50 depicts duration of objective response (DOR) per blinded independent central review (BICR) for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects. In particular, FIG. 50 shows a graph of responders without PD or Death (in %) versus time (in months).

[0168] FIG. 51 is a table showing the summary of subsequent therapies for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects. In FIG. 51, the superscript “a” indicates the following:a82 (33.6%) patients in the EV+P arm remained on treatment at DCO; all patients in chemotherapy arm were off study treatment. In FIG. 51, the superscript “b” indicates the following:bWhen platinum-based therapy and a PD-1 / L1 agent were given in the same line of therapy, the therapy was categorized under Platinum-based therapy.

[0169] FIG. 52 is a table showing the treatment-related adverse events for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects. In FIG. 52, the superscript “a” indicates the following:aTRAEs shown are any grade by preferred term in >20% of patients for any grade in either arm.

[0170] FIG. 53 is a table providing EV treatment-related adverse events of special interest (AESI) for subjects in the EV + Pembro and chemotherapy arms of the clinical study described in Example 4 in connection with cisplatin-eligible subjects.

[0171] FIG. 54 is a table providing pembrolizumab treatment-emergent adverse events of special interest (AEOSI) in connection with cisplatin-eligible subjects. In FIG. 54, the asterisk indicates the following: *There are differences in the rates of skin reactions reported for EV treatment-related AESIs and P TEAEs of special interest because these adverse events were reported via different methodologies developed for EV and P monotherapies, respectively.

[0172] FIG. 55 depicts progression-free survival (PFS) per blinded independent central review in the clinical study described in Section 6.5 for the pan-Asian subgroup. EV, enfortumab vedotin; Gem, gemcitabine; HR, hazard ratio; ITT, intention to treat; Pembro, pembrolizumab; PFS, progression-free survival; Plat, platinum.

[0173] FIG. 56 depicts overall survival (OS) per blinded independent central review in the clinical study described in Section 6.5 for the pan-Asian subgroup. EV, enfortumab vedotin; Gem, gemcitabine; HR, hazard ratio; ITT, intention to treat; OS, overall survival; Pembro, pembrolizumab; Plat, platinum.

[0174] FIG. 57A depicts time to pain progression (TTPP) for subjects treated with enfortumab vedotin combined with pembrolizumab (EV+P) versus subjects treated with Plat + Gem. FIG. 57B provides data regarding TTPP for subjects treated with EV+P versus subjects treated with Plat + Gem.

[0175] FIG. 58 depicts an EORTC-QLQ C30 Compliance. PRO FAS analysis. EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire; EV+P, Enfortumab vedotin plus pembrolizumab; PRO FAS, Patient-reported outcome full analysis set.

[0176] FIG. 59 depicts overall mean change from baseline at week 26 in Brief Pain Inventory - Short Form (BPLSF) worst pain score. BPI-SF, Brief Pain Inventory Short Form; EV+P, Enfortumab vedotin plus pembrolizumab; PBC, platinum-based chemotherapy.

[0177] FIG. 60 depicts LS mean change from baseline in BPI-SF scale scores through week 26. BPI-SF, Brief Pain Inventory Short Form; CI, confidence interval; EV+P, Enfortumab vedotin plus pembrolizumab; LS, least squares; SE, standard error.

[0178] FIG. 61 depicts overall mean change from baseline through week 26 in BPI-SF score among those with moderate to severe pain at baseline. BPI-SF, Brief Pain Inventory Short Form; EV+P, Enfortumab vedotin plus pembrolizumab; PBC, platinum-based chemotherapy; PRO, patient reported outcome.

[0179] FIG. 62 depicts LS mean change from baseline in BPI-SF scale scores through week 26 among those with moderate to severe pain at baseline. BPI-SF, Brief Pain Inventory Short Form; CI, confidence interval; EV+P, Enfortumab vedotin plus pembrolizumab; LS, least squares; SE, standard error.

[0180] FIG. 63A depicts overall mean change from baseline through week 26 in EORTC QLQ-C30 GHS / QoL. FIG. 63B depicts overall mean change from baseline through week 26 in functioning scale scores and GHS / QoL. EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire; EV+P,Enfortumab vedotin plus pembrolizumab; GHS, global health status; LS, least squares; QoL, quality of life; SE, standard error.

[0181] FIG. 64A depicts overall mean change from baseline through week 26 in EORTC QLQ-C30 GHS / QoL by cisplatin-eligibility: cisplatin-eligible. FIG. 64B depicts overall mean change from baseline through week 26 in EORTC QLQ-C30 GHS / QoL by cisplatineligibility: cisplatin-ineligible. EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire; GHS, global health status; LS, least squares; QoL, quality of life.

[0182] FIG. 65 depicts time to confirmed deterioration in EORTC QLQ-C30 QoL and functioning scales. CI, confidence interval; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire; EV+P, Enfortumab vedotin plus pembrolizumab; LS, least squares; mTTCD, median time to confirmed deterioration; PBC, platinum-based chemotherapy; QoL, quality of life; SD, standard deviation.

[0183] FIG. 66A depicts overall mean changes from baseline through week 26 in EORTC QLQ-C30 GHS / QoL. FIG. 66B depicts overall mean changes from baseline through week 26 in functioning scale scores in patients with moderate / severe pain at baseline.

[0184] FIG. 67 depicts H-score of Nectin-4 expression by biopsy origin (i.e., either primary or metastatic tissues).

[0185] FIG. 68A depicts H-scores of Nectin-4 expression at across both arms (N=800). The y-axis shows Nectin-4 expression at baseline (H-score) and the x-axis shows individual patients. FIG. 68B provides data regarding H-scores of Nectin-4 expression in the EV+P and chemotherapy arms in each of the following subgroups: <150, >150 to <225, and >225.

[0186] FIG. 69A and FIG. 69B depict Kaplan-Meier plots of PFS for the <275 and >275 Nectin-4 H-score subgroups, respectively.

[0187] FIG. 70A and FIG. 70B depict Kaplan-Meier plots of OS for the <275 and >275 Nectin-4 H-score subgroups, respectively.

[0188] FIG. 71A and FIG. 71B depict PFS and OS subgroup analyses by Nectin-4 H- scores, respectively.

[0189] FIG. 72 depicts ORR (%) for the <275 and >275 Nectin-4 H-score subgroups (wherein the median Nectin-4 H-score was 275 across patients in both arms), as well as for the <150, >150 to <225, and >225 Nectin-4 H-score subgroups.

[0190] FIG. 73 depicts provides the expression distribution of Nectin-4 and PD-L1 in the EV+P (N=442) and chemotherapy (N=444) arms for the <275 and >275 Nectin-4 H-scoresubgroups (wherein the median Nectin-4 H-score was 275 across patients in both arms), as well as for a subjects without nectin-4 results.

[0191] FIG. 74A, FIG. 74B, FIG. 74C, and FIG. 74D show Kaplan-Meier plots of PFS (%) for each of the following groups: (1) Subgroup having Nectin-4 H-score of <275 and a low level of PD-L1 expression (CPS <10) (see FIG. 74A); (2) Subgroup having Nectin-4 H- score of <275 and a high level of PD-L1 expression (CPS >10) (see FIG. 74B); (3) Subgroup having Nectin-4 H-score of >275 and a low level of PD-L1 expression (CPS <10) (see FIG. 74C); and (4) Subgroup having Nectin-4 H-score of >275 and a high level of PD-L1 expression (see FIG. 74D) (note for (1) to (4): the median Nectin-4 H-score was 275 across patients in both arms) (CPS >10).

[0192] FIG. 75A, FIG. 75B, FIG. 75C, and FIG. 75D show Kaplan-Meier plots of OS (%) for each of the following groups: (1) Subgroup having Nectin-4 H-score of <275 and a low level of PD-L1 expression (CPS <10) (see FIG. 75A); (2) Subgroup having Nectin-4 H- score of <275 and a high level of PD-L1 expression (CPS >10) (see FIG. 75B); (3) Subgroup having Nectin-4 H-score of >275 and a low level of PD-L1 expression (CPS <10) (see FIG. 75C); and (4) Subgroup having Nectin-4 H-score of >275 and a high level of PD-L1 expression (see FIG. 75D) (note for (1) to (4): the median Nectin-4 H-score was 275 across patients in both arms) (CPS >10).5. Detailed Description

[0193] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for describing particular embodiments only, and is not intended to be limiting.5.1 Definitions

[0194] Techniques and procedures described or referenced herein include those that are generally well understood and / or commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3d 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 Diibel eds., 2d ed. 2010).

[0195] Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in theart. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0196] The term “antibody,” “immunoglobulin,” or “Ig” is used interchangeably herein, and is used in the broadest sense and specifically covers, for example, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full length or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity), formed from at least two intact antibodies, single chain antibodies, and fragments thereof, as described below. An antibody can be human, humanized, chimeric and / or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc. The term “antibody” is intended to include a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy -terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). In specific embodiments, the specific molecular antigen can be bound by an antibody provided herein, including a polypeptide or an epitope. Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti -idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which refers to a portion of an antibody heavy or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc. , Fab fragments, F(ab’) fragments, F(ab)2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigenbinding site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found in, for example, 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; Pliickthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990). The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2) of immunoglobulin molecule. Antibodies may be agonistic antibodies or antagonistic antibodies.

[0197] The term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which can include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0198] An “antigen” is a structure to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, an antigen is associated with a cell, for example, is present on or in a cell, for example, a cancer cell.

[0199] An “intact” antibody is one comprising an antigen-binding site as well as a CL and at least heavy chain constant regions, CHI, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0200] The terms “antigen binding fragment,” “antigen binding domain,” “antigen binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., the CDRs). “Antigen-binding fragment” as used herein include “antibody fragment,” which comprise a portion of an intact antibody, such as the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include, without limitation, Fab, Fab’, F(ab’)2, and Fv fragments; diabodies and di-diabodies (see, 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., 2003, Nat. Med. 9: 129-34; WO 93 / 11161; and U.S. Pat. Nos. 5,837,242 and 6,492,123); single-chain antibody molecules (see, e.g., U.S. Pat. Nos. 4,946,778; 5,260,203; 5,482,858; and 5,476,786); dual variable domain antibodies (see, e.g., U.S. Pat. No. 7,612,181); single variable domain antibodies (sdAbs) (see, e.g., Woolven etal.., 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.

[0201] The terms “binds” or “binding” refer to an interaction between molecules including, for example, to form a complex. Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. A complex can also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as an antigen, is the affinity of the antibody or functional fragment for that epitope. The ratio of dissociation rate (koir) to association rate (kon) of a binding molecule (e.g., an antibody) to a monovalent antigen (koff / kon) is the dissociation constant KD, which is inversely related to affinity. The lower the KD value, the higher the affinity of the antibody. The value of KD varies for different complexes of antibody and antigen and depends on both konand koir. The dissociation constant KD for an antibody provided herein can be determined using any method provided herein or any other method well-known to those skilled in the art. The affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen. When complex antigens containing multiple, repeating antigenic determinants, such as a polyvalent antigen, come in contact with antibodies containing multiple binding sites, the interaction of antibody with antigen at one site will increase the probability of a reaction at a second site. The strength of such multiple interactions between a multivalent antibody and antigen is called the avidity.

[0202] In connection with the antibody or antigen binding fragment thereof described herein terms such as “bind to,” “that specifically bind to,” and analogous terms are also used interchangeably herein and refer to binding molecules of antigen binding domains that specifically bind to an antigen, such as a polypeptide. An antibody or antigen binding fragment that binds to or specifically binds to an antigen may be cross-reactive with related antigens. In certain embodiments, an antibody or antigen binding fragment that binds to or specifically binds to an antigen does not cross-react with other antigens. An antibody or antigen binding fragment that binds to or specifically binds to an antigen can be identified, for example, by immunoassays, Octet®, Biacore®, or other techniques known to those of skill in the art. In some embodiments, an antibody or antigen binding fragment binds to or specifically binds to an antigen when it binds to an antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such asradioimmunoassays (RIA) and enzyme linked immunosorbent assays (ELISAs). Typically, a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding binding specificity. In certain embodiments, the extent of binding of an antibody or antigen binding fragment to a “non-targef ’ protein is less than about 10% of the binding of the binding molecule or antigen binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIA. With regard terms such as “specific binding,” “specifically binds to,” or “is specific for” means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. An antibody or antigen binding fragment that binds to an antigen includes one that is capable of binding the antigen with sufficient affinity such that the binding molecule is useful, for example, as a diagnostic agent in targeting the antigen. In certain embodiments, an antibody or antigen binding fragment that binds to an antigen has a dissociation constant (KD) of less than or equal to 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, an antibody or antigen binding fragment binds to an epitope of an antigen that is conserved among the antigen from different species (e.g., between human and cyno species).

