Methods for treating patients with locally advanced or metastatic urothelial carcinoma using antibody-drug conjugates (ADCs) that bind to 191P4D12 protein in combination with pembrolizumab

Abstract

Provided herein are methods for treating cancer using antibody-drug conjugates (ADCs) that bind to the 191P4D12 protein (Nectin-4) and pembrolizumab.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 392,067, filed July 25, 2022, U.S. Patent Application No. 63 / 402,830, filed August 31, 2022, and U.S. Patent Application No. 63 / 504,183, filed May 24, 2023, the entire disclosures of each of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a computer readable sequence listing submitted herewith in XML file format, the entire contents of which are incorporated herein by reference in their entirety. The sequence listing XML file submitted herewith is named "14369-295-228_SEQLISTING.xml", was created on July 18, 2023, and is 62,806 bytes in size.

[0003] 1. Field Provided herein are methods for treating cancer using antibody-drug conjugates (ADCs) that bind to the 191P4D12 protein (Nectin-4). In particular, provided herein are methods for treating patients with unresectable locally advanced or metastatic urothelial carcinoma who cannot receive cisplatin-based chemotherapy using antibody-drug conjugates (ADCs) that bind to the 191P4D12 protein in combination with pembrolizumab. [Background technology]

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

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

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

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

[0008] Nectin-4 was originally identified by bioinformatics and cloned from human trachea (Reymond et al., J Biol Chem (2001) 276(46):43205-15). Using suppression subtractive hybridization on a pool of urothelial carcinoma specimens, it was confirmed that nectin-4 was significantly upregulated in urothelial carcinoma. Expression characterization in multiple tumor samples, 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 shown to be expressed in several cancers, particularly urothelial, breast, lung, pancreatic, and ovarian cancers. Higher expression levels are associated with disease progression and / or poor prognosis (Fabre-Lafay et al., BMC Cancer (2007); 7:73).

[0010] PD-1 PD-1 is recognized as an important molecule in immune regulation and the maintenance of peripheral immune tolerance. PD-1 is moderately expressed on naive T, B, and NKT cells and is upregulated by T / B cell receptor signaling in lymphocytes, monocytes, and myeloid cells (Sharpe, Arlene H. et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology (2007); 8:239-245).

[0011] Two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in a variety of tissues. For example, in large sample sets of ovarian, renal, colorectal, pancreatic, liver, and melanoma, PD-L1 expression has been shown to correlate with poor prognosis and shortened overall survival, regardless of subsequent treatment (Dong, Haidong et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002 Aug;8(8):793-800; Yang, Wanhua et al., PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci. 2008 Jun;49(6(2008):49:2518-2525; Ghebeh, Hazem et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal Carcinoma:correlation with important high-risk prognostic factors.Neoplasia(2006)8:190-198, Hamanishi, Junzo et al.,Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+T lymphocytes are prognostic factors of human ovarian cancer.Proc.Natl.Acad.Sci.USA(2007):104:3360-3365, Thompson, R Houston, and Eugene D Kwon, Significance of B7-H1 overexpression in kidney cancer.Clinical genitourin Cancer(2006):5:206-211、Nomi,Takeo et al.,Clinical significance and therapeutic potential of the programmed death-1 ligand / programmed death-1 pathway in human pancreatic cancer.Clinical Cancer Research(2007);13:2151-2157、Ohigashi,Yuichiro et al.,Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer.Clin.Cancer Research(2005):11:2947-2953、Inman,Brant A et al.,PD-L1(B7-H1)expression by urothelial carcinoma of the bladder and BCG-induced granulomata:associations with localized stage progression.Cancer(2007):109:1499-1505、Shimauchi,Takatoshi et al.,Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+T-cells in adult T-cell Leukemia / Lymphoma.Int.J.Cancer(2007):121:2585-2590、Gao,Qiang et al.,Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.Clinical Cancer Research(2009)15:971-979, Nakanishi, Juro et al., Overexpression of B7-H1(PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers.Cancer Immunol Immunother.(2007)56:1173-1182, Hino et al., Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma.Cancer(2010):00:1-9). Similarly, PD-1 expression on tumor-infiltrating lymphocytes represents 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: implications 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 has been found to correlate with poor prognosis in renal cancer (Thompson, R Houston et al., PD-1 is expressed by tumor-infiltrating cells and is associated with poor outcome for patients with renal carcinoma.Clinical Cancer Research (2007) 15:1757-1761). Therefore, it has been proposed that PD-L1-expressing tumor cells interact with PD-1-expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to a reduced immune response against tumors.

[0012] Several monoclonal antibodies that inhibit the interaction of PD-1 with one or both of its ligands, PD-L1 and PD-L2, have been approved for the treatment of cancer. Pembrolizumab (KEYTRUDA®, Merck & Co., Inc., Rahway, NJ, USA) is a potent humanized immunoglobulin G4 (IgG4) mAb that binds to the programmed cell death 1 (PD-1) receptor with high specificity, thereby 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 possesses high affinity for PD-1 and potent receptor-blocking activity. Keytruda® (pembrolizumab) is indicated for the treatment of patients across several indications, including as the first-line treatment of patients with microsatellite instability-high or mismatch repair-deficient (MSI-H / dMMR) unresectable or metastatic CRC. Pembrolizumab is the current standard of care in first-line MSI-H / dMMR mCRC.

[0013] urothelial cancer According to the International Agency for Research on Cancer (IARC), urothelial carcinoma accounts for more than 165,000 patient deaths annually, making it the ninth most common cancer worldwide. In Europe, approximately 151,000 newly diagnosed cases of urothelial carcinoma are associated with 52,000 annual deaths. In Japan, more than 22,000 newly diagnosed cases are associated with 7,600 annual deaths (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 December 19, 2017). In the United States, the National Cancer Institute estimates that over 79,000 new cases of bladder cancer were diagnosed in 2017, and over 16,800 people died from the disease (National Cancer Institute 2018).

[0014] Metastatic urothelial carcinoma has a 5-year mortality rate of approximately 85% (American Cancer Society (ACS) 2016).

[0015] Urothelial carcinoma 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 (the area inside the kidney where urine collects), ureters (the tubes that connect the kidneys to the bladder), and urethra.

[0016] First-line therapy for metastatic urothelial carcinoma in patients with adequate renal function consists of cis-diamminedichloroplatinum(II) (cisplatin)-based combinations, such as methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or gemcitabine and cisplatin, which have demonstrated objective response rates (ORRs) of up to 55%, with complete responses (CRs) occurring in approximately 12% of patients (von der Maase 2000). Despite initial chemotherapy sensitivity, patients are not cured, and outcomes for metastatic urothelial carcinoma after these regimens are poor, with a median progression-free interval of 7 months and a median overall survival (OS) of 14 months. Long-term survival rates are poor (approximately 15%), and the prognosis for patients with visceral metastases is particularly grim, with a 5-year survival rate of 7% (von der Maase 2005; Bellmunt 2011).

[0017] Nearly half of patients with urothelial carcinoma are unsuitable for cisplatin-containing chemotherapy due to impaired renal function, poor performance status, or comorbidities (Dash et al. Cancer (2006); 107(3):506-13). For 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 taxanes or gemcitabine (Cathomas 2015). In that setting, long-term survival rates are even lower (De Santis et al. J Clin Oncol (2009); 27(33):5634-9). In April 2017, the Food and Drug Administration (FDA) approved atezolizumab (TECENTRIQ®), an anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (CPI), as first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (la / mUC) who are cisplatin-ineligible. This accelerated approval was based on an open-label, single-arm study that demonstrated long duration of response, indicating activity in this difficult-to-treat population, with an objective response rate (ORR) of 23%, which was comparable across different target expression levels (Balar 2017). The median OS for these patients was 15.9 months; however, this was a single-arm study, and any OS benefit must be confirmed in randomized trials (Balar et al., Lancet (2017);389(10064):67-76).

[0018] Pembrolizumab (Keytruda®) received accelerated approval from the FDA in May 2017 as first-line treatment for patients with cisplatin-ineligible Ia / mUC. The trial results on which this approval was based demonstrated an ORR of 29%, with a median duration of response not reached at the time of analysis (median follow-up of 7.8 months) (Pembrolizumab Prescribing Information, Merck Sharp and Dohme Corp., 2017). In May 2018, the FDA issued a warning regarding decreased survival in patients with low PD-L1 expression treated with pembrolizumab or atezolizumab in the first-line setting compared with platinum-based chemotherapy. Subsequently, the labeling for these two CPIs was revised to require high PD-L1 expression in patients with first-line metastatic urothelial carcinoma eligible for platinum-containing chemotherapy. This development further limited options for patients with metastatic urothelial carcinoma with low PD-L1 expression.

[0019] Other options for patients who are ineligible for first-line cisplatin typically include carboplatin-based regimens or single-agent taxanes or gemcitabine (Cathomas et al., Hematol Oncol Clin North Am (2015); 29(2): 329-40.).

[0020] Few options are available for second-line treatment of metastatic disease. In the European Union, the small-molecule tubulin inhibitor vinflunine (Javlor®) was approved in 2009 based on modest activity (overall response rate 9%), a moderate 2-month survival benefit (6.9 months with vinflunine plus best supportive care (BSC) vs. 4.6 months with 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 granted accelerated approval of atezolizumab as first-line salvage therapy after platinum-based therapy for la / mUC in the United States, followed by EU approval in September 2017. In February 2017, nivolumab (Opdivo®) became the second immunotherapy to receive accelerated FDA approval, followed by EU approval in June 2017. In March and May 2017, the FDA granted accelerated approval to avelumab (Bavencio®) and durvalumab (Imfinzi™), respectively. These are PD-L1-blocking antibodies indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Pembrolizumab received regular FDA approval for second-line treatment in May 2017 (Keytruda Prescribing Information, Merck, May 2017). This approval was based on the first reported randomized experience with CPI in the post-platinum setting, where a phase 3 trial of 542 patients demonstrated an OS of 10.3 months compared with 7.4 months with taxane chemotherapy or vinflunine. Furthermore, the ORR was 21% with pembrolizumab and 11% with chemotherapy. No statistically significant difference in progression-free survival (PFS) was observed between the two groups (Bellmunt et al., N Engl J Med (2017); 376 (11): 1015-26). It was approved in the EU for the same indication in September 2017 and in Japan in January 2018.Other programmed cell death protein 1 (PD-1) and PD-L1 inhibitors are currently being evaluated as first- and second-line therapies in clinical trials for urothelial carcinoma (Mullane et al., Curr Opin Urol (2016); 26(6):556-63).

[0021] While CPIs offer a novel approach to the treatment of metastatic urothelial carcinoma, tumor responses have occurred in only a small number of patients, and improvements in long-term survival have only lasted a few months. For example, in May 2017, Roche announced that a confirmatory phase III trial of second-line atezolizumab failed to meet its primary endpoint of overall survival (OS) (Roche, press release, “Roche provides update on phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer,” 10 May 2017). Many patients with locally advanced or metastatic urothelial carcinoma do not respond to CPIs, and many of those who respond ultimately experience disease progression (Rosenberg et al., Lancet (2016); 387 (10031): 1909-20). Novel therapies remain necessary, particularly for patients who do not respond to CPIs or who progress after CPI therapy.

[0022] The lack of first-line therapy for patients with metastatic urothelial carcinoma and the limited activity observed with second-line chemotherapy are sufficient indicators of the large unmet medical need in this population.

[0023] bladder cancer Bladder cancer accounts for approximately 5 percent of all new cancer cases in men (the fifth most common neoplasm) and 3 percent of all new cancer cases in women (the eighth most common neoplasm). Incidence rates are gradually increasing with the aging population. The American Cancer Society (cancer.org) estimates that there are 81,400 new cases annually, including 62,100 in men and 19,300 in women, accounting for 4.5% of all cancer cases. The age-adjusted incidence rate in the United States is 20 per 100,000 people, including both men and women. Bladder cancer is estimated to cause 17,980 deaths annually (13,050 in men and 4,930 in women), accounting for 3% of all cancer-related deaths. Bladder cancer incidence and mortality rates increase significantly with age, making it a growing problem with an aging population. Approximately 580,000 people will be diagnosed with bladder cancer worldwide in 2020, and bladder cancer is estimated to cause approximately 210,000 deaths worldwide.

[0024] Most bladder cancers recur in the bladder. Bladder cancer is managed by transurethral cystectomy (TUR) combined with intravesical chemotherapy or intravesical immunotherapy. Multifocal and recurrent bladder cancers demonstrate the limitations of TUR. Most muscle-invasive cancers are not cured by TUR alone. Radical cystectomy and urinary diversion are the most effective means of eliminating cancer, but inevitably affect urinary and sexual function. There continues to be a great need for beneficial treatments for bladder cancer patients.

[0025] There is a great need for additional treatment methods for urothelial and bladder cancer. These include the use of antibodies and antibody-drug conjugates, including in combination with other agents, as treatment modalities. Summary of the Invention

[0026] 3. Summary of the Invention Provided herein are methods for treating various cancers in human subjects, including methods for treating patients with unresectable locally advanced or metastatic urothelial carcinoma who cannot receive cisplatin-based chemotherapy using an antibody-drug conjugate (ADC) that binds to the 191P4D12 protein, in combination with pembrolizumab.

[0027] In certain embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin therapy and has not previously been treated with an immune checkpoint inhibitor (CPI) (e.g., a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).

[0028] Embodiment 1. A method of treating cancer in a human 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 and administering 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); the anti-PD-1 antibody comprises (i) a light chain variable region comprising the light chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 24, 25, and 26, respectively; and (ii) a heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 29, 30, and 31, respectively; the anti-191P4D12 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a complementarity-determining region (CDR) of a heavy chain variable region having the amino acid sequence of the CDR set forth in SEQ ID NO: 22, and a light chain variable region comprising the CDR having the amino acid sequence of the CDR of a light chain variable region set forth in SEQ ID NO: 23; the subject has urothelial cancer or bladder cancer; the subject has not received immune checkpoint inhibitor (CPI) therapy, the subject is ineligible to receive cisplatin therapy (cisplatin ineligible), The method.

[0029] Embodiment 2. The method of embodiment 1, wherein the subject has visceral metastases.

[0030] Embodiment 3. The method of embodiment 1, wherein the subject has lymph node-only disease.

[0031] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the disease site is the upper urinary tract.

[0032] Embodiment 5. The method of any one of embodiments 1 to 3, wherein the disease site is the lower urinary tract.

[0033] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the subject has a PD-L1 expression combined positive score (CPS) of 10 or greater.

[0034] Embodiment 7. The method of any one of embodiments 1 to 5, wherein the subject has a PD-L1-expressing CPS of less than 10.

[0035] Embodiment 8. The method of any one of embodiments 1 to 6, wherein the subject has an H-score of 0 to 300 for Nectin-4.

[0036] Embodiment 9. The method of any one of embodiments 1 to 7, wherein the subject has an H-score of 0 to 200 for Nectin-4.

[0037] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the subject has an ECOG performance status score of 1 to 2.

[0038] Embodiment 11. The method of any one of embodiments 1-9, wherein the subject has one or more conditions selected from the group consisting of an ECOG performance status score of 2, impaired renal function, and hearing loss of Grade 2 or greater.

[0039] Embodiment 12. The method of any one of embodiments 1 to 9, wherein the subject has NYHA grade III heart failure.

[0040] Embodiment 13. The subject has an ECOG performance status score of 2, and wherein: The subject (i) has hemoglobin of 10 g / dL or more, (ii) has a GFR of 50 mL / min or more, and (iii) does not have NYHA stage III heart failure. 12. The method of embodiment 11.

[0041] Embodiment 14. The method of embodiment 11, wherein the renal impairment is determined by a creatinine clearance (CrCl) of less than 60 mL / min.

[0042] Embodiment 15. The method of embodiment 11, wherein the renal impairment is determined by a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min.

[0043] Embodiment 16. The method of embodiment 11, wherein the renal impairment is determined by a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min.

[0044] Embodiment 17. The subject is (i) absolute neutrophil count of 1500 / μL or greater; (ii) platelet count of 100,000 / μL or more; (iii) hemoglobin ≥ 9 g / dL; (iv) serum bilirubin not exceeding either 1.5 times the upper limit of normal (ULN) or 3 times the ULN for patients with Gilbert's disease; (v) CrCl of 30 mL / min or greater, and (vi) alanine aminotransferase and aspartate aminotransferase levels less than or equal to 3 times the ULN 17. The method of any one of embodiments 1 to 16, wherein the method has one or more conditions selected from the group consisting of:

[0045] Embodiment 18. The method of embodiment 17, wherein the subject has all of conditions (i) to (vi) described in embodiment 15.

[0046] Embodiment 19. The method of any one of embodiments 14 to 18, wherein the CrCl is measured by 24-hour urine collection or estimated by Cockcroft-Gault criteria.

[0047] Embodiment 20. The method of any one of embodiments 1-19, wherein the subject has sensory or motor neuropathy of grade 2 or less.

[0048] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the subject does not have active metastases in the central nervous system.

[0049] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the subject does not have uncontrolled diabetes.

[0050] Embodiment 23. The method of embodiment 22, wherein the uncontrolled diabetes is determined by a hemoglobin A1c (HbA1c) of 8% or greater, or an HbA1c of 7-8% in combination with associated diabetic symptoms that cannot otherwise be explained by diabetes.

[0051] Embodiment 24. The method of embodiment 23, wherein the associated diabetic symptoms include or consist of polyuria, polydipsia, or both polyuria and polydipsia.

[0052] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the subject has locally advanced or metastatic urothelial carcinoma.

[0053] Embodiment 26. The method of any one of embodiments 1 to 25, wherein the subject has locally advanced or metastatic bladder cancer.

[0054] Embodiment 27. 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 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; 27. The method according to any one of embodiments 1 to 26.

[0055] Embodiment 28. 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 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; 27. The method according to any one of embodiments 1 to 26.

[0056] Embodiment 29. The method of any one of embodiments 1 to 28, 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.

[0057] Embodiment 30. The method of any one of embodiments 1 to 29, wherein the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from amino acid 20 (glutamic acid) to amino acid 466 (lysine) of SEQ ID NO:7, and a light chain comprising the amino acid sequence ranging from amino acid 23 (aspartic acid) to amino acid 236 (cysteine) of SEQ ID NO:8.

[0058] Embodiment 31 The method of any one of embodiments 1 to 30, wherein the anti-191P4D12 antigen-binding fragment is a Fab, F(ab')2, Fv, or scFv.

[0059] Embodiment 32 The method of any one of embodiments 1 to 30, wherein the anti-191P4D12 antibody is a fully human antibody.

[0060] Embodiment 33 The method of any one of embodiments 1 to 30 and 32, wherein the anti-191P4D12 antibody is an IgG1 and the light chain is a kappa light chain.

[0061] Embodiment 34 The method of any one of embodiments 1 to 33, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof is recombinantly produced.

[0062] Embodiment 35. The method of any one of embodiments 1 to 34, wherein the anti-191P4D12 antibody or antigen-binding fragment is conjugated to each unit of MMAE via a linker.

[0063] Embodiment 36 The method of embodiment 35, wherein the linker is an enzyme-cleavable linker, and the linker forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof.

[0064] Embodiment 37. The method of embodiment 35 or 36, wherein the linker has the formula -Aa-Ww-Yy-, where -A- is an extender unit, a is 0 or 1, -W- is an amino acid unit, w is an integer ranging from 0 to 12, -Y- is a spacer unit, and y is 0, 1, or 2.

[0065] Embodiment 38. The extender unit has the structure of formula (1), wherein the amino acid unit is valine-citrulline and the spacer unit is a PAB group having the structure of formula (2): TIFF2025526346000002.tif70165 The method described in embodiment 37.

[0066] Embodiment 39. The method of embodiment 37 or 38, wherein the extender unit forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof, and the spacer unit is linked to MMAE via a carbamate group.

[0067] Embodiment 40. The method of any one of embodiments 1 to 39, wherein the ADC comprises 1 to 20 units of MMAE per antibody or antigen-binding fragment thereof.

[0068] Embodiment 41. The method of any one of embodiments 1 to 40, wherein the ADC comprises 1 to 10 units of MMAE per antibody or antigen-binding fragment thereof.

[0069] Embodiment 42. The method of any one of embodiments 1 to 41, wherein the ADC comprises 2 to 8 units of MMAE per antibody or antigen-binding fragment thereof.

[0070] Embodiment 43. The method of any one of embodiments 1 to 42, wherein the ADC comprises 3 to 5 units of MMAE per antibody or antigen-binding fragment thereof.

[0071] Embodiment 44. The ADC has the structure: TIFF2025526346000003.tif34165, wherein L- represents the anti-191P4D12 antibody or antigen-binding fragment thereof, and p is 1 to 10.

[0072] Embodiment 45. The method of embodiment 44, wherein p is 2 to 8.

[0073] Embodiment 46. The method of embodiment 44 or 45, wherein p is 3 to 5.