[0203] “Binding affinity” generally refers to the strength of the sum total of noncovalent 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 indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any ofwhich can be used for purposes of the present disclosure. Specific illustrative embodiments include the following. In one embodiment, the “KD” or “KD value” may be measured by assays known in the art, for example by a binding assay. The KD may be measured in a RIA, for example, performed with the Fab version of an antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). The KD or KD value may also be measured by using biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by Octet®, using, for example, a Octet®QK384 system, or by Biacore®, using, for example, a Biacore®TM- 2000 or a Biacore®TM-3000. An “on-rate” or “rate of association” or “association rate” or “kon” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the Octet®QK384, the Biacore®TM-2000, or the Biacore®TM-3000 system.

[0204] In certain embodiments, the antibodies or antigen binding fragments can comprise “chimeric” sequences in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81 :6851-55).

[0205] In certain embodiments, the antibodies or antigen binding fragments can comprise portions of “humanized” forms of nonhuman (e.g., murine) antibodies that are chimeric antibodies that include human immunoglobulins (e.g., recipient antibody) in which the native CDR residues are replaced by residues from the corresponding CDR of a nonhuman species (e.g., donor antibody) such as mouse, rat, rabbit, or nonhuman primate comprising the desired specificity, affinity, and capacity. In some instances, one or more FR region residues of the human immunoglobulin are replaced by corresponding nonhuman residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. A humanized antibody heavy or light chain can comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a nonhuman immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. In certain embodiments, the humanized antibody will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, Jones et al., 1986, Nature 321 :522-25; Riechmannet 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. Pat. Nos: 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.

[0206] In certain embodiments, the antibodies or antigen binding fragments can comprise portions of a “fully human antibody” or “human antibody,” wherein the terms are used interchangeably herein and refer to an antibody that comprises a human variable region and, for example, a human constant region. In specific embodiments, the terms refer to an antibody that comprises a variable region and constant region of human origin. “Fully human” antibodies, in certain embodiments, can also encompass antibodies which bind polypeptides and are encoded by nucleic acid sequences which are naturally occurring somatic variants of human germline immunoglobulin nucleic acid sequence. The term “fully human antibody” includes antibodies comprising variable and constant regions corresponding to human germline immunoglobulin sequences as described by Kabat et al. (See Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). A “human antibody” is one that possesses an amino acid sequence which corresponds to that of an antibody produced by a human and / or has been made using any of the techniques for making human antibodies. This definition of a human antibody specifically excludes a humanized antibody comprising nonhuman 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 etal., 1991, J. Mol. Biol. 222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1 : 755-68). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985); Boerner et al, 1991, J. Immunol. 147(l):86-95; and van Dijk and van de Winkel, 2001, Curr. Opin. Pharmacol. 5: 368-74. Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., mice (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66; Briiggemann and Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58; and U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al., 2006, Proc. Natl. Acad. Sci. USA 103:3557-62 regarding human antibodies generated via a human B-cell hybridoma technology.

[0207] In certain embodiments, the antibodies or antigen binding fragments can comprise portions of a “recombinant human antibody,” wherein the phrase includes human antibodiesthat are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse or cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see e.g., Taylor, L. D. et al. (1992) Awe / . Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies can have variable and constant regions derived from human germline immunoglobulin sequences (See Kabat, E. A. et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242). In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0208] In certain embodiments, the antibodies or antigen binding fragments can comprise a portion of a “monoclonal antibody,” wherein the term as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts, and each monoclonal antibody will typically recognize a single epitope on the antigen. In specific embodiments, a “monoclonal antibody,” as used herein, is an antibody produced by a single hybridoma or other cell. The term “monoclonal” is not limited to any particular method for making the antibody. For example, the monoclonal antibodies useful in the present disclosure may be prepared by the hybridoma methodology first described by Kohler et al., 1975, Nature 256:495, or may be made using recombinant DNA methods in bacterial or eukaryotic animal or plant cells (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J. Mol. Biol. 222:581-97, for example. Other methods for the preparation of clonal cell lines and of monoclonal antibodies expressed thereby are well-known in the art. See, e.g., Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed. 2002).

[0209] A typical 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while 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 regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and y chains and four CH domains for p and a isotypes. Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain (CL) at its other end. The VL is aligned with the VH, and the CL is aligned with the first constant domain of the heavy chain (CHI). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, for example, Basic and Clinical Immunology 71 (Stites et al. eds., 8th ed. 1994); and Immunobiology (Janeway et al. eds., 5thed. 2001).

[0210] The term “Fab” or “Fab region” refers to an antibody region that binds to antigens. A conventional IgG usually comprises two Fab regions, each residing on one of the two arms of the Y-shaped IgG structure. Each Fab region is typically composed of one variable region and one constant region of each of the heavy and the light chain. More specifically, the variable region and the constant region of the heavy chain in a Fab region are VH and CHI regions, and the variable region and the constant region of the light chain in a Fab region are VL and CL regions. The VH, CHI, VL, and CL in a Fab region can be arranged in various ways to confer an antigen binding capability according to the present disclosure. For example, VH and CHI regions can be on one polypeptide, and VL and CL regions can be on a separate polypeptide, similarly to a Fab region of a conventional IgG. Alternatively, VH, CHI, VL and CL regions can all be on the same polypeptide and oriented in different orders as described in more detail in the sections below.

[0211] The term “variable region,” “variable domain,” “V region,” or “V domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the aminoterminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen.However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist 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” that are each about 9-12 amino acids long. The variable regions of heavy and light chains each comprise four FRs, largely adopting a P sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases form part of, the P sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed. 1991)). The constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). The variable regions differ extensively in sequence between different antibodies. In specific embodiments, the variable region is a human variable region.

[0212] The term “variable region residue numbering according to Kabat” or “amino acid position numbering as in Kabat”, and variations thereof, refer to the numbering system used for heavy chain variable regions or light chain variable regions of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, an FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 and three inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody. Other numbering systems have been described, for example, by AbM, Chothia, Contact, IMGT, and AHon.

[0213] The term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy -terminal portion includes a constant region. The constant region can be one of five distinct types, (e.g., isotypes) referred to as alpha (a), delta (5), epsilon (a), gamma (y), and mu (p), based on the amino acid sequence of the heavy chain constant region. The distinct heavy chains differ in size: a, 5, and y contain approximately 450 amino acids, while p and a contain approximately 550 amino acids. When combined with a light chain, these distinct types of heavy chains give rise to five well-known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, respectively, including four subclasses of IgG, namely IgGl, IgG2, IgG3, and IgG4.

[0214] The term “light chain” when used in reference to an antibody refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy -terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, referred to as kappa (K) or lambda (X) based on the amino acid sequence of the constant domains.

[0215] As used herein, the terms “hypervariable region,” “HVR,” “Complementarity Determining Region,” and “CDR” are used interchangeably. A “CDR” refers to one of three hypervariable regions (Hl, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH P-sheet framework, or one of three hypervariable regions (LI, L2 or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences.

[0216] CDR regions are well-known to those skilled in the art and have been defined by well-known numbering systems. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat el al., supra). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modelingsoftware (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Diibel eds., 2d ed. 2010)). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. Another universal numbering system that has been developed and widely adopted is ImMunoGeneTics (IMGT) Information System® (Lafranc et al., 2003, Dev. Comp. Immunol. 27(l):55-77). IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pliickthun, 2001, J. Mol. Biol. 309: 657-70. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well-known to one skilled in the art (see, e.g., Kabat, supra,' Chothia and Lesk, supra,' Martin, supra, Lefranc et al., supra). The residues from each of these hypervariable regions or CDRs are noted below in Table 1.Table 1

[0217] The boundaries of a given CDR may vary depending on the scheme used for identification. Thus, unless otherwise specified, the terms “CDR” and “complementarydetermining region” of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., “CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, or Contact method. In other cases, the particular amino acid sequence of a CDR is given.

[0218] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 or 26-35A (Hl), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in the VH.

[0219] The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The term refers to the portion of an immunoglobulin molecule comprising a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site. The constant region may contain the CHI, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0220] The term “framework” or “FR” refers to those variable region residues flanking the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues.

[0221] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations comprising a mixture of antibodies with and without the K447 residue. A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include Clq binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cellreceptor), etc. 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 domain) and can be assessed using various assays known to those skilled in the art. A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification (e.g., substituting, addition, or deletion). In certain embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, or from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of a parent polypeptide. The variant Fc region herein can possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, or at least about 90% homology therewith, for example, at least about 95% homology therewith.

[0222] As used herein, an “epitope” is a term in the art and refers to a localized region of an antigen to which a binding molecule (e.g., an antibody) can specifically bind. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous epitope. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope). It will be appreciated by one of skill in the art that, in general, a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. For example, in some embodiments, a binding molecule binds to a group of amino acids regardless of whether they are folded in a natural three dimensional protein structure. In other embodiments, a binding molecule requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.

[0223] The terms “polypeptide” and “peptide” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure may be based uponantibodies or other members of the immunoglobulin superfamily, in certain embodiments, a “polypeptide” can occur as a single chain or as two or more associated chains.

[0224] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the Federal or a state government, or listed in United States Pharmacopeia, European Pharmacopeia, or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0225] “Excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. The term “excipient” can also refer to a diluent, adjuvant (e.g., Freunds’ adjuvant (complete or incomplete) or vehicle.

[0226] In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. In some embodiments, a pharmaceutically acceptable excipient is an aqueous pH buffered solution.

[0227] The abbreviation “MMAE” refers to monomethyl auristatin E.

[0228] Unless otherwise indicated by context, a hyphen (-) designates the point of attachment to the pendant molecule.

[0229] The term “Chemotherapeutic Agent” refers to all chemical compounds that are effective in inhibiting tumor growth. Non-limiting examples of chemotherapeutic agents include alkylating agents; for example, nitrogen mustards, ethyleneimine compounds and alkyl sulphonates; antimetabolites, for example, folic acid, purine or pyrimidine antagonists;mitotic inhibitors, for example, anti-tubulin agents such as vinca alkaloids, auristatins and derivatives of podophyllotoxin; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, for example, DNA minor groove binders; and growth factor receptor antagonists. In addition, chemotherapeutic agents include cytotoxic agents (as defined herein), antibodies, biological molecules and small molecules.

[0230] As used herein, the term “conservative substitution” refers to substitutions of amino acids are known to those of skill in this art and may be made generally without altering the biological activity of the resulting molecule. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson, et al., MOLECULAR BIOLOGY OF THE GENE, The Benjamin / Cummings Pub. Co., p. 224 (4th Edition 1987)). Such exemplary substitutions are preferably made in accordance with those set forth in Table 2 and Table 3. For example, such changes include substituting any of isoleucine (I), valine (V), and leucine (L) for any other of these hydrophobic amino acids; aspartic acid (D) for glutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) and vice versa; and serine (S) for threonine (T) and vice versa. Other substitutions can also be considered conservative, depending on the environment of the particular amino acid and its role in the three-dimensional structure of the protein. For example, glycine (G) and alanine (A) can frequently be interchangeable, as can alanine (A) and valine (V). Methionine (M), which is relatively hydrophobic, can frequently be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are frequently interchangeable in locations in which the significant feature of the amino acid residue is its charge and the differing pK’s of these two amino acid residues are not significant. Still other changes can be considered “conservative” in particular environments (see, e.g. Table 3 herein; pages 13-15 “Biochemistry” 2nd ED. Lubert Stryer ed (Stanford University); Henikoff et al., PNAS 1992 Vol 89 10915-10919; Lei et al., J Biol Chem 1995 May 19; 270(20): 11882-11886). Other substitutions are also permissible and may be determined empirically or in accord with known conservative substitutions.Table 2. Amino Acid AbbreviationsTable 3. Amino Acid Substitution or Similarity MatrixAdapted from the GCG Software 9.0 BLOSUM62 amino acid substitution matrix (block substitution matrix). The higher the value, the more likely a substitution is found in related, natural proteins.A C D E F G H I K L M N P Q R S T V W Y .4 0 -2 -1 -2 0 -2 -1 -1 -1 -1 -2 -1 -1 -1 1 0 0 -3 -2 A9 -3 -4 -2 -3 -3 -1 -3 -1 -1 -3 -3 -3 -3 -1 -1 -1 -2 -2 C6 2 -3 -1 -1 -3 -1 -4 -3 1 -1 0 -2 0 -1 -3 -4 -3 D5 -3 -2 0 -3 1 -3 -2 0 -1 2 0 0 -1 -2 -3 -2 E6 -3 -1 0 -3 0 0 -3 -4 -3 -3 -2 -2 -1 1 3 F6 -2 -4 -2 -4 -3 0 -2 -2 -2 0 -2 -3 -2 -3 G8 -3 -1 -3 -2 1 -2 0 0 -1 -2 -3 -2 2 H4 -3 2 1 -3 -3 -3 -3 -2 -1 3 -3 -1 15 -2 -1 0 -1 1 2 0 -1 -2 -3 -2 K4 2 -3 -3 -2 -2 -2 -1 1 -2 -1 L5 -2 -2 0 -1 -1 -1 1 -1 -1 M6 -2 0 0 1 0 -3 -4 -2 N7 -1 -2 -1 -1 -2 -4 -3 P5 1 0 -1 -2 -2 -1 Q 5 -1 -1 -3 -3 -2 R4 1 -2 -3 -2 S5 0 -2 -2 T4 -3 -1 V11 2 W7 Y

[0231] The term “homology” or “homologous” is intended to mean a sequence similarity between two polynucleotides or between two polypeptides. Similarity can be determined by comparing a position in each sequence, which can be aligned for purposes of comparison. If a given position of two polypeptide sequences is not identical, the similarity or conservativeness of that position can be determined by assessing the similarity of the amino acid of the position, for example, according to Table 3. A degree of similarity between sequences is a function of the number of matching or homologous positions shared by the sequences. The alignment of two sequences to determine their percent sequence similarity can be done using software programs known in the art, such as, for example, those described in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1999). Preferably, default parameters are used for the alignment, examples of which are set forth below. One alignment program well known in the art that can be used is BLAST set to default parameters. In particular, programs are BLASTN and BLASTP, using the following default parameters: Genetic code = standard; filter = none; strand = both; cutoff = 60; expect = 10; Matrix = BLOSUM62; Descriptions = 50 sequences; sort by = HIGH SCORE; Databases = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translations + SwissProtein + SPupdate + PIR. Details of these programs can be found at the National Center for Biotechnology Information.

[0232] The term “homologs” of to a given amino acid sequence or a nucleic acid sequence is intended to indicate that the corresponding sequences of the “homologs” having substantial identity or homology to the given amino acid sequence or nucleic acid sequence.

[0233] The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2264 2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873 5877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et aL, 1990, J. Mol. Biol. 215:403. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein moleculedescribed herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul etal., 1997, Nucleic Acids Res. 25:3389 3402.Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11 17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0234] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0235] The term “cytotoxic agent” refers to a substance that inhibits or prevents the expression activity of cells, function of cells and / or causes destruction of cells. The term is intended to include radioactive isotopes, 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 thereof. Examples of cytotoxic agents include, but are not limited to auristatins (e.g., auristatin E, auristatin F, MMAE and MMAF), auromycins, maytansinoids, ricin, ricin A-chain, combrestatin, duocarmycins, dolastatins, doxorubicin, daunorubicin, taxols, cisplatin, ccl065, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, Sapaonaria officinalis inhibitor, and glucocorticoid and other chemotherapeutic agents, as well as radioisotopes such as At211, 1131, 1125, Y90, Re186, Re188, Sm153, Bi212or213, P32and radioactive isotopes of Lu including Lu177. Antibodies may also be conjugated to an anticancer pro-drug activating enzyme capable of converting the pro-drug to its active form.

[0236] The term “effective amount” or “therapeutically effective amount” as used herein refers to the amount of binding molecule (e.g., an antibody) or pharmaceutical composition provided herein which is sufficient to result in the desired outcome.

[0237] The terms “subject” and “patient” may be used interchangeably. As used herein, in certain embodiments, a subject is a mammal, such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc. or a primate (e.g., monkey and human). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal, e.g., a human, diagnosed with a condition or disorder. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a condition or disorder.

[0238] “Administer” or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other method of physical delivery described herein or known in the art.

[0239] As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and / or duration of a disease or condition resulting from the administration of one or more therapies. Treating may be determined by assessing whether there has been a decrease, alleviation and / or mitigation of one or more symptoms associated with the underlying disorder such that an improvement is observed with the patient, despite that the patient may still be afflicted with the underlying disorder. The term “treating” includes both managing and ameliorating the disease. The terms “manage,” “managing,” and “management” refer to the beneficial effects that a subject derives from a therapy which does not necessarily result in a cure of the disease.

[0240] The terms “prevent,” “preventing,” and “prevention” refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptom(s) (e.g., a cancer).

[0241] The term “cancer” or “cancer cell” is used herein to denote a tissue or cell found in a neoplasm which possesses characteristics which differentiate it from normal tissue or tissue cells. Among such characteristics include but are not limited to: degree of anaplasia, irregularity in shape, indistinctness of cell outline, nuclear size, changes in structure of nucleus or cytoplasm, other phenotypic changes, presence of cellular proteins indicative of a cancerous or pre-cancerous state, increased number of mitoses, and ability to metastasize. Words pertaining to “cancer” include carcinoma, sarcoma, tumor, epithelioma, leukemia, lymphoma, polyp, and scirrus, transformation, neoplasm, and the like.

[0242] As used herein, a “locally advanced” cancer refers to a cancer that has spread from where it started to nearby tissue or lymph nodes.

[0243] As used herein, a “metastatic” cancer refers to a cancer that has spread from where it started to different part of the body.

[0244] As used herein, the term “major surgery” may refer to a surgery that involves opening one of the major body cavities, such as, but not limited to, the abdomen (i.e., laparotomy), chest (i.e., thoracotomy), or skull (i.e., craniotomy).

[0245] The terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of a given value or range.

[0246] As used in the present disclosure and claims, the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise.

[0247] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodiments are described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.

[0248] The term “and / or” as used in a phrase such as “A and / or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass 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).

[0249] The term “variant” refers to a molecule that exhibits a variation from a described type or norm, such as a protein that has one or more different amino acid residues in the corresponding position(s) of a specifically described protein (e.g. the 191P4D12 protein shown in FIG. 1A.) An analog is an example of a variant protein. Splice isoforms and single nucleotides polymorphisms (SNPs) are further examples of variants.

[0250] The “191P4D12 proteins” and / or “191P4D12 related proteins” of the disclosure include those specifically identified herein (see, FIG. 1A), as well as allelic variants, conservative substitution variants, analogs and homologs that can be isolated / generated and characterized without undue experimentation following the methods outlined herein or readily available in the art. Fusion proteins that combine parts of different 191P4D12 proteins or fragments thereof, as well as fusion proteins of a 191P4D12 protein and a heterologous polypeptide are also included. Such 191P4D12 proteins are collectively referred to as the 191P4D12-related proteins, the proteins of the disclosure, or 191P4D12. The term “191P4D12-related protein” refers to a polypeptide fragment or a 191P4D12 protein sequence of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than 25 amino acids; or, at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100,105, 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 or more amino acids. The term “191P4D12” is used interchangeably with nectin-45.2 Methods of Treating Cancer

[0251] Urothelial carcinoma (UC), a carcinoma that encompasses both lower and upper urinary tract, is a malignancy with high unmet medical need. The worldwide 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 relatively low (~5%) survival rates at 5 years.

[0252] For decades, platinum -based chemotherapy has been the first-line standard of care(SOC) for la / mUC. Despite survival benefits, treatment outcomes remain poor. Most patients initially respond to cisplatin- or carboplatin-based chemotherapy, however many patients will progress within 7 months, highlighting the need for new therapies in the first-line setting. Treatment guidelines recommend avelumab maintenance therapy as an option for a subset of patients with la / mUC who have not progressed with platinum-containing chemotherapy; however, most patients are unable to or do not receive maintenance therapy primarily because of disease progression or death (include proper references) on their initial therapy.

[0253] The disclosure thus provides demonstrated efficacious methods to treat patients (e.g., cisplatin eligible and ineligible patients) with 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) (e.g., patients who have not received any previous treatment for the cancer).

[0254] In embodiments that refer to a method of treatment as described herein, such embodiments are also further embodiments to the antibody drug conjugate (ADC) and / or anti-PD-1 antibody, for use in the combination treatment, or to the use of the ADC and / or anti-PD-1 antibody in the manufacture of a medicament for use in the combination treatment.5.2.1 Methods of Treating Cancer in General and for Selected Patients

[0255] Provided herein are methods for the first-line and second-line treatment of various cancers in subjects, including subjects with unresectable locally advanced or metastatic urothelial cancer (la / mUC) who are cisplatin eligible and ineligible, using an antibody drug conjugate (ADC) that binds 191P4D12 in combination with an anti-PD-1 antibody (e.g., pembrolizumab).

[0256] In one aspect, provided herein are methods for the treatment of cancer in a subject using an ADC that binds 191P4D12 and an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the human subject treated with the methods provided herein has not received previous cancer treatment other than the ADC that binds 191P4D12. In certain embodiments, the human subject treated with the methods provided herein has not received previous treatment that includes or consists 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, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In particular embodiments, the CPI is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject treated with the methods provided herein has not received previous treatment that includes or consists of an PD-(L)-1 inhibitor. A PD-(L)-1 inhibitor is a PD-1 inhibitor or PD-L1 inhibitor. In some embodiments, the PD- (L)-l inhibitor is an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the PD-(L)-1 inhibitor is a PD-1 inhibitor or PD-L1 inhibitor. In particular embodiments, the PD-(L)-1 inhibitor is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject treated with the methods provided herein has not received an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists). In particular embodiments, the agent directed to another stimulatory or co inhibitory T-cell receptor is a CD137 agonist, a CTLA 4 inhibitor, or an OX-40 agonist. In some embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment. In other embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment and has not received previous treatment including or consisting of a CPI. In certain embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin treatment, has not received previous treatment including or consisting of a CPI, and has not received prior systemic therapy with the exceptions of neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments, the human subject treated with the methods provided herein is eligible to receive cisplatin treatment. In other embodiments, the human subject treated with the methods provided herein is eligible to receive cisplatin treatment and has not received previous treatment including or consisting of a CPI. In certain embodiments, the human subject treated with the methods provided herein is eligible to receive cisplatin treatment, has not received previous treatment including orconsisting of a CPI, and has not received prior systemic therapy with the exceptions of neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In certain embodiments, the human subject treated with the methods provided herein is eligible to receive cisplatin treatment, has not received previous treatment including or consisting of a CPI, and has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments, the human subject treated with the methods provided herein is eligible to receive carboplatin treatment. In other embodiments, the human subject treated with the methods provided herein is eligible to receive carboplatin treatment and has not received previous treatment including or consisting of a CPI. In certain embodiments, the human subject treated with the methods provided herein is eligible to receive carboplatin treatment, has not received previous treatment including or consisting of a CPI, and has not received prior systemic therapy with the exceptions of neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In certain embodiments, the human subject treated with the methods provided herein is eligible to receive carboplatin treatment, has not received previous treatment including or consisting of a CPI, and has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments, the human subject treated with the methods provided herein is ineligible or eligible to receive cisplatin treatment. In other embodiments, the human subject treated with the methods provided herein is ineligible or eligible to receive cisplatin treatment and has not received previous treatment including or consisting of a CPI. In certain embodiments, the human subject treated with the methods provided herein is ineligible or eligible to receive cisplatin treatment, has not received previous treatment including or consisting of a CPI, and has not received prior systemic therapy with the exceptions of neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In certain embodiments, the human subject treated with the methods provided herein is ineligible or eligible to receive cisplatin treatment, has not received previous treatment including or consisting of a CPI, and has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments, the cancer is urothelial cancer. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is cancer of the renal pelvis. In certain embodiments, the cancer is cancer of the ureter. In certain embodiments, the cancer is cancer of the urethra. In one embodiment, the cancer is locally advanced cancer. In another embodiment, the cancer ismetastatic cancer. In a further embodiment, the cancer is locally advanced urothelial cancer. In a further embodiment, the cancer is unresectable locally advanced urothelial cancer. In yet another embodiment, the cancer is metastatic urothelial cancer. In one embodiment, the cancer is locally advanced bladder cancer. In another embodiment, the cancer is metastatic bladder cancer.5.2.1.1 Cisplatin Ineligible Patients and Cisplatin Eligible Patients