[0074] Embodiment 47. The method of any one of embodiments 44 to 46, wherein p is 3 to 4.

[0075] Embodiment 48. The method of any one of embodiments 44 to 47, wherein p is about 4.

[0076] Embodiment 49. The method of any one of embodiments 44 to 47, wherein the effective amount of the antibody-drug conjugate has a mean p value of about 3.8.

[0077] Embodiment 50. The method of any one of embodiments 1 to 49, 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.

[0078] Embodiment 51. The method of any one of embodiments 1-50, wherein the ADC is administered to the subject at a dose of about 0.25 mg / kg of the subject's body weight, about 0.5 mg / kg of the subject's body weight, about 0.75 mg / kg of the subject's body weight, about 1.0 mg / kg of the subject's body weight, about 1.25 mg / kg of the subject's body weight, about 1.5 mg / kg of the subject's body weight, about 1.75 mg / kg of the subject's body weight, about 2.0 mg / kg of the subject's body weight, about 2.25 mg / kg of the subject's body weight, or about 2.5 mg / kg of the subject's body weight.

[0079] Embodiment 52 The method of any one of embodiments 1 to 51, wherein the ADC is administered to the subject at a dose of about 1 mg / kg of the subject's body weight.

[0080] Embodiment 53. The method of any one of embodiments 1 to 51, wherein the ADC is administered to the subject at a dose of about 1.25 mg / kg of the subject's body weight.

[0081] Embodiment 54. The method of any one of embodiments 1 to 53, wherein the ADC is administered to the subject by intravenous (IV) injection or infusion.

[0082] Embodiment 55. The method of any one of embodiments 1 to 54, wherein the ADC is administered to the subject by IV injection or infusion for up to 2 days of a 21-day treatment cycle.

[0083] Embodiment 56. The method of any one of embodiments 1 to 55, wherein the ADC is administered to the subject by IV injection or infusion on days 1 and 8 of a 21-day treatment cycle.

[0084] Embodiment 57. The method of any one of embodiments 1 to 56, wherein the ADC is administered to the subject by IV injection or infusion over about 30 minutes for up to 2 days of a 21-day treatment cycle.

[0085] Embodiment 58. The method of any one of embodiments 1 to 57, wherein the ADC is administered by IV injection or infusion over about 30 minutes on days 1 and 8 of a 21-day treatment cycle.

[0086] Embodiment 59. The method of any one of embodiments 1 to 58, wherein the ADC is formulated into a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN-20), and trehalose dehydrate.

[0087] Embodiment 60. The method of any one of embodiments 1 to 59, 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.

[0088] Embodiment 61. The method of any one of embodiments 1 to 59, 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.

[0089] Embodiment 62. The ADC has the structure: TIFF2025526346000004.tif34165, wherein L- represents the antibody or antigen-binding fragment thereof and p is about 3 to about 4; the anti-191P4D12 antibody comprises a heavy chain comprising an amino acid sequence ranging from amino acid 20 (glutamic acid) to amino acid 466 (lysine) of SEQ ID NO:7 and a light chain comprising an amino acid sequence ranging from amino acid 23 (aspartic acid) to amino acid 236 (cysteine) of SEQ ID NO:8; and the ADC is administered at a dose of about 1.25 mg / kg of the subject's body weight, administered by IV injection or infusion over about 30 minutes on days 1 and 8 of a 21-day treatment cycle.

[0090] Embodiment 63. The method of any one of embodiments 1 to 60, wherein the anti-PD-1 antibody is administered to the subject at a dose of about 100 mg to about 400 mg.

[0091] Embodiment 64. The method of any one of embodiments 1 to 61, wherein the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg.

[0092] Embodiment 65. (a) the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg; (b) After step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 400 mg every 42 days.

[0093] Embodiment 66. The method of any one of embodiments 1 to 65, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on one day of the 21-day treatment cycle.

[0094] Embodiment 67. The method of any one of embodiments 1 to 66, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on day 1 of each 21-day treatment cycle.

[0095] Embodiment 68. The method of any one of embodiments 1 to 67, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over about 30 minutes on one day of the 21-day treatment cycle.

[0096] Embodiment 69. The method of any one of embodiments 1 to 66, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over about 30 minutes on day 1 of each 21-day treatment cycle.

[0097] Embodiment 70. The method of any one of embodiments 1 to 69, wherein the subject exhibits a complete response after the treatment.

[0098] Embodiment 71. The method of any one of embodiments 1 to 69, wherein the subject exhibits a partial response after the treatment.

[0099] Embodiment 72. The method of any one of embodiments 1 to 69, wherein the subject exhibits a complete or partial response after the treatment.

[0100] Embodiment 73. The method of any one of embodiments 1 to 69, wherein the subject exhibits stable disease after the treatment.

[0101] Embodiment 74. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least 6 months or about 6 months after the treatment.

[0102] Embodiment 75. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least 12 months or about 12 months after the treatment.

[0103] Embodiment 76. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least 24 months or about 24 months after the treatment.

[0104] Embodiment 77. The method of any one of embodiments 1 to 69, wherein the subject has a duration of response of at least 27 months or about 27 months after the treatment.

[0105] Embodiment 78. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least 6 months or about 6 months after the treatment.

[0106] Embodiment 79. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least 8 months or about 8 months after the treatment.

[0107] Embodiment 80. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least 12 months or about 12 months after said treatment.

[0108] Embodiment 81. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least 20 months or about 20 months after said treatment.

[0109] Embodiment 82. The method of any one of embodiments 1 to 69, wherein the subject has a progression-free survival of at least or about 29 months after said treatment.

[0110] Embodiment 83. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least 22 months or about 22 months after said treatment.

[0111] Embodiment 84. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least 27 months or about 27 months after said treatment.

[0112] Embodiment 85. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival of at least 30 months or about 30 months after said treatment.

[0113] Embodiment 86. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival after the treatment in the range of 19 to 25 months.

[0114] Embodiment 87. The method of any one of embodiments 1 to 69, wherein the subject has an overall survival after the treatment in the range of 28 to 32 months.

[0115] Embodiment 88. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated with the method and the percentage of subjects in the treated population who experience a complete response is at least 10% or about 10%.

[0116] Embodiment 89. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated by the method and the percentage of subjects in the treated population who exhibit a partial response is at least 54% or about 54%.

[0117] Embodiment 90. The method of any one of embodiments 1 to 69, wherein the population of subjects treated with the method has an objective response rate of at least 65% or about 65% of the treated population.

[0118] Embodiment 91. The method of any one of embodiments 1 to 69, wherein the population of subjects treated with the method has an objective response rate in the treated population in the range of 53% to 75%.

[0119] Embodiment 92. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated by the method and the percentage of subjects in the treated population exhibiting stable disease is at least 22% or about 22%.

[0120] Embodiment 93. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a duration of response of at least 6 months or about 6 months for the treated population.

[0121] Embodiment 94. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a duration of response of at least 12 months or about 12 months for the treated population.

[0122] Embodiment 95. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a duration of response of at least 24 months or about 24 months for the treated population.

[0123] Embodiment 96. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a duration of response of at least 27 months or about 27 months for the treated population.

[0124] Embodiment 97. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated by the method and the progression-free survival of the treated population is at least 6 months or about 6 months.

[0125] Embodiment 98. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a progression-free survival of at least 12 months or about 12 months.

[0126] Embodiment 99. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a progression-free survival of at least 20 months or about 20 months.

[0127] Embodiment 100. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated by said method and the progression-free survival of said treated population is at least 29 months or about 29 months.

[0128] Embodiment 101. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated by the method and the median overall survival of the treated population is at least 22 months or about 22 months.

[0129] Embodiment 102. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has a median overall survival of at least 27 months or about 27 months.

[0130] Embodiment 103. The method of any one of embodiments 1 to 69, wherein a population of subjects is treated by the method and the median overall survival of the treated population is at least 30 months or about 30 months.

[0131] Embodiment 104. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has an overall survival of the treated population in the range of 19 to 25 months.

[0132] Embodiment 105. The method of any one of embodiments 1 to 69, wherein the population of subjects treated by the method has an overall survival of the treated population in the range of 30 to 32 months.

[0133] Embodiment 106. The method of any one of embodiments 1 to 70 and 72, wherein the complete response rate is at least 10% or about 10% for the population of subjects treated with the method.

[0134] Embodiment 107. The method of any one of embodiments 1 to 69, 71, and 72, wherein the partial response rate is at least 54% or about 54% for the population of subjects treated with the method.

[0135] Embodiment 108. The method of any one of embodiments 1 to 72, wherein the objective response rate is at least 65% or about 65% for the population of subjects treated with said method.

[0136] Embodiment 109. The method of any one of embodiments 1 to 72, wherein the objective response rate is between 53% and 75% for the population of subjects treated with the method.

[0137] Embodiment 110. The method of any one of embodiments 1 to 69 and 73, wherein the stable disease rate is at least or about 22% for the population of subjects treated with the method.

[0138] Embodiment 111. The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least 6 months or about 6 months for the population of subjects treated with the method.

[0139] Embodiment 112. The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least 12 months or about 12 months for the population of subjects treated with the method.

[0140] Embodiment 113. The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least 24 months or about 24 months for the population of subjects treated with the method.

[0141] Embodiment 114. The method of any one of embodiments 1 to 69 and 74 to 77, wherein the duration of response is at least 27 months or about 27 months for the population of subjects treated with the method.

[0142] Embodiment 115. The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival is at least 6 months or about 6 months for the population of subjects treated with the method.

[0143] Embodiment 116. The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival is at least 12 months or about 12 months for the population of subjects treated with the method.

[0144] Embodiment 117. The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival is at least 20 months or about 20 months for the population of subjects treated with the method.

[0145] Embodiment 118. The method of any one of embodiments 1 to 69 and 78 to 82, wherein the progression-free survival is at least or about 29 months for the population of subjects treated with the method.

[0146] Embodiment 119. The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least or about 22 months for the population of subjects treated with the method.

[0147] Embodiment 120. The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least or about 27 months for the population of subjects treated with the method.

[0148] Embodiment 121. The method of any one of embodiments 1 to 69 and 83 to 87, wherein the median overall survival is at least 30 months or about 30 months for the population of subjects treated with the method.

[0149] Embodiment 122. The method of any one of embodiments 1 to 69, 79, and 80, wherein the overall survival is 19 to 25 months for the population of subjects treated with the method.