[0257] Cisplatin Ineligible Patients'. Various conditions can be used to determine the cisplatin ineligibility for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraphs. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function (e.g., glomerular filtration rate (GFR) or creatinine clearance <60 mL / min but >30 mL / min (estimated by the Cockcroft-Gault formula, modification of diet in renal disease [MDRD] or 24 hour urine)). In certain embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of no less than Grade 2 hearing loss (e.g., CI CTCAE Version 4.03 Grade > 2 hearing loss). In certain embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and impaired renal function. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of impaired renalfunction, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, impaired renal function, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of impaired renal function, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0258] Impaired renal function can be determined as various means known and available in the art. Various embodiments are provided herein to determine the impaired renal function for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraph. In one embodiment, the impaired renal function is determined by glomerular filtration rate (GFR) less than 60 mL / min. In some embodiments, the impaired renal function is determined by GFR less than 60 but no less than 30 mL / min. In certain embodiments, the impaired renal function is determined by GFR less than 30 but no less than 15 mL / min. In some embodiments of the methods provided in this paragraph, the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD],

[0259] In a further embodiment, the impaired renal function is determined by creatinine clearance (CrCl) less than 60 mL / min. In some embodiments, the impaired renal function is determined by CrCl less than 60 but no less than 30 mL / min. In certain embodiments, the impaired renal function is determined by CrCl less than 30 but no less than 15 mL / min. Insome embodiments of the methods provided in this paragraph, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria.

[0260] As such, some specific conditions based on GFR or creatinine clearance can be used to determine the cisplatin ineligibility for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraphs. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL / min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 60 mL / min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL / min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL / min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, GFR less than 60 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, GFR less than 60 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of GFR less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, GFR less than 60 mL / min, and no less than Grade 2 hearing loss, in any combination or permutation. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of GFR 1 less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, GFR less than 60 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of GFR less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the GFR is measured by 24 hour urine collection. Inother embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD], In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0261] In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL / min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 60 mL / min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL / min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL / min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, CrCl less than 60 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, CrCl less than 60 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of CrCl less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, CrCl less than 60 mL / min, and no less than Grade 2 hearing loss, in any combination or permutation. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of CrCl less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, CrCl less than 60 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions fordetermining the cisplatin ineligibility comprise or consist of all three of CrCl less than 60 mL / min, and no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0262] Alternatively, other specific conditions based on GFR or creatinine clearance can be used to determine the cisplatin ineligibility for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraphs. In some embodiments, embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL / min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and GFR less than 60 but no less than 30 mL / min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL / min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL / min and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of GFR less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL / min, and noless than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of GFR less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, GFR less than 60 but no less than 30 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of GFR less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD], In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0263] In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL / min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and CrCl less than 60 but no less than 30 mL / min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL / min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL / min and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL / min, and no less thanGrade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of CrCl less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL / min, and no less than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of CrCl less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, CrCl less than 60 but no less than 30 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of CrCl less than 60 but no less than 30 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0264] Similarly, further specific conditions based on GFR or creatinine clearance can be used to determine the cisplatin ineligibility for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraphs. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL / min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2 and GFR less than 30 but no less than 15 mL / min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL / min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL / min, and NYHA Class III heart failure. In yet other embodiments,the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of GFR less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of GFR less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of GFR less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, GFR less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of GFR less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD], In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2, the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0265] In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL / min. In one embodiment, the conditions for determining the cisplatin ineligibility comprise or consist of ECOGperformance status score of 2 and CrCl less than 30 but no less than 15 mL / min. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL / min and no less than Grade 2 hearing loss. In further embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL / min, and NYHA Class III heart failure. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss. In yet other embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of CrCl less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any one of CrCl less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of any two of CrCl less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure, in any combination or permutation. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of ECOG performance status score of 2, CrCl less than 30 but no less than 15 mL / min, and no less than Grade 2 hearing loss. In some embodiments, the conditions for determining the cisplatin ineligibility comprise or consist of all three of CrCl less than 30 but no less than 15 mL / min, no less than Grade 2 hearing loss, and NYHA Class III heart failure. In some embodiments of the methods provided in this paragraph, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided in this paragraph, the CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject did not receive prior systemic treatment for locally advanced or metastatic disease. In some embodiments, the subject has received neoadjuvant or adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy. In some embodiments of the methods provided herein, wherein the subject has ECOG performance status score of 2,the subject (i) has Hemoglobin >10 g / dL; (ii) has GFR > 50 mL / min; and (iii) does not have NYHA Class III heart failure.

[0266] Cisplatin Eligible Patients'. Various conditions can be used to determine the cisplatin ineligibility (e.g., cisplatin eligible) for the human subjects for the methods provided herein, including but not limited to the methods of the preceding paragraphs. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) or creatinine clearance >60 mL / min (estimated by the Cockcroft-Gault formula, modification of diet in renal disease [MDRD] or 24 hour urine). In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of NCI CTCAE Grade <1 audiometric hearing loss. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of no NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) or creatinine clearance >60 mL / min and NCI CTCAE Grade <1 audiometric hearing loss. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) or creatinine clearance >60 mL / min and no NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of NCI CTCAE Grade <1 audiometric hearing loss and no NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) or creatinine clearance >60 mL / min, NCI CTCAE Grade <1 audiometric hearing loss, and no NYHA Class III heart failure.

[0267] In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) >60 mL / min and NCI CTCAE Grade <1 audiometric hearing loss. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) >60 mL / min and no NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of NCI CTCAE Grade <1 audiometric hearing loss and no NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of glomerular filtration rate (GFR) >60 mL / min, NCI CTCAE Grade <1 audiometric hearing loss, and no NYHA Class III heart failure.

[0268] In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of creatinine clearance >60 mL / min and NCI CTCAE Grade <1 audiometric hearing loss. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of creatinine clearance >60 mL / min and no NYHA Class IIIheart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of NCI CTCAE Grade <1 audiometric hearing loss and no NYHA Class III heart failure. In one embodiment, the conditions for determining the cisplatin eligibility comprise or consist of creatinine clearance >60 mL / min, NCI CTCAE Grade <1 audiometric hearing loss, and no NYHA Class III heart failure.5.2.1.2 Additional Patient Demographics

[0269] Additionally, the human subjects for whom the methods provided herein can be used are human subjects having various other conditions. In some embodiments, the human subjects are cisplatin eligible or ineligible. In one embodiment, the human subjects for whom the methods provided herein may have histologically documented locally advanced or metastatic urothelial (previously known as transitional cell) cancer (e.g., cancer of the bladder, renal pelvis, ureter, or urethra). In some embodiments, the human subjects for whom the methods provided herein may be eligible for CPI therapy. In certain embodiments, the human subjects for whom the methods provided herein may have measurable disease according to RECIST Version 1.1. In certain embodiments, the human subjects for whom the methods provided herein may have measurable disease according to RECIST Version 1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy. In certain embodiments, the human subjects for whom the methods provided herein did not receive prior systemic therapy for locally advanced or metastatic cancer. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 1. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 1 to 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 1 or 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 to 1. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 or 1. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 to 2. In yet other embodiments, the human subjects for whom the methods provided herein can have ECOG performance status score of 0 or 2. In yet other embodiments, the human subjects forwhom the methods provided herein can have ECOG performance status score of 0, 1, or 2. In one embodiment, the human subjects for whom the methods provided herein may have an anticipated life expectancy of >12 weeks. Some embodiments of the methods provided in this paragraph may have any of the preceding embodiments in any combination or permutation.

[0270] In further embodiments of the methods provided herein, including the methods of the preceding paragraphs, the human subjects for whom the methods provided herein can be used are human subjects having various other conditions. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have 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 or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, or (ii) have the condition of 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 or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, or (ii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of 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 or antigen binding fragment thereof, or (ii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, (ii) have the condition of 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 or antigen binding fragment thereof, or (iii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, and (ii) have the condition of 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 or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, and (ii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of 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 or antigen binding fragment thereof, and (ii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, (ii) have the condition of 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 or antigen binding fragment thereof, and (iii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, the human subjects for whom the methods provided herein can be used also (i) have the condition of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN, (ii) have the condition of 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 or antigen binding fragment thereof, and / or (iii) have not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof.

[0271] In further embodiments of the methods provided herein, including the methods of the preceding paragraphs, the human subjects for whom the methods provided herein can be used are human subjects having various other conditions. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count (ANC) no less than 1500 / pL. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 5.6 mmol / L. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 5.6 mmol / L. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of upper limit of normal (ULN), direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of CrCl no less than 30 mL / min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of GFR no less than 30 mL / min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of CrCl or GFR no less than 30 mL / min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the condition of CrCl no less than 30 mL / min, wherein the subjects have total bilirubin levels >1.5* institutional ULN and / or <1.5 ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the condition of GFR no less than 30 mL / min, wherein the subjects have total bilirubin levels >1.5* institutional ULN and / or <1.5 ULN. In another embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN. In one embodiment, the humansubjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and platelet count no less than 100,000 / pL. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and hemoglobin no less than 9 g / dL or 5.6 mmol / L. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, and CrCl or GFR no less than 30 mL / min. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and CrCl no less than 30 mL / min, wherein the subjects have total bilirubin levels >1.5* institutional ULN and / or <1.5 ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and ALT and AST no more than 2.5 fold of ULN. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100, 000 / pL and hemoglobin no less than 9 g / dL or 5.6 mmol / L. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and CrCl or GFR no less than 30 mL / min. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In yet other embodiments,the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L and ALT and AST no more than 2.5 fold of ULN. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease and CrCl no less than 30 mL / min. In another embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease and ALT and AST no more than 2.5 fold of ULN. In another embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of CrCl or GFR no less than 30 mL / min and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, and hemoglobin no less than 9 g / dL or 5.6 mmol / L. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L and total bilirubin no more than either of 1.5 times of ULN or 3 times ULN for patients with Gilbert’s disease. In certainembodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and ALT and AST no more than 2.5 fold of ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patientswith Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or5.6 mmol / L, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absoluteneutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR no less than 30mL / min, and ALT and AST no more than 2.5 fold of ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no lessthan 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR no less than 30 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than1500 / JJ.L, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any one of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any two of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any three of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any four of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any five of absolute neutrophil count no less than 1500 / pL, platelet count no less than100,000 / JJ.L, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of all six of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin < ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR no less than 30 mL / min, and ALT and AST no more than 2.5 fold of ULN.

[0272] In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the condition of CrCl >60 mL / min, wherein the subjects have total bilirubin levels >1.5 X institutional ULN and / or ^ 1.5 ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the condition of GFR >60 mL / min, wherein the subjects have total bilirubin levels >1.5 X institutional ULN and / or ^ 1.5 ULN. In another embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.5 fold of ULN. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and platelet count no less than 100, 000 / pL. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and hemoglobin no less than 9 g / dL or 5.6 mmol / L. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, and CrCl or GFR >60 mL / min. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absoluteneutrophil count no less than 1500 / pL and CrCl >60 mL / min, wherein the subjects have total bilirubin levels >1.5 X institutional ULN and / or ^ 1.5 ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL and ALT and AST no more than 2.5 fold of ULN. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and hemoglobin no less than 9 g / dL or 5.6 mmol / L. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and CrCl or GFR >60 mL / min. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L and ALT and AST no more than 2.5 fold of ULN. In one embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease and CrCl >60 mL / min. In another embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3times ULN for patients with Gilbert’s disease and ALT and AST no more than 2.5 fold of ULN. In another embodiment, the human subjects for whom the methods provided herein can be used also have the conditions of CrCl or GFR >60 mL / min and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, and hemoglobin no less than 9 g / dL or 5.6 mmol / L. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL and total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 x ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L and total bilirubin no more than either of 1.5 times of ULN or 3 times ULN for patients with Gilbert’s disease. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and ALT and AST no more than 2.5 fold of ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, total bilirubin no morethan either of 1.5 times of ULN, direct bilirubin ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and total bilirubin no more than either of 1.5 times of ULN, direct bilirubin U ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin U ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 x ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60 mL / min. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60mL / min. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 x ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin NULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60 mL / min. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In yet other embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’ s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN,direct bilirubin ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In further embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 x ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and CrCl or GFR >60 mL / min. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the humansubjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 x ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any one of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any two of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL,hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any three of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any four of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubin N ULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 x ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of any five of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100,000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can be used also have the conditions of all six of absolute neutrophil count no less than 1500 / pL, platelet count no less than 100, 000 / pL, hemoglobin no less than 9 g / dL or 5.6 mmol / L, total bilirubin no more than either of 1.5 times of ULN, direct bilirubinULN, wherein the human subjects have the conditions of total bilirubin levels >1.5 X ULN, or total bilirubin 3 times ULN for patients with Gilbert’s disease, CrCl or GFR >60 mL / min, and ALT and AST no more than 2.5 fold of ULN.

[0273] In certain embodiments, including any of the embodiments disclosed herein, such as any of the above embodiments, the human subjects for whom the methods provided herein may have treated central nervous system (CNS) metastases that have been clinically stablefor at least 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In certain embodiments, the human subjects (1) may have 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 or antigen binding fragment thereof, and (2) have the condition of ALT and AST no more than 2.5 fold of ULN. In certain embodiments, the human subjects (1) may have 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 or antigen binding fragment thereof, (2) have the condition of ALT and AST no more than 2.5 fold of ULN, and (3) may not have received major surgery within 4 weeks prior to the administration of the ADC and the anti- PD-1 antibody or antigen binding fragment thereof.

[0274] In certain embodiments, including any of the embodiments disclosed herein, such as any of the above embodiments, the human subjects for whom the methods provided herein may not have received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof. In certain embodiments, the human subjects (1) may have 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 or antigen binding fragment thereof, and (2) may not have received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof.

[0275] In certain embodiments, the human subjects for whom the methods provided herein may have previously had prostate cancer treated surgically or with radiation therapy at least 1 year prior to treatment with any of the methods provided herein, wherein the subject is prostate cancer-free and wherein (i) if the subject has undergone or received radical prostatectomy, the subject must have undetectable PSA for >1 year prior to treatment with any of the methods provided herein, (ii) if the subject has received radiation, the subject has a PSA doubling time >1 year (based on at least 3 values determined >1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (e.g., <2.0 ng / mL above nadir). In certain embodiments, the human subjects for whom the methods provided herein may have untreated low-risk prostate cancer, wherein the subject has a Gleason score <6, on active surveillance with PSA doubling time >1 year (based on at least 3 values determined >1 month apart).

[0276] In other embodiments of the methods provided herein, including the methods of the preceding paragraphs, the human subjects for whom the methods provided herein can beused are human subjects free from certain conditions. In one embodiment, the human subjects for whom the methods provided herein have not received any prior treatment with a CPI. A CPI is defined as a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subjects for whom the methods provided herein have not received a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor. In certain embodiments, the human subjects for whom the methods provided herein have not received atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject treated with the methods provided herein has not received previous treatment that includes or consists of an PD-(L)-1 inhibitor. A PD-(L)-1 inhibitor is a PD-1 inhibitor or 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 PD-L1 inhibitor. In particular embodiments, the PD-(L)-1 inhibitor is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subjects for whom the methods provided herein have not received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (including, but not limited to, CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists). In certain embodiments, the human subjects for whom the methods provided herein have not received any prior treatment with CD137 agonists, CTLA 4 inhibitors, or OX-40 agonists. In certain embodiments, the human subjects have received anti-cancer treatment with chemotherapy, biologies, or inventigational agents, wherein the human subjects have completed the anticancer treatment 4 or more weeks prior to receiving a first dose of an antibody drug conjugate (ADC) that binds 191P4D12 in combination with an anti-PD-1 antibody (e.g., pembrolizumab). In one embodiment, the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy. In one embodiment, the human subjects for whom the methods provided herein can have no active central nervous system metastases. In one embodiment, the human subjects for whom the methods provided herein can have no uncontrolled diabetes. In one embodiment, the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy and no active central nervous system metastases. In some embodiments, the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy and no uncontrolled diabetes. In yet other embodiments, the human subjects for whom the methods provided herein can have no more than Grade 2 sensory or motor neuropathy no active central nervous system metastases, and no uncontrolled diabetes. Insome embodiments, the human subjects for whom the methods provided herein can have any one of no more than Grade 2 sensory or motor neuropathy, no active central nervous system metastases, and no uncontrolled diabetes. In some embodiments, the human subjects for whom the methods provided herein can have any two of no more than Grade 2 sensory or motor neuropathy, no active central nervous system metastases, and no uncontrolled diabetes, in any combination or permutation. In some embodiments, the human subjects for whom the methods provided herein can have all three of no more than Grade 2 sensory or motor neuropathy, no active central nervous system metastases, and no uncontrolled diabetes. In one embodiment of the methods provided in this paragraph, the uncontrolled diabetes is determined by hemoglobin Ale (HbAlc) no less than 8%. In some embodiments of the methods provided in this paragraph, the uncontrolled diabetes is determined by HbAlc between 7 and 8% with associated diabetes symptoms that are not otherwise explained. In further embodiments of the methods provided in this paragraph, the associated diabetes symptoms comprise or consist of polyuria. In some other embodiments of the methods provided in this paragraph, the associated diabetes symptoms comprise or consist of polydipsia. In yet other embodiments of the methods provided in this paragraph, the associated diabetes symptoms comprise or consist of both polyuria and polydipsia.

[0277] In certain embodiments, the human subjects for whom the methods provided herein may have no ongoing clinically significant toxicity associated with prior treatment that has not resolved to < Grade 1 or returned to baseline. In certain embodiments, the human subjects for whom the methods provided herein may have no ongoing clinically significant toxicity associated with prior treatment that has not resolved to < Grade 1 or returned to baseline, wherein the prior treatment is radiotherapy or surgery. In certain embodiments, the prior treatment is radiotherapy. In certain embodiments, the prior treatment is surgery. In one embodiment, the human subjects for whom the methods provided herein may have no conditions requiring high doses of steroids (e.g., >10 mg / day of prednisone or equivalent) or other immunosuppressive medications. In one embodiment, the human subjects for whom the methods provided herein may have no conditions requiring high doses of steroids or other immunosuppressive medications, wherein the steroids or other immunosuppressive medications are not inhaled or topical steroids. In certain embodiments, the human subjects for whom the methods provided herein may have no history of another invasive malignancy within 3 years before treatment with the methods provided herein. In certain embodiments, the human subjects for whom the methods provided herein may have no evidence of residual disease from a previously diagnosed malignancy. In certain embodiments, the humansubjects for whom the methods provided herein may not receive systemic antimicrobial treatment for active infection, wherein the infection is a viral, bacterial, or fungal infection. In certain embodiments, the human subjects for whom the methods provided herein does not have active hepatitis B, wherein the hepatitis B is HBsAg reactive. In certain embodiments, the human subjects for whom the methods provided herein may have no active hepatitis C infection or known human immunodeficiency virus (HIV) infection. In certain embodiments, the human subjects for whom the methods provided herein may have no active tuberculosis. In certain embodiments, the human subjects for whom the methods provided herein may have no documented history of a cerebral vascular event (e.g., a stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV. In certain embodiments, the human subjects for whom the methods provided herein may have no radiotherapy within 2 weeks prior to treatment or major surgery within 4 weeks prior to treatment with the methods provided herein. In certain embodiments, the human subjects for whom the methods provided herein may have no treatment with chemotherapy, biologies, or investigational agents not completed 4 weeks prior to treatment with the methods provided herein. In certain embodiments, the human subjects for whom the methods provided herein may have no known severe (> Grade 3) hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20). In certain embodiments, the human subjects for whom the methods provided herein may have no known severe (> Grade 3) hypersensitivity to pembrolizumab or to any excipient contained in the drug formulations of pembrolizumab. In certain embodiments, the human subjects for whom the methods provided herein may have no known severe (> Grade 3) hypersensitivity to gemcitabine. In certain embodiments, the human subjects for whom the methods provided herein may have no active keratitis or corneal ulcerations. In certain embodiments, the human subjects for whom the methods provided herein may have no active autoimmune disease that has required systemic treatment in past 2 years (e.g., use of disease modifying agents, corticosteroids, or immunosuppressive drugs). In certain embodiments, the human subjects for whom the methods provided herein may have no active autoimmune disease that has required systemic treatment in past 2 years, wherein the systemic treatment comprises disease modifying agents, corticosteroids, or immunosuppressive drugs. In some embodiments, the systemic treatment is not replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency). In some embodiments, the systemic treatment is not thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency. In some embodiments, the systemic treatment is not corticosteroids, wherein the corticosteroids are administered for less than 7 days. In some embodiments, the human subjects have vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma / atopy. In some embodiments, the systemic treatment is not bronchodilators, inhaled steroids, or local steroids administered by injection. In some embodiments, the human subjects have hypothyroidism, wherein the hypothyroidism is stable with hormone replacement therapy. In some embodiments, the human subjects have Sjogren’s syndrome. In certain embodiments, the human subjects for whom the methods provided herein may have no history of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. In certain embodiments, the human subjects for whom the methods provided herein may have no prior allogeneic stem cell or solid organ transplant. In certain embodiments, the human subjects for whom the methods provided herein may not have received a live, attenuated vaccine within 30 days prior to treatment with the methods provided herein. In particular, embodiments, the live vaccine is a measles, mumps, rubella, varicella / zoster (chicken pox), yellow fever, rabies, Bacillus Calmette Guerin (BCG), or typhoid vaccine. In particular, embodiments, the live, attenuated vaccine is an intranasal influenza vaccine. In certain embodiments, the human subjects for whom the methods provided herein may have no underlying medical condition that impairs the ability of the subject to receive or tolerate the methods provided herein.

[0278] In some embodiments of the methods provided herein, the CrCl is measured by 24 hour urine collection. In other embodiments of the methods provided herein, the CrCl is estimated by the Cockcroft-Gault criteria.

[0279] In some embodiments of the methods provided herein, the GFR is measured by 24 hour urine collection. In other embodiments of the methods provided herein, the GFR is estimated by the Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, the GFR is measured by modification of diet in renal disease [MDRD],

[0280] In some embodiments of the methods provided herein, the subject has been treated with one or more other cancer treatments. In certain embodiments of the methods provided herein, the urothelial cancer, including locally advanced or metastatic urothelial cancer, has been treated with one or more other cancer treatments.

[0281] In some embodiments, the CPI described herein can comprise or consist of any CPI as described in this Section (Section 5.2.1).

[0282] In all the methods provided herein and specifically those described in the preceding paragraphs: the ADCs that can be used are described in Sections 3, 5.2, 5.3, 5.4, 5.5, and 6, selection of patients for treatment is described herein and exemplified in this Section (Section 5.2) and Sections 3 and 6, dosing regimens and pharmaceutical composition for administering the therapeutic agent are described in this Section (Section 5.2), Sections5.4, 5.6, 5.7 and 6 below, the biomarkers that can be used for identifying the therapeutic agents, selecting the patients, determining the outcome of these methods, and / or serving as criteria in any way for these methods are described herein and exemplified in this Section (Section 5.2, including 5.2.1 and 5.2.2) and Section 6, the biomarkers can be determined as described in Section 5.9 or as known in the art, therapeutic outcomes for the methods provided herein are described in this Section (Section 5.2 including Section 5.2.1.4) and Sections 3 and 6, additional therapeutic outcomes for the methods provided herein can be improvement of the biomarkers described herein, for example, those described and exemplified in this Section (Section 5.2 including 5.2.2) and Sections 3 and 6, and combination therapies including the ADCs and other therapeutic agents are described in this Section (Section 5.2) and in Section 5.5. Therefore, a person skilled in the art would understand that the methods provided herein include all permutations and combinations of the patients, therapeutic agents, dosing regiments, biomarkers, and therapeutic outcomes as described above and below.