[0150] Embodiment 123. The method of any one of embodiments 1 to 69, 79, and 80, wherein the overall survival is 30 to 32 months for the population of subjects treated with the method. [Brief explanation of the drawings]

[0151] [Figure 1A-1] 1 shows the nucleotide and amino acid sequences of the Nectin-4 protein. [Figure 1A-2] See legend to Figure 1A-1. [Figure 1B] The nucleotide and amino acid sequences of the heavy chain of Ha22-2(2.4)6.1 are shown. [Figure 1C] The nucleotide and amino acid sequences of the light chain of Ha22-2(2.4)6.1 are shown. [Figure 1D] The amino acid sequence of the heavy chain of Ha22-2(2.4)6.1 is shown. [Figure 1E] The amino acid sequence of the light chain of Ha22-2(2.4)6.1 is shown. [Figure 2] The overall study design of the clinical trial described in Section 6.1 is presented. [Figure 3] This represents the experimental phase of the clinical trial, a phase 1b / 2 study of enfortumab vedotin in combination with pembrolizumab as first-line treatment in patients with unresectable locally advanced or metastatic urothelial carcinoma (la / mUC) who cannot receive cisplatin-based chemotherapy, as described in Section 6.1. [Figure 4-1] The European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life (QLQ-C-30) assessment (EORTC-QLQ-C-30, current version, version 3) is presented as described in Section 6.1. [Figure 4-2] See description of Figure 4-1. [Figure 5-1] The five items of the EuroQol (EQ-5D-5L) described in Section 6.1 are presented. [Figure 5-2] See description of Figure 5-1. [Figure 6] Tumor regression (i.e., tumor size (% change from baseline)) for individual patients in clinical trials as described in Section 6.1 is shown. [Figure 7] The percent change from baseline over time (in months) in the sum of diameters of target lesions by blinded independent central review of the clinical trial as described in Section 6.1 is shown. [Figure 8]

[0033] Figure 6 shows ORR subgroup analyses for patients who received the combination of enfortumab vedotin and pembrolizumab (i.e., EV+pembro group) in the clinical trials described in Section 6.1. [Figure 9] ORR subgroup analysis of patients treated with enfortumab vedotin monotherapy (i.e., EV Mono group) in the clinical trials described in Section 6.1 is shown. [Figure 10] H-scores of Nectin-4 expression at baseline and best response by blinded independent central review in clinical trials as described in Section 6.1 are shown. [Figure 11] H-scores of Nectin-4 expression at baseline and best overall response by blinded independent central review in clinical trials as described in Section 6.1 are shown. [Figure 12] Duration of response (DOR) by blinded independent central review for the clinical trials described in Section 6.1 is shown. [Figure 13] Progression-free survival by blinded independent central review is shown for the clinical trials described in Section 6.1. [Figure 14] Overall survival is shown for the clinical trials described in Section 6.1. [Figure 15] Duration of response (DOR) by blinded independent central review for the clinical trials described in Section 6.2 is shown. [Figure 16] Progression-free survival by blinded independent central review is shown for the clinical trials described in Section 6.2. [Figure 17] Overall survival is shown for the clinical trials described in Section 6.2. DETAILED DESCRIPTION OF THE INVENTION

[0152] 5. Detailed Description Before describing the present disclosure in detail, it is to be understood that the disclosure is not limited to the particular embodiments described herein, and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0153] 5.1 Definition The techniques and procedures described or referenced herein include those that are generally well understood and / or commonly employed by those of skill in the art using conventional methodology, such as, for example, the widely utilized methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3rd ed. 2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Dubel eds., 2nd ed. 2010).

[0154] Unless otherwise defined herein, the technical and scientific terms used in this description have the meanings that are commonly understood by those skilled in the art. For the purposes of interpreting this specification, the following explanations of terms shall apply, and where appropriate, terms used in the singular shall also include the plural, and vice versa. In the event that the explanations of terms set forth conflict with documents incorporated herein by reference, the explanations of terms set forth below shall prevail.

[0155] The terms "antibody," "immunoglobulin," or "Ig" are used interchangeably herein and are used in the broadest sense, specifically encompassing, for example, monoclonal antibodies (including agonist, antagonist, neutralizing, full-length, or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or univalent antibodies, multivalent antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies, so long as they exhibit the desired biological activity), single-chain antibodies, and fragments thereof, as described below. Antibodies may be human, humanized, chimeric, and / or affinity-matured antibodies, as well as antibodies from other species, e.g., mouse and rabbit. The term "antibody" is intended to include polypeptide products of B cells within the immunoglobulin class of polypeptides that are capable of binding to a specific molecular antigen and are composed of two identical pairs of polypeptide chains, each pair having one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), with the amino-terminal portion of each chain containing a variable region of about 100 to about 130 or more amino acids and the carboxy-terminal portion of each chain containing a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2nd ed. 1995); and Kuby, Immunology (3rd ed. 1997). In specific embodiments, the specific molecular antigen can be bound by the antibodies provided herein and comprises a polypeptide or 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, where a functional fragment 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 is derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fvs (scFvs) (including, e.g., monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab') fragments, F(ab') fragments, disulfide-linked Fvs (dsFvs), Fd fragments, Fv fragments, diabodies, triabodies, tetrabodies, and minibodies.In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, such as molecules containing an antigen-binding domain or site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Pluckthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (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., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule. The antibodies can be agonist or antagonist antibodies.

[0156] The term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which may include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0157] An "antigen" is a structure to which an antibody can selectively bind. Target antigens can be polypeptides, carbohydrates, nucleic acids, lipids, haptens, or other natural or synthetic compounds. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, e.g., present on or within a cell, e.g., on or within a cancer cell.

[0158] An "intact" antibody is one that comprises an antigen-binding site and a CL and at least a heavy chain constant region, CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0159] The terms "antigen-binding fragment," "antigen-binding domain," "antigen-binding region," and similar terms refer to a portion of an antibody (e.g., a CDR) that contains amino acid residues that interact with an antigen and confer specificity and affinity for the antigen to the binding agent. As used herein, "antigen-binding fragment" includes an "antibody fragment" that contains a portion of an intact antibody, e.g., the antigen-binding region or variable region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab'), and Fv fragments; diabodies and di-diabodies (e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. 90:6444-48; Lu et al., 2005, J. Biol. Chem. 280:19665-72; Hudson et al., 2005, J. Biol. Chem. 280:19665-72). 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 et al., 1999, Immunogenetics 50:98-101; and Streltsov et al., 2004, Proc Natl Acad Sci USA. 101:12444-49); and multispecific antibodies formed from antibody fragments.

[0160] The terms "bind" or "binding" refer to interactions between molecules, including, for example, forming a complex. The interaction can be a non-covalent interaction, including, for example, hydrogen bonding interactions, ionic bonding interactions, 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 all non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as an antigen, is the affinity of the antibody or functional fragment for that epitope. The dissociation rate (k off ) and association rate (k on ) ratio (k off / k on ) is the dissociation constant K D which is inversely proportional to the affinity. D The lower the value, the higher the affinity of the antibody. D The value of k varies for different antibody-antigen complexes. on and k off The dissociation constant K of the antibodies provided herein depends on both D The affinity of an antibody can be determined using any method provided herein or any other method known to those skilled in the art. The affinity at one binding site does not necessarily reflect the true strength of the interaction between an antibody and an antigen. When a complex antigen containing multiple repeat antigenic determinants, such as a multivalent antigen, contacts an antibody containing multiple binding sites, the interaction between the antibody and the antigen at one site increases the probability of a reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity.

[0161] In connection with the antibodies or antigen-binding fragments thereof described herein, terms such as "binds to," "specifically binds to," and similar terms are also used interchangeably herein and refer to binding molecules of an antigen-binding domain, such as polypeptides, that specifically bind to an antigen. Antibodies or antigen-binding fragments that bind to or specifically bind to an antigen may be cross-reactive with related antigens. In certain embodiments, antibodies or antigen-binding fragments that bind to or specifically bind to an antigen do not cross-react with other antigens. Antibodies or antigen-binding fragments that bind to or specifically bind to an antigen can be identified, for example, by immunoassays, Octet®, Biacore®, or other techniques known to those skilled in the art. In some embodiments, an antibody or antigen-binding fragment binds to or specifically binds to an antigen if it binds to the antigen with higher affinity than any cross-reactive antigens as determined using experimental techniques such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). Typically, a specific or selective response is at least twice the background signal or noise, and may be greater than 10 times the background. For a discussion of binding specificity, see, for example, Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989). In certain embodiments, the extent of binding of an antibody or antigen-binding fragment to a "non-target" protein is less than about 10% of the binding of the binding molecule or antigen-binding domain to its specific target antigen, as determined, for example, by fluorescence-activated cell sorting (FACS) analysis or RIA. Terms such as "specific binding," "specifically binds to," or "specific for" refer to binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule, which is generally a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule similar to the target, such as an excess of unlabeled target. In this case, specific binding is indicated if the binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled target.Antibodies or antigen-binding fragments that bind to an antigen include those that can bind to the antigen with sufficient affinity so that the binding molecule is useful, for example, as a diagnostic agent in targeting the antigen. In certain embodiments, antibodies or antigen-binding fragments that bind to an antigen have an affinity of less than 1000 nM, less than 800 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, less than 1 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM a dissociation constant (K) of less than 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. D In certain embodiments, the antibody or antigen-binding fragment binds to an epitope of an antigen that is conserved among antigens from different species (e.g., between the human species and the cynomolgus monkey species).

[0162] "Binding affinity" generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., a binding protein such as an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a binding molecule X for its binding partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies generally bind antigens slowly and tend to dissociate easily, whereas high affinity antibodies generally bind antigens faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present disclosure. Specific exemplary embodiments include the following. In one embodiment, "K D " or "K DThe "K value" can be measured by assays known in the art, for example, binding assays. D K may be measured, for example, in an RIA performed using the Fab version of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). D or K D The value may also be measured by using biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays, for example by Octet® using an Octet® QK384 system, or by Biacore® using, for example, a Biacore® TM-2000 or Biacore® TM-3000. "On-rate" or "rate of association" or "association rate" or "k" may also be determined using the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, for example, using an Octet® QK384, Biacore® TM-2000, or Biacore® TM-3000 system.

[0163] In certain embodiments, antibodies or antigen-binding fragments can include "chimeric" sequences in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies 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).