[0283] In certain embodiments, the methods provided herein are used for treating subjects having urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used for treating subjects who have urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein.

[0284] In certain embodiments, the methods provided herein are used for treating subjects having locally advanced urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used for treating subjects who have locally advanced urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein and who have been previously treated with a CPI or a PD-(L)-1 inhibitor.

[0285] In certain embodiments, the methods provided herein are used for treating subjects having metastatic cancers that express 191P4D12 RNA, express 191P4D12 protein, orexpress both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used for treating subjects who have metastatic urothelial cancers that express 191P4D12 RNA, express 191P4D12 protein, or express both 191P4D12 RNA and 191P4D12 protein.

[0286] In some embodiments, the 191P4D12 RNA expression in the cancers is determined by polynucleotide hybridization, sequencing (assessing the relative abundance of the sequences), and / or PCR (including RT-PCR). In some embodiments, the 191P4D12 protein expression in the cancers is determined by IHC, analysis in fluorescence-activated cell sorting (FACS), and / or western blotting. In some embodiments, the 191P4D12 protein expression in the cancers is determined by more than one method. In some embodiments, the 191P4D12 protein expression in the cancers is determined by two methods of IHC.

[0287] In some embodiments, the locally advanced or metastatic urothelial cancers are confirmed histologically, cytologically, or both histologically and cytologically. In some embodiments, the locally advanced or metastatic bladder cancers are confirmed histologically, cytologically, or both histologically and cytologically.

[0288] In some embodiments, the subject has visceral metastases. In some embodiments, the subject has lymph nodes only disease. In some embodiments, the disease site of origin is in the upper tract. In some embodiments, the disease site of origin is in the lower tract.

[0289] In some embodiments, the subject has a PD-L1 expression combined positive score (CPS) greater than or equal to 10. PD-L1 protein expression is determined by using the Combined Positive Score (CPS), which is the number of PD-L1 positive cells (i.e., tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, and then multiplied by 100. In some embodiments, the subject has a PD-L1 expression CPS less than 10. Nectin H-scores range from 0-300, based upon the following calculation: H-score = [(0 x % negative cells) + (1 x %weakly positive cells) + (2 x %moderately positive cells) + (3 x %strongly positive cells)]. Urothelial cancer generally has a median H-score from 260- 270. In some embodiments, the subject has a Nectin-4 H-score between 0 and 300. In some embodiments, the subject has a Nectin-4 H-score between 0 and 250, between 0 and 200, between 0 and 150, between 0 and 100, or between 0 and 50. In some embodiments, the subject has a Nectin-4 H-score between 0 and 200. In some embodiments, the subject has a Nectin-4 H-score between 0 and 150. In some embodiments, the method does not comprise determining PD-L1 expression or Nectin-4 expression of the subject. In some embodiments, the method does not comprise determining PD-L1 expression or Nectin-4 expression of the subject prior to treatment of the subject with the ADC. In some embodiments, the methoddoes not comprise determining PD-L1 expression of the subject. In some embodiments, the method does not comprise determining PD-L1 expression of the subject prior to treatment of the subject with the ADC. In some embodiments, the method does not comprise determining Nectin-4 expression of the subject. In some embodiments, the method does not comprise determining Nectin-4 expression of the subject prior to treatment of the subject with the ADC.5.2.1.3 Checkpoint Inhibitors and Combination Therapy withPembrolizumab

[0290] Checkpoint Inhibitors

[0291] In some embodiments, the subjects that can be treated in the methods provided herein have certain phenotypic or genotypic characteristics. In some embodiments, the subjects have any permutation and combination of the phenotypic or genotypic characteristics described herein.

[0292] In some embodiments, the phenotypic or genotypic characteristics are determined histologically, cytologically, or both histologically and cytologically. In some embodiments of methods provided herein, the histological and / or the cytological determination of the phenotypic and / or genotypic characteristics are performed as described in American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines based on the most recently analyzed tissue, which is incorporated herein in their entirety by reference. In some embodiments, the phenotypic or genotypic characteristics are determined by sequencing including the next generation sequencing (e.g. NGS from Illumina, Inc), DNA hybridization, and / or RNA hybridization.

[0293] 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 and the preceding paragraphs, the human subjects for whom the methods are provided herein have not received any prior treatment with a CPI. A CPI is defined as a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subjects for whom the methods provided herein have not received prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor. In certain embodiments, the human subjects for whom the methods provided herein have not received prior treatment with atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab.

[0294] 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 and thepreceding paragraphs, the human subjects for whom the methods are provided herein have not received any prior treatment with a PD-(L)-1 inhibitor. A PD-(L)-1 inhibitor is defined as a PD-1 inhibitor or PD-L1 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). Thus, PD-(L)-1 inhibitors include CPI inhibitors that are PD-1 inhibitors or PD-L1 inhibitors. In some embodiments, the human subjects for whom the methods provided herein have not received prior treatment with a PD-1 inhibitor or a PD-L1 inhibitor. In certain embodiments, the human subjects for whom the methods provided herein have not received prior treatment with atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab.

[0295] As used herein, the term “immune checkpoint inhibitor” or “checkpoint inhibitor” (CPI) refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 72, 252-264). Other exemplary checkpoint proteins include LAG-3, B7, TIM3 (HAVCR2), 0X40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. These proteins appear responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

[0296] In certain embodiments, the checkpoint inhibitor for the methods provided herein can be an inhibitors or activators against a checkpoint protein that upregulated in cancer. In some specific embodiments, the checkpoint inhibitor for the methods provided herein can be an inhibitors or activators against a checkpoint protein including LAG-3, B7, TIM3 (HAVCR2), 0X40 (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 can be an inhibitors or activators selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a B7 inhibitor, a TIM3 (HAVCR2) inhibitor, an 0X40 (CD 134) inhibitor, a GITR agonist, a CD 137 agonist, or a CD40 agonist, a VTCN1 inhibitor, an IDO1 inhibitor, a CD276 inhibitor, a PVRIG inhibitor, a TIGIT inhibitor, a CD25 (IL2RA) inhibitor, an IFNAR2 inhibitor, an IFNAR1 inhibitor, a CSF1R inhibitor, a VSIR (VISTA) inhibitor, or a therapeutic agent targeting HLA. Such inhibitors, activators, or therapeutic agents are further provided below.

[0297] 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 anti-CTLA-4 antibodies include, but are not limited to, those described in US Patent Nos: 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 in their entireties. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab 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™.

[0298] 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 US Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT Patent Application Publication Nos. W02003042402, WO2008156712, W02010089411, W02010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, all of which are incorporated herein in their entireties.

[0299] “PD-1 antagonist” means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or Natural Killer T cell) and in specific embodiments also blocks binding of PD- L2 expressed on a cancer cell to the immune-cell expressed PD-1. 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 treatment method, medicaments and uses of the present invention in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and in specific embodiments blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0300] 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, SCH 900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, and is marketed under the trade name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab.Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is CT-011, a humanized antibody. CT-011 administered alone has failed to show response in treating acute myeloid leukemia (AML) at relapse. In yet another embodiment, the anti-PD-1 antibody is AMP-224, a fusion protein. In another embodiment, the PD-1 antibody is BGB-A317. BGB- A317 is a monoclonal antibody in which the ability to bind Fc gamma receptor I is specifically engineered out, and which has a unique binding signature to PD-1 with high affinity and superior target specificity. In one embodiment, the PD-1 antibody is cemiplimab. In another embodiment, the PD-1 antibody is camrelizumab. In a further embodiment, the PD-1 antibody is sintilimab. In some embodiments, the PD-1 antibody is tislelizumab. 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 toripalimab.

[0301] In certain embodiments, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-Ll antibody. In one embodiment, the anti- PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-Ll 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 a further embodiment, the PD-L1 inhibitor is avelumab.

[0302] 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.

[0303] In one embodiment, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al., J. Immunol., 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

[0304] In one embodiment, the checkpoint inhibitors 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).

[0305] In one embodiment, the checkpoint inhibitors 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).

[0306] In one embodiment, the checkpoint inhibitor is an 0X40 (CD 134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-0X40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.

[0307] 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.

[0308] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF- 05082566.

[0309] 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.

[0310] In one embodiment, the checkpoint inhibitor is recombinant human interleukin- 15 (rhIL-15).

[0311] In one embodiment, the checkpoint inhibitor is a VTCN inhibitor. In one embodiment, the VTCN inhibitor is FPA150.

[0312] 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 I0M-E. In another embodiment, the IDO inhibitor is or I0M-D.

[0313] 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 AB 154. 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.

[0314] 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 VSIRinhibitor is MTIG7192A. In another embodiment, the VSIR inhibitor is CA-170. In yet another embodiment, the VSIR inhibitor is JNJ 61610588. In one embodiment, the VSIR inhibitor is HMBD-002.

[0315] 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.

[0316] 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.

[0317] In some embodiments, the checkpoint inhibitor is an IFNAR1 inhibitor. In certain embodiments, the IFNAR1 inhibitor is an anti-IFNARl antibody. In one embodiment, the IFNAR1 inhibitor is anifrolumab. In another embodiment, the IFNAR1 inhibitor is sifalimumab.

[0318] In some embodiments, the checkpoint inhibitor is a CSF1R inhibitor. In certain embodiments, the CSF1R inhibitor is an anti-CSFIR antibody. In one embodiment, the CSF1R inhibitor is pexidartinib. In another embodiment, the CSF1R inhibitor is emactuzumab. In yet another embodiment, the CSF1R inhibitor is cabiralizumab. 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.

[0319] In some embodiments, the checkpoint inhibitor is a therapeutic agent targeting HLA. In certain embodiments, the therapeutic agent targeting HLA is an anti-HLA antibody. In one embodiment, the therapeutic agent targeting HLA is GSK01. In another embodiment, the therapeutic agent targeting HLA is IMC-C103C. In yet another embodiment, the therapeutic agent targeting HLA is IMC-F106C. In one embodiment, the therapeutic agent targeting HLA is IMC-G107C. In another embodiment, the therapeutic agent targeting HLA is ABBV-184.

[0320] The methods described herein can be used in combination with one or more second active agents as described herein where appropriate for treating diseases described herein and understood in the art.

[0321] PD-1 Antagonists and Pembrolizumab

[0322] Provided herein are methods for the treatment of various cancers in subjects, including subjects with unresectable locally advanced or metastatic urothelial cancer (la / mUC) who are unable to receive cisplatin-based chemotherapy, using an antibody drug conjugate (ADC) that binds 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.

[0323] “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab) alternatively referred to herein as “pembro,” is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences and CDRs described in Table 4. Pembrolizumab has been 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).

[0324] As used herein, a “pembrolizumab variant” or “a variant thereof’ pertaining to a pembrolizumab sequence means a monoclonal antibody that comprises heavy chain and light chain sequences that are substantially identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six, five, four, three, two or one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e.g., the variant positions are located in the FR regions or the constant region, and optionally has a deletion of the C- terminal lysine residue of the heavy chain. In other words, pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively. A pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0325] In one embodiment, the PD-1 antagonist useful in the treatment, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, that specifically binds to PD-1 or PD-L1, and preferably specifically binds 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 IgGl, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgGl or IgG4constant 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.

[0326] Examples of mAbs that bind to human PD-1, and useful in the treatment method, medicaments and uses of the present invention, are described in U.S. patent nos. US7488802, US7521051, US8008449, US8354509, and US8168757, and International application publn. nos. W02004 / 004771, W02004 / 072286, W02004 / 056875, US2011 / 0271358, and WO 2008 / 156712. Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include: pembrolizumab (also known as MK-3475), a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and that comprises the heavy and light chain amino acid sequences shown in Table 2; nivolumab (BMS-936558), a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013) and that comprises the heavy and light chain amino acid sequences shown in Table 2; the humanized antibodies h409Al 1, h409A16 and h409A17, which are described in WO2008 / 156712, and AMP-514, which is being developed by Medlmmune; cemiplimab; camrelizumab; sintilimab; tislelizumab; and toripalimab. Additional anti-PD-1 antibodies contemplated for use herein include MEDI0680 (U.S. Patent no. 8609089), BGB-A317 (U.S. Patent publ. no. 2015 / 0079109), INCSHR1210 (SHR-1210) (PCT International application publ. no. WO2015 / 085847), REGN-2810 (PCT International application publ. no.WO2015 / 112800), PDR001 (PCT International application publ. no. WO2015 / 112900), TSR-042 (ANB011) (PCT International application publ. no. WO2014 / 179664) and STI- 1110 (PCT International application publ. no. WO2014 / 194302).

[0327] Examples of mAbs that bind to human PD-L1, and useful in the treatment method, medicaments and uses of the present invention, are described in US8383796. Specific antihuman PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include BMS-936559, MEDI4736, and MSB0010718C.

[0328] 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), cemiplimab (LIBTAYO™, Regeneron Pharmaceuticals, Tarrytown, NY, USA) avelumab (BAVENCIO™, Merck KGaA, Darmstadt, Germany) or dostarlimab (JEMPERLI™, GlaxoSmithKline LLC, Philadelphia, PA). In other embodiments, the PD-1 antagonist is pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD,USA), PDR001 (U.S. Pat. No. 9,683,048), BGB-A317 (U.S. Pat. No. 8,735,553), or MGA012 (MacroGenics, Rockville, MD).

[0329] In one embodiment, the PD-1 antagonist useful in the methods of the invention is an anti -PD-1 antibody that blocks the binding of PD-1 to PD-L1 and PD-L2.

[0330] In some embodiments of the treatment methods, the anti -PD-1 antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:32 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO: 27;

[0331] In some embodiments of the treatment methods, medicaments and uses of the present invention, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that comprises: (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.

[0332] In some embodiments of the treatment methods, medicaments and uses of the present invention, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that comprises: (a) a light chain variable region comprising 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 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 heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:31, respectively.

[0333] In some embodiments of the treatment methods, medicaments and uses of the present invention, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, that comprises: (a) a light chain variable region comprising light chain CDR1 consisting of the amino acid sequence of SEQ ID NO:24, a light chain CDR2 consisting of the amino acid sequence of SEQ ID NO:25, and a light chain CDR3 consisting of the amino acid sequence of SEQ ID NO:26, respectively, and (b) a heavy chain variable region comprising heavy chain CDR1 consisting of the amino acid sequence of SEQ ID NO:29, a 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.

[0334] In other embodiments of the treatment methods, medicaments and uses of the present invention, the PD-1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, 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. A variant of a heavy chain variable region sequence is identical to the reference sequence except having up to six conservative amino acid substitutions in the framework region (i.e., outside of the CDRs). A variant of a light chain variable region sequence is identical to the reference sequence except having up to three conservative amino acid substitutions in the framework region (i.e., outside of the CDRs).

[0335] In another embodiment of the treatment methods, medicaments and uses 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 comprising SEQ ID NO: 33 and (b) a light chain comprising SEQ ID NO:28. In one embodiment, the PD-1 antagonist is an anti-PD-1 antibody that comprises two heavy chains and two light chains, and wherein the heavy and light chains comprise the amino acid sequences in SEQ ID NO:33 and SEQ ID NO:28, respectively.

[0336] In all of the above treatment methods, medicaments 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 treatment methods, medicaments and uses, the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof, that specifically binds to PD-1 or to PD-L1 and blocks the binding of PD- L1 to PD-1.

[0337] Table 4 below provides a list of the amino acid sequences of exemplary anti-PD-1 mAbs for use in the treatment method, medicaments and uses of the present invention.Table 4. Exemplary PD-1 Antibody SequencesTable 5. Additional PD-1 Antibodies and Antigen Binding Fragments Useful in the Formulations, Methods and Uses Provided Herein

[0338] In one embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region, e.g. a human constant region, such as gl, g2, g3, or g4 human heavy chain constant region or a variant thereof. In another embodiment, the anti- PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region, e.g. a human light chain constant region, such as lambda or kappa human light chain region or a variant thereof. By way of example, and not limitation, the human heavy chain constant region can be g4 and the human light chain constant region can be kappa. In an alternative embodiment, the Fc region of the antibody is g4 with a Ser228Pro mutation (Schuurman, J et.al., Mol. Immunol. 38: 1-8, 2001). In some embodiments, different constant domains maybe appended to humanized VL and VH regions derived from the CDRs provided herein. For example, if a particular intended use of an antibody (or fragment) of the present invention were to call for altered effector functions, a heavy chain constant domain other than human IgGl may be used, or hybrid IgGl / IgG4 may be utilized. Although human IgGl antibodies provide for long half-life and for effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody. In such instances a human IgG4 constant domain, for example, may be used. The present invention includes the use of anti-PD-1 antibodies or antigen-binding fragments thereof which comprise an IgG4 constant domain. In one embodiment, the IgG4 constant domain can differ from the native human IgG4 constant domain (Swiss-Prot Accession No. P01861.1) at a position corresponding to position 228 in the EU system and position 241 in the KABAT system, where the native Seri 08 is replaced with Pro, in order to prevent a potential inter-chain disulfide bond between Cysl06 and Cysl09 (corresponding to positions Cys 226 and Cys 229 in the EU system and positions Cys 239 and Cys 242 in the KABAT system) that could interfere with proper intra-chain disulfide bond formation. See Angal et al. (1993) Mol. Imunol. 30: 105. In other instances, a modified IgGl constant domain which has been modified to increase half-life or reduce effector function can be used.

[0339] In another embodiment, the PD-1 antagonist is an antibody or antigen binding protein that has a variable light domain and / or a variable heavy domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence identity to one of the variable light domains or variable heavy domains described above, and exhibits specific binding to PD-1. In another embodiment of the methods of treatment of the invention, the PD-1 antagonist is an antibody or antigen binding protein comprising variable light and variable heavy domains having up to 1, 2, 3, 4, or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0340] In some embodiments, the checkpoint inhibitor is administered after the administration of the ADCs provided herein. In other embodiments, the checkpoint inhibitor is administered simultaneously (e.g., in the same dosing period) with the ADCs provided herein. In yet other embodiments, the checkpoint inhibitor is administered after the administration of the ADCs provided herein.

[0341] In some embodiments, the amount of the checkpoint inhibitor for the various methods provided herein can be determined by standard clinical techniques. In certain embodiments, the amount of the PD-1 antagonist, e.g., pembrolizumab, for the various methods are provided in Section 5.6.

[0342] In some embodiments, the subjects that can be treated in the methods provided herein is a mammal. In some embodiments, the subjects that can be treated in the methods provided herein is a human.5.2.1.4 Therapeutic Outcome of the Methods Provided Herein

[0343] The methods provided herein, including in methods described in this Section (Section 5.2) and Sections 3 and 6, can provide beneficial therapeutic outcomes for cisplatin eligible and ineligible human subjects. In one embodiment, the human subject has a complete response following the treatment by a method provided herein. In another embodiment, the human subject has a partial response following the treatment by a method provided herein. In another embodiment, the human subject has complete response or a partial response following the treatment by a method provided herein.

[0344] In some embodiments, the response (complete or partial response) is determined by evaluating the tumor or cancer site (lesions). The criteria for determining complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) are described in FIG. 3A, FIG. 3B, and FIG. 3C.

[0345] In some embodiments, the human subjects and patients are used interchangeably. Therefore, a person skilled in the art would understand that the human subjects can be interchangeable with patients in any of the methods provided herein.

[0346] The therapeutic outcome of the methods provided herein thus can be evaluated based on any one or more of the response criteria described above.

[0347] In one embodiment, the human subject has a partial response following the treatment by a method provided herein. In another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 35% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In a further embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 40% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In yet another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about45% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In one embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 50% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 55% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In a further embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 60% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In yet another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 65% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In one embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 70% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 75% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In a further embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 80% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In yet another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 85% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In one embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 90% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In another embodiment, the human subject has a partial response following the treatment by a method provided herein, wherein the partial response is defined by an at least or about 95% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. In some embodiments, the diameter is determined according to the longest diameter of a lesion. In certain embodiments,the diameter is determined according to the longest diameter of a lesion in the plane of measurement. In some embodiments, the diameter is determined according to the longest diameter of a lesion in the plane of measurement with a minimal size of 10mm by CT scan. In certain embodiments, the diameter is determined according to the longest diameter of a lesion in the plane of measurement with a minimal size of 10mm by CT scan and CT slice thickness no greater than 5 mm.

[0348] The therapeutic outcomes of the methods provided herein can also be evaluated based on whether the disease is stable following the treatment. In one embodiment, the human subject has a stable disease following the treatment by a method provided herein. In another embodiment, the human subject does not have a progressive disease following the treatment by a method provided herein.

[0349] Alternatively, therapeutic outcomes based on the complete response, partial response, or stable disease can be evaluated with respect to a population of human subjects treated by a method provided herein by evaluating the percentage of the subjects having complete response, partial response, or stable disease in the treated population. As such, in some embodiments, the therapeutic outcome or efficacy measure applies to outcomes achieved by actually treating a population of subjects. In other embodiments, the therapeutic outcome or efficacy measure refers to the outcome or efficacy that is capable of being achieved if a population of human subjects was treated with a method as disclosed herein. While the following sections discuss the treatment of an actual population of human subjects, is should be understood that corresponding methods in which the outcome or efficacy measure is capable of being achieved in a patient population are also encompassed herein. In short, both scenarios described above apply to the following sections; only one scenario is described below in the interest of simplicity and to avoid redundancy.

[0350] In some embodiments of the methods provided herein, including, but not limited to, in Sections 3, 5.3, 5.8, and 6 and this Section (Section 5.2), the ADC is enfortumab vedotin. In certain embodiments of the methods provided herein, including, but not limited to, in Sections 3, 5.3, 5.8, and 6 and this Section (Section 5.2), the ADC is a biosimilar of enfortumab vedotin. In some embodiments of the methods provided herein, including, but not limited to, in Sections 3, 5.2.1.3, 5.8, and 6 and this Section (Section 5.2), the PD-1 antagonist or anti-PD-1 antibody is pembrolizumab.

[0351] In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 15%. In another embodiment, a population of thehuman subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 20%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 25%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 29.1%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 30%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 31%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 32%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 33%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 34%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having complete response in the treated population is at least or about 35%.

[0352] In one embodiment, the complete response rate is at least or about 10% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 15% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 20% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 25% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 29.1% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 30% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 31% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 32% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 33% for a population of subjects treated with theI l lmethod. In another embodiment, the complete response rate is at least or about 34% for a population of subjects treated with the method. In another embodiment, the complete response rate is at least or about 35% for a population of subjects treated with the method.

[0353] Similarly, using percentage of partial response as the criteria, in one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 15%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 20%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 25%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 30%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 35%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 38.7%. In one embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 40%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 45%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 50%. In another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 55%. In a further embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 60%. In yet another embodiment, a population of the human subjects is treated by a method provided herein, wherein the percentage of the subjects having partial response in the treated population is at least or about 65%.

[0354] In one embodiment, the partial response rate is at least or about 15% for a population of subjects treated with the method. In another embodiment, the partial responserate is at least or about 25% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 20% for a population of subjects treated with the method. In another embodiment, the partial response rate is at least or about 25% for a population of subjects treated with ...

Claims

What is claimed is:

1. A method of treating cancer in a subject, comprising administering to the subject:(a) an effective amount of an antibody drug conjugate (ADC) comprising an anti- 191P4D12 antibody or antigen binding fragment thereof, and(b) an effective amount of an anti-PD-1 antibody or 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 regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:32 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs 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 complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject has urothelial or bladder cancer; and wherein the subject is eligible to receive cisplatin treatment (cisplatin eligible).

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

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

4. The method of any one of claims 1 to 3, wherein the subject has NCI CTCAE Grade <1 audiometric hearing loss.

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

6. The method of any one of claims 1 to 5, wherein:(a) the subject has a progression free survival of at least or about 10, 11, 12, 13,14, 14.6, 15, 16, 17, 18, or 19 months following the treatment, optionally wherein the subject has a progression free survival of at least or about 14.6 months following the treatment, further optionally wherein the subject has a progression free survival of 14 to 15 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10, 11, 12, 13, 14, 14.6,15, 16, 17, 18, or 19 months, optionally wherein median progression free survival in the treated population is at least or about 14.6 months, further optionally wherein median progression free survival in the treated population is 14 to 15 months; or(c) median progression free survival is at least or about 10, 11, 12, 13, 14, 14.6, 15, 16, 17, 18, or 19 months for a population of subjects treated with the method, optionally wherein median progression free survival is at least or about 14.6 months for a population of subjects treated with the method, further optionally wherein median progression free survival is 14 to 15 months for a population of subjects treated with the method.