[0164] In certain embodiments, an antibody or antigen-binding fragment can comprise a portion of a "humanized" form of a non-human (e.g., murine) antibody, which is a chimeric antibody comprising a human immunoglobulin (e.g., recipient antibody) in which native CDR residues are replaced by residues from a corresponding CDR (e.g., donor antibody) of a non-human species, such as mouse, rat, rabbit, or non-human primate, containing the desired specificity, affinity, and capacity. In some cases, one or more FR region residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. The heavy or light chain of a humanized antibody 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 non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. In certain embodiments, a humanized antibody comprises 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; Riechmann et al., 1988, Nature 332:323-29; Presta, 1992, Curr. Op. Struct. Biol. 2:593-96; Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; U.S. Patent Nos. 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.

[0165] In certain embodiments, an antibody or antigen-binding fragment can comprise a portion of a "fully human antibody" or "human antibody," which terms are used interchangeably herein and refer to an antibody comprising a human variable region and, for example, a human constant region. In specific embodiments, these terms refer to an antibody comprising variable and constant regions of human origin. A "fully human" antibody, in certain embodiments, can also encompass antibodies that bind to a polypeptide and are encoded by nucleic acid sequences that are naturally occurring somatic variants of human germline immunoglobulin nucleic acid sequences. The term "fully human antibody" includes antibodies comprising variable and constant regions that correspond to human germline immunoglobulin sequences described by Kabat et al. (See Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242). A "human antibody" is one that has an amino acid sequence that corresponds to that of an antibody produced by a human and / or has been produced using any of the techniques for producing human antibodies. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol. 227:381; Marks et al., 1991, J. Mol. Biol. 222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1:755-68). Methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77(1985); Boerner et al., 1991, J. Immunol. 147(1):86-95; and van Dijk and van de Winkel, 2001, Curr. Opin. Pharmacol. 5:368-74 can also be used to prepare human monoclonal antibodies.Human antibodies can be prepared by administering antigen to transgenic animals, e.g., mice, that have been engineered to produce such antibodies in response to antigen challenge but whose endogenous gene loci have been disabled (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66; Bruggemann 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, e.g., Li et al., 2006, Proc. Natl. Acad. Sci. USA 103:3557-62 regarding human antibodies generated via human B-cell hybridoma technology.

[0166] In certain embodiments, an antibody or antigen-binding fragment can comprise a portion of a "recombinant human antibody," which phrase includes human antibodies that are prepared, expressed, generated, or isolated by recombinant means, e.g., 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 a cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see, e.g., Taylor, LD et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means, including splicing of human immunoglobulin gene sequences into 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, USDapartment of Health and Human Services, NIH Publication No. 91-3242). However, in certain embodiments, such recombinant human antibodies have been subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally occur within the human antibody germline repertoire in vivo.

[0167] In certain embodiments, an antibody or antigen-binding fragment can comprise a portion of a "monoclonal antibody," a term used herein to refer to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible minor naturally occurring mutations, and each monoclonal antibody typically recognizes a single epitope on an 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 a particular method for producing the antibody. For example, monoclonal antibodies useful in the present disclosure may be prepared by the hybridoma method first described by Kohler et al., 1975, Nature 256:495, or may be produced using recombinant DNA methods in bacterial or eukaryotic animal or plant cells (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J. Mol. Biol. 222:581-97. Other methods for preparing clonal cell lines and the monoclonal antibodies expressed thereby are well known in the art. See, for example, Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed. 2002).

[0168] A typical four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgG, the four-chain unit is generally approximately 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, and the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has a variable domain (VH) at its N-terminus, followed by three constant domains (CH) for each of the α and γ chains, and four CH domains for the μ and ε isotypes. Each L chain has a variable domain (VL) at its N-terminus, followed by a constant domain (CL) at its other end. The VL aligns with the VH, and the CL aligns with the first constant domain (CH1) of the heavy chain. Specific amino acid residues are believed to form an interface between the light chain variable domain and the heavy chain variable domain. The pairing of a VH and VL forms a single antigen-binding site. For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology 71 (Stites et al. eds., 8th ed. 1994); and Immunobiology (Janeway et al. eds., 5th ed. 2001).

[0169] The term "Fab" or "Fab region" refers to the antibody region that binds to an antigen. Conventional IgGs usually contain two Fab regions, each present in one of the two arms of the Y-shaped IgG structure. Each Fab region typically consists of one variable region and one constant region from each of the heavy and light chains. More specifically, the variable and constant regions of the heavy chain in the Fab region are the VH and CH1 regions, and the variable and constant regions of the light chain in the Fab region are the VL and CL regions. The VH, CH1, VL, and CL regions within the Fab region can be arranged in various ways to confer antigen-binding capability according to the present disclosure. For example, as with the Fab region of a conventional IgG, the VH and CH1 regions can be on one polypeptide, while the VL and CL regions can be on separate polypeptides. Alternatively, the VH, CH1, VL, and CL regions can all be on the same polypeptide and oriented in different orders, as described in more detail in the following sections.

[0170] The terms "variable region," "variable domain," "V region," or "V domain" refer to the portion of an antibody light or heavy chain, generally located at the amino terminus of the light or heavy chain, approximately 120 to 130 amino acids in length for heavy chains and approximately 100 to 110 amino acids in length for light chains, that is used in the binding and specificity of each particular antibody for its particular antigen. The variable region of a heavy chain is sometimes referred to as "VH." The variable region of a light chain is sometimes referred to as "VL." The term "variable" refers to the fact that certain segments of the variable region vary significantly in sequence among antibodies. The V region mediates antigen binding and determines the specificity of a particular antibody for a particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable region. Instead, V regions consist of less variable (e.g., relatively invariant) stretches of about 15 to about 30 amino acids called framework regions (FRs), separated by shorter regions of greater variability (e.g., extreme variability) called "hypervariable regions," each about 9 to 12 amino acids long. The variable regions of the heavy and light chains each contain four FRs, which adopt a primarily β-sheet configuration, connected by three hypervariable regions that form loops that connect and, in some cases, form part of the β-sheet structure. The hypervariable regions of each chain are held in close proximity by the FRs and, together with the hypervariable regions of 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 directly involved in binding of antibodies to antigens but exhibit various effector functions, such as antibody participation in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The variable regions vary significantly in sequence among different antibodies. In a specific embodiment, the variable region is a human variable region.

[0171] The terms "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 the heavy or light chain variable regions of a 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 shortening of, or insertions into, the FRs or CDRs of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 (residue 52a according to Kabat) and three inserted residues after residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody's sequence with the "standard" Kabat numbered sequence at the regions of homology. The Kabat numbering system is commonly used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The "EU numbering system" or "EU index" is commonly used when referring to residues within the immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Other numbering systems are described, for example, by AbM, Chothia, Contact, IMGT, and AHon.

[0172] The term "heavy chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 50 to 70 kDa, the amino-terminal portion of which contains a variable region of approximately 120 to 130 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The constant region can be one of five different types (e.g., isotypes), designated alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. Different heavy chains vary in size, with α, δ, and γ containing approximately 450 amino acids, and μ and ε containing approximately 550 amino acids. When combined with light chains, these different types of heavy chains give rise to five well-known classes (e.g., isotypes) of antibodies: IgA, IgD, IgE, IgG, and IgM, each of which contains four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4.

[0173] The term "light chain," when used in reference to an antibody, refers to a polypeptide chain of about 25 kDa, the amino-terminal portion of which contains a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types, called kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain.

[0174] As used herein, the terms "hypervariable region," "HVR," "complementarity-determining region," and "CDR" are used interchangeably. "CDR" refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of an immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of an antibody VL β-sheet framework. Thus, CDRs are variable region sequences interspersed within framework region sequences.

[0175] CDR regions are well known to those skilled in the art and are defined by well-known numbering systems. For example, Kabat complementarity-determining regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., supra). Instead, Chothia refers to the position of the structural loop (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17). When numbered using Kabat's numbering rules, the end of the Chothia CDR-H1 loop varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places insertions at H35A and H35B; if neither 35A nor 35B 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). AbM hypervariable regions represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Dubel eds., 2nd ed. 2010)). The "contact" hypervariable regions are based on the analysis of available complex crystal structures. Another universal numbering system that has been developed and widely adopted is the ImMunoGeneTics (IMGT) Information System® (Lafranc et al., 2003, Dev. Comp. Immunol. 27(1):55-77). IMGT is an integrated information system specialized for immunoglobulins (IGs), T cell receptors (TCRs), and major histocompatibility complexes (MHCs) of humans and other vertebrates. Herein, CDRs are referred to both with respect to amino acid sequence and location within the light or heavy chain. Because the "locations" of CDRs within the structure of immunoglobulin variable domains are conserved across species and reside within structures called loops, CDR and framework residues are readily identified by using a numbering system that aligns variable domain sequences according to structural features.This information can be used to graft and replace CDR residues from one species' immunoglobulin onto an acceptor framework, typically from a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, 2001, J. Mol. Biol. 309:657-70. For example, the correspondence between numbering systems, including the Kabat numbering and the IMGT-specific numbering system, is well known to those of skill in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). Residues from each of these hypervariable regions or CDRs are shown in Table 1 below.

[0176] [Table 1]

[0177] The boundaries of a given CDR may vary depending on the scheme used for identification. Thus, unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof, e.g., a variable region, and individual CDRs of an antibody or region thereof (e.g., "CDR-H1, CDR-H2"), should be understood to encompass complementarity determining regions defined by any of the known schemes described hereinabove. In some cases, a scheme for identifying a particular CDR or CDRs is specified, such as CDRs defined by the Kabat, Chothia, or Contact methods. In other cases, the specific amino acid sequences of the CDRs are given.

[0178] The hypervariable regions may include "extended hypervariable regions" such as: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH.

[0179] The term "constant region" or "constant domain" refers to the carboxy-terminal portions of the light and heavy chains that are not directly involved in binding the antibody to an antigen but exhibit various effector functions, such as interaction with Fc receptors. This term refers to the portion of the immunoglobulin molecule that contains a more conserved amino acid sequence compared to the other portions of the immunoglobulin, the variable region, which contains the antigen-binding site. The constant region may include the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0180] The term "framework" or "FR" refers to variable region residues that flank the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are variable domain residues other than hypervariable region or CDR residues.

[0181] The term "Fc region" herein is used to define the 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 can vary, the human IgG heavy chain Fc region is often defined to extend from the amino acid residue at position Cys226 or the amino acid residue at position Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include antibody populations in which all K447 residues have been removed, antibody populations in which the K447 residue has not been removed, and antibody populations containing a mixture of antibodies with and without the K447 residue. A "functional Fc region" possesses the "effector functions" of a native-sequence Fc region. Exemplary "effector functions" include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and the like. Such effector functions generally require that the Fc region be combined with a binding region or domain (e.g., an antibody variable region or domain) and can be assessed using a variety of assays known to those skilled in the art. A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by at least one amino acid modification (e.g., substitution, addition, or deletion). In certain embodiments, the variant Fc region has at least one amino acid substitution compared to the native-sequence Fc region or the Fc region of a parent polypeptide, e.g., from about 1 to about 10 amino acid substitutions, or from about 1 to about 5 amino acid substitutions in the native-sequence Fc region or the Fc region of a parent polypeptide. The variant Fc region herein may have at least about 80% homology to a native sequence Fc region and / or the Fc region of a parent polypeptide, or at least about 90% homology thereto, for example, at least about 95% homology thereto.

[0182] As used herein, "epitope" is a term of 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, a conformational epitope, a non-linear epitope, or a 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 it can include amino acids from two or more discontinuous regions of the polypeptide (a "conformational," "non-linear," or "discontinuous" epitope). In general, those skilled in the art will understand that a linear epitope may or may not depend on secondary, tertiary, or quaternary structure. For example, in some embodiments, a binding molecule binds to a group of amino acids regardless of whether they are folded into a native three-dimensional protein structure. In other embodiments, the binding molecule requires the amino acid residues that make up the epitope to adopt a particular conformation (eg, a bend, twist, turn, or fold) in order to recognize and bind to the epitope.

[0183] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may comprise modified amino acids, and may be interrupted by non-amino acids. The term also encompasses amino acid polymers that are modified, naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are 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. Because the polypeptides of the present disclosure may be based on antibodies or other members of the immunoglobulin superfamily, it is understood that in certain embodiments, a "polypeptide" can exist as a single chain or as two or more associated chains.

[0184] As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of a federal or state government or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0185] "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 enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizing agents, wetting agents, and mixtures thereof. The term "excipient" can also refer to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), or vehicle.

[0186] In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, a pharmaceutically acceptable excipient is nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. In some embodiments, the pharmaceutically acceptable excipient is an aqueous pH buffered solution.

[0187] The abbreviation "MMAE" refers to monomethyl auristatin E.

[0188] Unless the context dictates otherwise, a hyphen (-) designates the point of attachment to the pendant molecule.

[0189] The term "chemotherapeutic agent" refers to any chemical compound that is effective in inhibiting tumor growth. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as nitrogen mustard, ethyleneimine compounds, and alkylsulfonates; antimetabolites, such as folic acid, purine, or pyrimidine antagonists; mitotic inhibitors, such as antitubulin agents, such as derivatives of vinca alkaloids, auristatins, and podophyllotoxins; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, such as 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.

[0190] As used herein, the term "conservative substitution" is known to those skilled in the art and generally refers to an amino acid substitution that may be made without altering the biological activity of the resulting molecule. Those skilled in the art generally recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, for example, Watson et al., MOLECULAR BIOLOGY OF THE GENE, The Benjamin / Cummings Pub. Co., p. 224 (4th Edition 1987)). Such exemplary substitutions are preferably made in accordance with the substitutions shown in Tables 2 and 3. For example, such changes include substituting any of isoleucine (I), valine (V), and leucine (L) for any other of these hydrophobic amino acids; substituting glutamic acid (E) with aspartic acid (D) and vice versa; substituting asparagine (N) with glutamine (Q) and vice versa; and substituting threonine (T) with serine (S) and vice versa. Other substitutions can also be considered conservative, depending on the particular amino acid's environment and its role in the protein's three-dimensional structure. For example, glycine (G) and alanine (A) can often be interchangeable, as can alanine (A) and valine (V). Methionine (M), which is relatively hydrophobic, can often be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are often interchangeable in positions where the important feature of an amino acid residue is its charge, and the different pKs of these two amino acid residues are not important. Still other changes may be considered "conservative" in particular circumstances (see, e.g., Table 3 herein; pages 13-15 of "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 permissible and may be determined empirically or in accordance with known conservative substitutions.

[0191] [Table 2]

[0192] [Table 3]

[0193] The term "homology" or "homologous" is intended to refer to the sequence similarity between two polynucleotides or two polypeptides. Similarity can be determined by comparing positions in each sequence that can be aligned for comparison purposes. If a given position in two polypeptide sequences is not identical, the similarity or conservation of that position can be determined by evaluating the amino acid similarity at that position, for example, according to Table 3. The degree of similarity between sequences is a function of the number of matching or homologous positions shared by the sequences. Alignment of two sequences to determine percent sequence similarity can be performed using software programs known in the art, such as those described in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1999). Preferably, default parameters are used for alignment, an example of which is provided below. One alignment program known in the art that can be used is BLAST set to default parameters. In particular, the programs are BLASTN and BLASTP, using the following default parameters: genetic code = standard; filter = none; strand = both; cutoff = 60; expectation = 10; matrix = BLOSUM62; description = 50 sequences; sort order = high score; database = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translation + SwissProtein + SPupdate + PIR. More information about these programs can be found at the National Center for Biotechnology Information.

[0194] The term "homolog" of a given amino acid or nucleic acid sequence is intended to indicate a corresponding sequence of the "homolog" having substantial identity or homology to the given amino acid or nucleic acid sequence.

[0195] 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 comparing two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. USA 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, for example, using the NBLAST nucleotide program parameters set to score=100 and word length=12 to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed using, for example, XBLAST program parameters set to score 50 and word length = 3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI BLAST can be used to perform an iterated search that detects distant relationships between molecules (ibid.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) on the World Wide Web at ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for sequence comparison is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17.Such an algorithm is incorporated into 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.

[0196] 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.

[0197] The term "cytotoxic agent" refers to a substance that inhibits or prevents the development, activity, function, and / or causes destruction of cells. This term is intended to include radioisotopes, chemotherapeutic agents, and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and / or variants. Examples of cytotoxic agents include auristatins (e.g., auristatin E, auristatin F, MMAE, and MMAF), aureomycin, maytansinoids, ricin, ricin A chain, combrestatins, duocarmycins, dolastatins, doxorubicin, daunorubicin, taxol, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxyanthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, α-sarcin, gelonin, mitogenin, restrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, soapwort (Sapaonaria officinalis) inhibitors, and glucocorticoids and other chemotherapeutic agents, as well as At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 or Bi213 , P 32 Radioactive isotopes such as Lu 177 Examples of radioisotopes of Lu include, but are not limited to, radioactive isotopes of Lu, including: The antibody may also be conjugated to an anti-cancer prodrug-activating enzyme capable of converting a prodrug to its active form.

[0198] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a binding molecule (e.g., an antibody) or pharmaceutical composition provided herein sufficient to effect a desired result.

[0199] 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., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkeys and humans). In certain embodiments, a subject is a human. In one embodiment, a subject is a mammal, e.g., a human, diagnosed with a condition or disorder. In another embodiment, a subject is a mammal, e.g., a human, at risk of developing a condition or disorder.

[0200] "Administering" or "administration" refers to the act of injecting or otherwise physically delivering a substance present outside the body to a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0201] As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or amelioration of the progression, severity, and / or duration of a disease or condition resulting from the administration of one or more therapies. Treatment may be determined by assessing whether there has been a reduction, alleviation, and / or relief of one or more symptoms associated with the underlying disease, such that an improvement is observed for the patient, even though the patient may still be suffering from the underlying disease. The term "treating" includes both management and amelioration of disease. The terms "manage," "managing," and "management" refer to the beneficial effects a subject derives from a therapy that does not necessarily result in a cure of the disease.

[0202] The terms "prevent," "preventing," and "prevention" refer to reducing the likelihood of the occurrence (or recurrence) of a disease, disorder, condition, or one or more associated symptoms (e.g., cancer).

[0203] The terms "cancer" or "cancer cells" are used herein to refer to tissue or cells found in neoplasms that have characteristics that distinguish them from normal tissue or tissue cells. Such characteristics include, but are not limited to, the degree of anaplasia, irregular shape, unclear cell outlines, nuclear size, changes in nuclear or cytoplasmic structure, other phenotypic changes, the presence of cellular proteins indicative of cancer or precancerous conditions, an increased number of mitoses, and the ability to metastasize. Words related to "cancer" include carcinoma, sarcoma, tumor, epithelioma, leukemia, lymphoma, polyp, and scirrhous carcinoma, transformation, neoplasia, etc.

[0204] As used herein, "locally advanced" cancer refers to cancer that has spread from where it began to nearby tissues or lymph nodes.

[0205] As used herein, "metastatic" cancer refers to cancer that has spread from where it began to another part of the body.

[0206] 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.

[0207] As used in this disclosure and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0208] Whenever an embodiment is described herein using the term "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided. Also, whenever an embodiment is described herein using the phrase "consisting essentially of," it is understood that other similar embodiments described in terms of "consisting of" are also provided.

[0209] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B; A or B; A alone; and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to 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.

[0210] The term "variant" refers to a molecule that exhibits variation from a described type or reference, such as a protein with one or more different amino acid residues at the corresponding position(s) of a specifically described protein (e.g., the 191P4D12 protein shown in Figure 1A). Analogs are an example of a variant protein. Splice isoforms and single nucleotide polymorphisms (SNPs) are further examples of variants.

[0211] "191P4D12 proteins" and / or "191P4D12-related proteins" of the present disclosure include those specifically identified herein (see FIG. 1A), as well as allelic variants, conservatively substituted variants, analogs, and homologs, which can be isolated / produced and characterized without undue experimentation according to the methods outlined herein or readily available in the art. Also included are fusion proteins that combine portions or fragments of different 191P4D12 proteins, and fusion proteins of a 191P4D12 protein with a heterologous polypeptide. Such 191P4D12 proteins are collectively referred to as 191P4D12-related proteins, proteins of the present disclosure, or 191P4D12. The term "191P4D12-related protein" refers to a 191P4D12-related protein that is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than 25 amino acids, or at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least The term "191P4D12" refers to a polypeptide fragment or 191P4D12 protein sequence of at least 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 330, at least 335, at least 339 or more amino acids. The term "191P4D12" is used interchangeably with Nectin-4.