7. The method of any one of claims 1 to 5, wherein:(a) the subject has an overall survival of at least or about 27, 28, 29, 30, 31, 31.5, 32, 33, 34, 35, or 36 months following the treatment, optionally wherein the subject has an overall survival of at least or about 31.5 months following the treatment, further optionally wherein the subject has an overall survival of 31 to 32 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 27, 28, 29, 30, 31, 31.5, 32, 33,34, 35, or 36 months, optionally wherein median overall survival in the treated population is at least or about 31.5 months, further optionally wherein median overall survival in the treated population is 31 to 32 months; or(c) median overall survival is at least or about 27, 28, 29, 30, 31, 31.5, 32, 33, 34,35, or 36 months for a population of subjects treated with the method, optionally whererin median overall survival is at least or about 31.5 months for a population of subjects treated with the method, further optionally wherein median overall survival is 31 to 32 months for a population of subjects treated with the method.

8. A method of treating cancer in a subject, comprising administering to the subject:(a) an effective amount of an antibody drug conjugate (ADC) comprising an anti- 191P4D12 antibody or antigen binding fragment thereof, and(b) an effective amount of an anti-PD-1 antibody or 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 regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:32 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs 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 complementarity determining regions (CDRs) comprising the amino acid sequences of the CDRs of the heavy chain variable region set forth in SEQ ID NO:22 and a light chain variable region comprising CDRs comprising the amino acid sequences of the CDRs of the light chain variable region set forth in SEQ ID NO:23; wherein the subject has urothelial or bladder cancer; and wherein:(i) the subject has aspartate transferase (AST) and alanine transaminase (ALT) no more than 2.5 fold of upper limit of normal (ULN),(ii) 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 or antigen binding fragment thereof, and / or(iii) the subject has not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof.

9. The method of claim 8, wherein 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 or antigen binding fragment thereof; and wherein the subject has not received major surgery within 4 weeks prior to the administration of the ADC and the anti-PD-1 antibody or antigen binding fragment thereof.

10. The method of claim 8 or 9, wherein:(a) the subject has a progression free survival of at least or about 12.5 months following the treatment, optionally wherein the subject has a progression free survival of 12 to 13 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 12.5 months, optionally wherein median progression free survival in the treated population is 12 to 13 months; or(c) median progression free survival is at least or about 12.5 months for a population of subjects treated with the method, optionally wherein median progression free survival is 12 to 13 months for a population of subjects treated with the method.

11. The method of claim 8 or 9, wherein:(a) the subject has an overall survival of at least or about 31.5 months following the treatment, optionally wherein the subject has an overall survival of 31 to 32 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median overall survival in the treated population is at least or about 31.5 months, optionally wherein median overall survival in the treated population is 31 to 32 months; or(c) median overall survival is at least or about 31.5 months for a population of subjects treated with the method, optionally wherein median overall survival is 31 to 32 months for a population of subjects treated with the method.

12. The method of claim 8 or 9, wherein the subject is eligible to receive cisplatin treatment (cisplatin eligible), and wherein:(a) the subject has a progression free survival of at least or about 14.6 months following the treatment, optionally wherein the subject has a progression free survival of 14 to 15 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 14.6 months, optionally wherein median progression free survival in the treated population is 14 to 15 months; or(c) median progression free survival is at least or about 14.6 months for a population of subjects treated with the method, optionally wherein median progression free survival is 14 to 15 months for a population of subjects treated with the method.

13. The method of claim 8 or 9, wherein the subject is ineligible to receive cisplatin treatment (cisplatin eligible), and wherein:(a) the subject has a progression free survival of at least or about 10.6 months following the treatment, optionally wherein the subject has a progression free survival of 10 to 11 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10.6 months, optionally wherein median progression free survival in the treated population is 10 to 11 months; or(c) median progression free survival is at least or about 10.6 months for a population of subjects treated with the method, optionally wherein median progression free survival is 10 to 11 months for a population of subjects treated with the method.

14. The method of any one of claims 1 to 5, 8 or 9, wherein the subject has expression of PD-L1 no less than CPS of 10, and optionally wherein:(a) the subject has a progression free survival of at least or about 18.5 months following the treatment, optionally wherein the subject has a progression free survival of 18 to 19 months following the treatment;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 18.5 months, optionally wherein median progression free survival in the treated population is 18 to 19 months; or(c) median progression free survival is at least or about 18.5 months for a population of subjects treated with the method, optionally wherein median progression free survival is 18 to 19 months for a population of subjects treated with the method.

15. The method of any one of claims 1 to 5, 8 or 9, wherein the subject has expression of PD-L1 less than CPS of 10, and optionally wherein:(a) the subject has a progression free survival of at least or about 10.5 months following the treatment, optionally wherein the subject has a progression free survival of 10 to 11 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10.5 months, optionally wherein median progression free survival in the treated population is 10 to 11 months; or(c) median progression free survival is at least or about 10.5 months for a population of subjects treated with the method, optionally wherein median progression free survival is 10 to 11 months for a population of subjects treated with the method.

16. The method of any one of claims 1 to 5, 8 or 9, wherein the subject does not have liver metastases, and optionally wherein:(a) the subject has a progression free survival of at least or about 16.4 months following the treatment, optionally wherein the subject has a progression free survival of 16 to 17 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 16.4 months, optionally wherein median progression free survival in the treated population is 16 to 17 months; or(c) median progression free survival is at least or about 16.4 months for a population of subjects treated with the method, optionally wherein median progression free survival is 16 to 17 months for a population of subjects treated with the method.

17. The method of any one of claims 1 to 5, 8 or 9, wherein the subject has liver metastases, and optionally wherein:(a) the subject has a progression free survival of at least or about 8.2 months following the treatment, optionally wherein the subject has a progression free survival of 8 to 9 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 8.2 months, optionally wherein median progression free survival in the treated population is 8 to 9 months; or(c) median progression free survival is at least or about 8.2 months for a population of subjects treated with the method, optionally wherein median progression free survival is 8 to 9 months for a population of subjects treated with the method.

18. The method of any one of claims 1 to 5, 8 or 9, wherein the race of the subject is white, and optionally wherein:(a) the subject has a progression free survival of at least or about 10.4 months, optionally wherein the subject has a progression free survival of 10 to 11 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 10.4 months, optionally wherein median progression free survival in the treated population is 10 to 11 months; or(c) median progression free survival is at least or about 10.4 months for a population of subjects treated with the method, optionally wherein median progression free survival is 10 to 11 months for a population of subjects treated with the method.

19. The method of any one of claims 1 to 5, 8 or 9, wherein the race of the subject is not white, and optionally wherein:(a) the subject has a progression free survival of at least or about 22.3 months, optionally wherein the subject has a progression free survival of 22 to 23 months;(b) a population of the subjects is treated by the methods, and wherein median progression free survival in the treated population is at least or about 22.3 months, optionally wherein median progression free survival in the treated population is 22 to 23 months; or(c) median progression free survival is at least or about 22.3 months for a population of subjects treated with the method, optionally wherein median progression free survival is 22 to 23 months for a population of subjects treated with the method.

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

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

22. The method of any one of claims 1 to 21, wherein the disease site of origin is in the upper tract.

23. The method of any one of claims 1 to 21, wherein the disease site of origin is in the lower tract.

24. The method of any one of claims 1 to 23, wherein the subject has a PD-L1 expression combined positive score (CPS) greater than or equal to 10.

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

26. The method of any one of claims 1 to 19, wherein the subject has a Nectin-4 H- score between 0 and 300.

27. The method of any one of claims 1 to 19, wherein the subject has a Nectin-4 H- score between 0 and 200.

28. The method of any one of claims 1 to 19, wherein the subject has a Nectin-4 H- score between 0 and 150.

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

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

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

32. The method of any one of claims 1 to 31, wherein the anti-PD-1 antibody or antigen binding fragment thereof comprises: (a) a light chain variable region comprising 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 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 heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:31, respectively.

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

34. The method of any one of claims 1 to 33, wherein the anti-PD-1 antibody or antigen binding fragment thereof 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.

35. The method of any one of claims 1 to 33, wherein the anti-PD-1 antibody comprises (a) a heavy chain comprising SEQ ID NO: 33 and (b) a light chain comprising SEQ ID NO:28.

36. The method of any one of claims 1 to 35, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO:9, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 11; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14, or wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 16, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 17, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 19, CDR-L2 comprising the amino acid sequence of SEQ ID NO:20, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:21.

37. The method of any one of claims 1 to 35, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO:9, CDR-H2 consisting of the amino acid sequence of SEQ IDNO: 10, CDR-H3 consisting of the amino acid sequence of SEQ ID NO: 11; CDR-L1consisting 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 wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO: 16, CDR-H2 consisting of the amino acid sequence of SEQ ID NO: 17, CDR-H3 consisting of the amino acid sequence of SEQ ID NO: 18; CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 19, CDR-L2 consisting of the amino acid sequence of SEQ ID NO:20, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO:21.

38. The method of any one of claims 1 to 37, wherein the anti-191P4D12 antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.

39. The method of any one of claims 1 to 38, wherein the anti-191P4D12 antibody comprises a heavy chain comprising the 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 comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8.

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

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

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

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

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

45. The method of claim 44, wherein the linker is an enzyme-cleavable linker, and wherein the linker forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof.

46. The method of claim 44 or 45, wherein the linker has a formula of: -Aa-Ww- Yy-; wherein -A- is a stretcher unit, a is 0 or 1; -W- is an amino acid unit, w is an integer ranging from 0 to 12; and -Y- is a spacer unit, y is 0, 1, or 2.

47. The method of claim 46, wherein the stretcher unit has the structure of Formula (1) below; the amino acid unit is valine-citrulline; and the spacer unit is a PAB group comprising the structure of Formula (2) below:Formula (2).

48. The method of claim 46 or 47, wherein the stretcher unit forms a bond with a sulfur atom of the antibody or antigen binding fragment thereof; and wherein the spacer unit is linked to MMAE via a carbamate group.

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

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

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

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

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

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

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

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

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

58. The method of any one of claims 53 to 56, wherein the average p value of the effective amount of the antibody drug conjugates is about 3.8.

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

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

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

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

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

64. The method of any one of claims 1 to 63, wherein the ADC is administered to the subject by an IV injection or infusion up to 2 days of a 21 -day treatment cycle.

65. The method of any one of claims 1 to 64, wherein the ADC is administered to the subject by an IV injection or infusion on days 1 and 8 of a 21 -day treatment cycle.

66. The method of any one of claims 1 to 65, wherein the ADC is administered to the subject by an IV injection or infusion over about 30 minutes up to 2 days of a 21 -day treatment cycle.

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

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

69. The method of any one of claims 1 to 68, wherein the ADC is formulated in 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 wherein the pH of the pharmaceutical composition is about 6.0 at 25°C.

70. The method of any one of claims 1 to 68, wherein the ADC is formulated in 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 wherein the pH of the pharmaceutical composition is about 6.0 at 25°C.

71. The method of any one of claims 1 to 70, wherein the ADC has the following structure:wherein L- represents the antibody or antigen binding fragment thereof and p is from about 3 to about 4, the anti-191P4D12 antibody comprises a heavy chain comprising the 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 comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, wherein the ADC is administered at a dose of about 1.25 mg / kg of the subject’s body weight, and wherein the dose is administered by an IV injection or infusion over about 30 minutes on days 1 and 8 of a 21 -day treatment cycle.

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

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

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

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

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

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

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

79. The method of any one of claims 1 to 78, whereby the subject has a complete response following the treatment.

80. The method of any one of claims 1 to 78, wherein the subject has a partial response following the treatment.

81. The method of any one of claims 1 to 78, wherein the subject has a stable disease following the treatment.

82. The method of any one of claims 1 to 81, wherein the subject has a Brief Pain Inventory Short Form (BPI-SF) worst pain score of about zero (0) prior to administration of the ADC to the subject, and wherein after administration of the ADC to the subject, the subject has an improved BPI-SF worst pain score.

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

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

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

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

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

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

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