[0212] 5.2 Cancer treatment methods Urothelial carcinoma and bladder cancer (including locally advanced urothelial carcinoma, metastatic urothelial carcinoma, locally advanced bladder cancer, and metastatic bladder cancer) in patients who are cisplatin-ineligible are particularly difficult to treat. These patients are typically frail and suffer from multiple comorbidities beyond their urothelial carcinoma / bladder cancer, and are unable to tolerate additional treatments, leading many to discontinue therapy altogether. As a result, these patients have a poor prognosis and few treatment options. This disclosure is based in part on the results of an initial clinical trial demonstrating objective responses to the combination of enfortumab vedotin and pembrolizumab administered as first-line treatment in patients with unresectable locally advanced or metastatic urothelial carcinoma (la / mUC) who are ineligible for cisplatin-based chemotherapy. Thus, the present disclosure provides a proven, effective method for treating patients with urothelial carcinoma and / or bladder cancer (including locally advanced urothelial carcinoma, metastatic urothelial carcinoma, locally advanced bladder cancer, and metastatic bladder cancer) who cannot receive cisplatin-based chemotherapy in this setting due to insufficient renal function or other conditions as provided herein. Prior to the results described herein, there was considerable uncertainty as to whether the methods provided herein would be effective, as this patient population has historically proven very difficult to treat. As further described below, the level of efficacy obtained was particularly remarkable and surprising.

[0213] 5.2.1 Cancer treatment methods for general and selected patients Provided herein are methods for the first- and second-line treatment of various cancers in subjects, including subjects with unresectable locally advanced or metastatic urothelial carcinoma (la / mUC) who cannot receive cisplatin-based chemotherapy, using antibody-drug conjugates (ADCs) that bind 191P4D12 in combination with an anti-PD-1 antibody (e.g., pembrolizumab).

[0214] In one aspect, provided herein are methods of treating cancer in a subject using an ADC that binds 191P4D12 and an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, a human subject treated with the methods provided herein has not previously received a cancer treatment other than an ADC that binds 191P4D12. In certain embodiments, a human subject treated with the methods provided herein has not previously received a treatment comprising or consisting of an immune checkpoint inhibitor (CPI). In some embodiments, the CPI is an anti-PD-1 antibody (e.g., pembrolizumab). In some embodiments, the CPI is a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In certain embodiments, the CPI is atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject treated with the methods provided herein has not previously received an agent directed against another stimulatory or co-inhibitory T cell receptor (including, but not limited to, a CD137 agonist, a CTLA4 inhibitor, or an OX-40 agonist). In certain embodiments, the agent directed against another stimulatory or co-inhibitory T cell receptor is a CD137 agonist, a CTLA4 inhibitor, or an OX-40 agonist. In some embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin therapy. In other embodiments, the human subject treated with the methods provided herein is ineligible to receive cisplatin therapy and has not previously received a therapy comprising or consisting of a CPI. In certain embodiments, the human subjects treated with the methods provided herein are ineligible to receive cisplatin therapy, have not previously received therapy containing or consisting of a CPI, and have not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization.In still further embodiments, the human subjects treated with the methods provided herein are ineligible for cisplatin therapy, have not previously received therapy containing or consisting of a CPI, have not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization, and have not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments, the cancer is urothelial carcinoma. 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 is metastatic cancer. In a further embodiment, the cancer is locally advanced urothelial carcinoma. In a further embodiment, the cancer is unresectable locally advanced urothelial carcinoma. In yet another embodiment, the cancer is metastatic urothelial carcinoma. In one embodiment, the cancer is locally advanced bladder cancer. In another embodiment, the cancer is metastatic bladder cancer.

[0215] 5.2.1.1 Cisplatin-ineligible patients Various criteria for determining cisplatin ineligibility of a human subject can be used for the methods provided herein, including but not limited to the method in the preceding paragraph. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of renal dysfunction (e.g., a glomerular filtration rate (GFR) of less than 60 mL / min but greater than or equal to 30 mL / min or a creatinine clearance (estimated by the Cockcroft-Gault formula, modification of diet in renal disease [MDRD], or 24-hour urine)). In certain embodiments, the criteria for determining cisplatin ineligibility include or consist of hearing loss of grade 2 or greater (e.g., hearing loss of grade 2 or greater in NCI CTCAE version 4.03). In certain embodiments, the criteria for determining cisplatin ineligibility include or consist of NYHA grade III heart failure. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and renal impairment. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and hearing loss of grade 2 or greater. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of renal impairment and hearing loss of grade 2 or greater. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of renal impairment and NYHA III heart failure. In yet other embodiments, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, renal impairment, and hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of renal impairment, hearing loss of grade 2 or greater, and NYHA III heart failure.In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, renal impairment, and hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of renal impairment, hearing loss of grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of an ECOG performance status score of 2, renal impairment, and hearing loss of grade 2 or greater, in any combination or permutation. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of renal impairment, hearing loss of grade 2 or greater, and NYHA III heart failure, in any combination or permutation. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of an ECOG performance status score of 2, renal impairment, and hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of the following: renal dysfunction, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments of the methods provided herein, the subject has not received prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if the subject has an ECOG performance status score of 2, the subject (i) has hemoglobin of 10 g / dL or greater, (ii) has a GFR of 50 mL / min or greater, and (iii) does not have NYHA III heart failure.

[0216] Renal dysfunction can be determined by various means known and available in the art. Various embodiments for determining renal dysfunction in a human subject are provided herein for the methods provided herein, including but not limited to the method in the preceding paragraph. In one embodiment, renal dysfunction is determined by a glomerular filtration rate (GFR) of less than 60 mL / min. In some embodiments, renal dysfunction is determined by a GFR of less than 60 mL / min but greater than or equal to 30 mL / min. In certain embodiments, renal dysfunction is determined by a GFR of less than 30 mL / min but greater than or equal to 15 mL / min. In some embodiments of the methods provided in this paragraph, the GFR is measured by a 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 Modifications of Diet in Renal Disease [MDRD].

[0217] In further embodiments, renal dysfunction is determined by a creatinine clearance (CrCl) of less than 60 mL / min. In some embodiments, renal dysfunction is determined by a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min. In certain embodiments, renal dysfunction is determined by a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min. In some embodiments of the methods provided in this paragraph, CrCl is measured by a 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria.

[0218] Thus, for the methods provided herein, including but not limited to the method in the preceding paragraph, several specific criteria based on GFR or creatinine clearance can be used to determine cisplatin ineligibility of a human subject. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a CrCl of less than 60 mL / min. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min and Grade 2 or greater hearing loss. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min and NYHA stage III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a GFR of less than 60 mL / min, and Grade 2 or greater hearing loss. In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, a GFR of less than 60 mL / min, and hearing loss of Grade 2 or greater. In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of a GFR of less than 60 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of an ECOG performance status score of 2, a GFR of less than 60 mL / min, and hearing loss of Grade 2 or greater, in any combination or permutation.In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: a GFR of less than 60 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of an ECOG performance status score of 2, a GFR of less than 60 mL / min, and hearing loss of Grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of a GFR of less than 60 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments of the methods provided in this paragraph, the GFR is measured by a 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 Modifications of Diet in Renal Disease [MDRD]. In some embodiments of the methods provided herein, the subject has not received prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if the subject has an ECOG performance status score of 2, the subject (i) has hemoglobin of 10 g / dL or greater, (ii) has a GFR of 50 mL / min or greater, and (iii) does not have NYHA stage III heart failure.

[0219] In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a CrCl of less than 60 mL / min. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min and hearing loss of grade 2 or greater. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min and NYHA III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a CrCl of less than 60 mL / min, and hearing loss of grade 2 or greater. In yet another embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min, hearing loss of grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, a CrCl of less than 60 mL / min, and a hearing loss of Grade 2 or greater. In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of a CrCl of less than 60 mL / min, a hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of an ECOG performance status score of 2, a CrCl of less than 60 mL / min, and a hearing loss of Grade 2 or greater, in any combination or permutation. In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of a CrCl of less than 60 mL / min, a hearing loss of Grade 2 or greater, and NYHA III heart failure, in any combination or permutation.In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of the following: an ECOG performance status score of 2, a CrCl of less than 60 mL / min, and a hearing loss of Grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of the following: a CrCl of less than 60 mL / min, a hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by a 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject has not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has hemoglobin equal to or greater than 10 g / dL, (ii) has a GFR equal to or greater than 50 mL / min, and (iii) does not have NYHA stage III heart failure.

[0220] Alternatively, other specific criteria based on GFR or creatinine clearance for determining cisplatin ineligibility of a human subject can be used for the methods provided herein, including, but not limited to, the method in the preceding paragraph. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min but greater than or equal to 30 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a GFR of less than 60 mL / min but greater than or equal to 30 mL / min. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min but greater than or equal to 30 mL / min and Grade 2 or greater hearing loss. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min but greater than or equal to 30 mL / min and NYHA Class III heart failure. In still other embodiments, the conditions for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, and hearing loss of grade 2 or greater. In still other embodiments, the conditions for determining cisplatin ineligibility include or consist of a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of grade 2 or greater, and NYHA III heart failure. In some embodiments, the conditions for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, and hearing loss of grade 2 or greater. In some embodiments, the conditions for determining cisplatin ineligibility include or consist of any one of a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of grade 2 or greater, and NYHA III heart failure.In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: an ECOG performance status score of 2, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, and a hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, a hearing loss of grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of an ECOG performance status score of 2, a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, and a hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of the following: a GFR of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of Grade 2 or greater, and NYHA 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 Modifications of Diet in Renal Disease [MDRD]. In some embodiments of the methods provided herein, the subject has not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has hemoglobin equal to or greater than 10 g / dL, (ii) has a GFR equal to or greater than 50 mL / min, and (iii) does not have NYHA stage III heart failure.

[0221] In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min and Grade 2 or greater hearing loss. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min and NYHA III heart failure. In yet another embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, and Grade 2 or greater hearing loss. In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, and hearing loss of Grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of an ECOG performance status score of 2, a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, and hearing loss of Grade 2 or greater, in any combination or permutation.In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of an ECOG performance status score of 2, a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, and hearing loss of Grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of a CrCl of less than 60 mL / min but greater than or equal to 30 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by a 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject has not received prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if the subject has an ECOG performance status score of 2, the subject (i) has hemoglobin of 10 g / dL or greater, (ii) has a GFR of 50 mL / min or greater, and (iii) does not have NYHA stage III heart failure.

[0222] Similarly, for the methods provided herein, including but not limited to the method in the preceding paragraph, more specific criteria based on GFR or creatinine clearance for determining cisplatin ineligibility of a human subject can be used. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 30 mL / min but greater than or equal to 15 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a GFR of less than 30 mL / min but greater than or equal to 15 mL / min. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 30 mL / min but greater than or equal to 15 mL / min and hearing loss of grade 2 or greater. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a GFR of less than 30 mL / min but greater than or equal to 15 mL / min and NYHA stage III heart failure. In still other embodiments, the conditions for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, and hearing loss of grade 2 or greater. In still other embodiments, the conditions for determining cisplatin ineligibility include or consist of a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of grade 2 or greater, and NYHA III heart failure. In some embodiments, the conditions for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, and hearing loss of grade 2 or greater. In some embodiments, the conditions for determining cisplatin ineligibility include or consist of any one of a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of grade 2 or greater, and NYHA III heart failure.In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: an ECOG performance status score of 2, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, and a hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, a hearing loss of grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of an ECOG performance status score of 2, a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, and a hearing loss of grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of the following: a GFR of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of Grade 2 or greater, and NYHA 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 Modifications of Diet in Renal Disease [MDRD]. In some embodiments of the methods provided herein, the subject has not previously received systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if a subject has an ECOG performance status score of 2, the subject (i) has hemoglobin equal to or greater than 10 g / dL, (ii) has a GFR equal to or greater than 50 mL / min, and (iii) does not have NYHA stage III heart failure.

[0223] In some embodiments, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min. In one embodiment, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2 and a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min and hearing loss of grade 2 or greater. In a further embodiment, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min and NYHA III heart failure. In yet other embodiments, the criteria for determining cisplatin ineligibility include or consist of an ECOG performance status score of 2, a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, and hearing loss of grade 2 or greater. In still other embodiments, the criteria for determining cisplatin ineligibility include or consist of a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of an ECOG performance status score of 2, a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, and hearing loss of Grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any one of a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of an ECOG performance status score of 2, a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, and hearing loss of Grade 2 or greater, in any combination or permutation.In some embodiments, the criteria for determining cisplatin ineligibility include or consist of any two of the following, in any combination or permutation: a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of an ECOG performance status score of 2, a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, and hearing loss of Grade 2 or greater. In some embodiments, the criteria for determining cisplatin ineligibility include or consist of all three of a CrCl of less than 30 mL / min but greater than or equal to 15 mL / min, hearing loss of Grade 2 or greater, and NYHA III heart failure. In some embodiments of the methods provided in this paragraph, CrCl is measured by a 24-hour urine collection. In other embodiments of the methods provided in this paragraph, CrCl is estimated by the Cockcroft-Gault criteria. In some embodiments of the methods provided herein, the subject has not received prior systemic treatment for locally advanced or metastatic disease. In some embodiments of the methods provided herein, the subject has not received adjuvant / neoadjuvant platinum-based therapy within 12 months prior to randomization. In some embodiments of the methods provided herein, if the subject has an ECOG performance status score of 2, the subject (i) has hemoglobin of 10 g / dL or greater, (ii) has a GFR of 50 mL / min or greater, and (iii) does not have NYHA stage III heart failure.

[0224] 5.2.1.2 Additional patient demographics Furthermore, the human subjects to whom the methods provided herein may be used include those with a variety of other conditions. In one embodiment, the human subject to whom the methods provided herein may be used may have histologically proven locally advanced or metastatic urothelial (formerly known as transitional cell) cancer (e.g., cancer of the bladder, renal pelvis, ureter, or urethra). In some embodiments, the human subject to whom the methods provided herein may be used may be eligible for CPI therapy. In certain embodiments, the human subject to whom the methods provided herein may be used may have measurable disease according to RECIST version 1.1. In other embodiments, the human subject to whom the methods provided herein may be used may have disease that has progressed to be considered measurable in an area previously treated with radiation. In yet other embodiments, the human subject to whom the methods provided herein may be used may have an ECOG performance status score of 0. In yet other embodiments, the human subject to whom the methods provided herein may be used may have an ECOG performance status score of 1. In yet other embodiments, the human subject to whom the methods provided herein may be used may have an ECOG performance status score of 2. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 1 to 2. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 1 or 2. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 0 to 1. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 0 or 1. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 0 to 2. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 0 or 2. In still other embodiments, a human subject to which the methods provided herein are administered may have an ECOG performance status score of 0, 1, or 2.In one embodiment, a human subject to whom the methods provided herein are administered may have an expected life expectancy of 3 months or more. Some embodiments of the methods provided in this paragraph may have any of the foregoing embodiments in any combination or permutation.

[0225] In further embodiments of the methods provided herein, including the method of the preceding paragraph, human subjects for whom the methods provided herein may be used are human subjects with various other conditions. In one embodiment, a human subject for whom the methods provided herein may be used also has an absolute neutrophil count (ANC) of 1500 / μL or greater. In some embodiments, a human subject for whom the methods provided herein may be used also has a platelet count of 100,000 / μL or greater. In certain embodiments, a human subject for whom the methods provided herein may be used also has a hemoglobin of 9 g / dL or greater. In certain embodiments, a human subject for whom the methods provided herein may be used also has a hemoglobin of 9 g / dL or greater, where the subject is not erythropoietin-dependent and the subject has not received a packed red blood cell (pRBC) transfusion within two weeks prior to treatment. In certain embodiments, a human subject for whom the methods provided herein may be used also has a hemoglobin of 5.6 mmol / L or greater. In certain embodiments, human subjects for whom the methods provided herein can be used also have a hemoglobin level of 5.6 mmol / L or greater, where the subject is not erythropoietin-dependent and the subject has not received a packed red blood cell (pRBC) transfusion within two weeks prior to treatment. In certain embodiments, human subjects for whom the methods provided herein can be used also have a hemoglobin level of 9 g / dL or greater than 5.6 mmol / L. In other embodiments, human subjects for whom the methods provided herein can be used also have a serum bilirubin level of 1.5 times the upper limit of normal (ULN) or less, a direct bilirubin level below the ULN (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease patients, a serum bilirubin level of 3 times the ULN or less. In yet other embodiments, human subjects for whom the methods provided herein can be used also have a CrCl level of 30 mL / min or greater. In yet other embodiments, human subjects for whom the methods provided herein can be used also have a GFR level of 30 mL / min or greater. In still other embodiments, the human subjects for which the methods provided herein can be used also have a CrCl or GFR of 30 mL / min or greater.In yet other embodiments, a human subject for whom the methods provided herein may be used also has a CrCl of 30 mL / min or greater, wherein the subject has a creatinine level greater than 1.5 times the institutional ULN and / or less than or equal to 1.5 times the ULN. In yet other embodiments, a human subject for whom the methods provided herein may be used also has a GFR of 30 mL / min or greater, wherein the subject has a creatinine level greater than 1.5 times the institutional ULN and / or less than or equal to 1.5 times the ULN. In another embodiment, a human subject for whom the methods provided herein may be used also has an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level less than or equal to 3 times the ULN. In one embodiment, a human subject for whom the methods provided herein may be used also has an absolute neutrophil count of 1500 / μL or greater and a platelet count of 100,000 / μL or greater. In some embodiments, human subjects for whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater and a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater. In certain embodiments, human subjects for whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater and a serum bilirubin of 1.5 times the ULN or less, a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less. In other embodiments, human subjects for whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater and a CrCl or GFR of 30 mL / min or greater. In other embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater and a CrCl of 30 mL / min or greater (wherein the subject has a creatinine level greater than 1.5 times the institutional ULN and / or less than or equal to 1.5 times the ULN). In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater and ALT and AST levels less than or equal to 3 times the ULN.In further embodiments, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater and a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater. In one embodiment, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater and a serum bilirubin of 1.5 times the ULN or less, a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater and a CrCl or GFR of 30 mL / min or greater. In certain embodiments, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater and an ALT and AST of 3 times the ULN or less. In other embodiments, human subjects for whom the methods provided herein may be used also have a hemoglobin of 9 g / dL or 5.6 mmol / L or greater, and a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less. In still other embodiments, human subjects for whom the methods provided herein may be used also have a hemoglobin of 9 g / dL or 5.6 mmol / L or greater, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects for whom the methods provided herein may be used also have a hemoglobin of 9 g / dL or 5.6 mmol / L or greater, and an ALT and AST of 3 times the ULN or less. In one embodiment, the human subject for whom the methods provided herein can be used also has either a serum bilirubin of 1.5 times the ULN or less, a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease patients, a serum bilirubin of 3 times the ULN or less, and a CrCl of 30 mL / min or greater.In another embodiment, a human subject for whom the methods provided herein can be used also has a serum bilirubin of 1.5 times the ULN or less, a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, as well as an ALT and AST of 3 times the ULN or less. In another embodiment, a human subject for whom the methods provided herein can be used also has a CrCl or GFR of 30 mL / min or more, and an ALT and AST of 3 times the ULN or less. In other embodiments, a human subject for whom the methods provided herein can be used also has an absolute neutrophil count of 1500 / μL or more, a platelet count of 100,000 / μL or more, and a hemoglobin of 9 g / dL or more. In still other embodiments, human subjects for whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, and either a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 100% or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less. In further embodiments, human subjects for whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects for whom the methods provided herein may be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, and an ALT and AST of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a hemoglobin of 9 g / dL or 5.6 mmol / L or greater, and a serum bilirubin not exceeding either 1.5 times the ULN or, for patients with Gilbert's disease, 3 times the ULN. In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a hemoglobin of 9 g / dL or 5.6 mmol / L or greater, and a CrCl or GFR of 30 mL / min or greater.In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L, and ALT and AST levels of 3 times the ULN or less. In still other embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin level of 3 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, for Gilbert's disease patients, a serum bilirubin level of 3 times the ULN or less, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, and an ALT and AST of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, and a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less. In certain embodiments, human subjects for whom the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, and a CrCl or GFR of 30 mL / min or greater.In some embodiments, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, and an ALT and AST level of 3 times the ULN or less. In other embodiments, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin level of 3 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin level of 3 times the ULN or less, and a CrCl or GFR of 30 mL / min or greater. In yet other embodiments, human subjects for whom the methods provided herein may be used also have a platelet count of 100,000 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin level of 3 times the ULN or less. a platelet count of ≥ 100,000 / μL, a serum bilirubin of ≤ 1.5 times the ULN, or a direct bilirubin of ≤ ULN (wherein the human subject has a total bilirubin level of > 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of ≤ 3 times the ULN, and ALT and AST of ≤ 3 times the ULN. In some embodiments, human subjects for whom the methods provided herein can be used also have a platelet count of ≥ 100,000 / μL, a CrCl or GFR of ≥ 30 mL / min, and ALT and AST of ≤ 3 times the ULN. In yet other embodiments, human subjects for whom the methods provided herein can be used also have hemoglobin equal to or greater than 9 g / dL or 5.6 mmol / L, serum bilirubin equal to or less than 1.5 times the ULN, or direct bilirubin equal to or less than the ULN (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, for Gilbert's disease patients, serum bilirubin equal to or less than 3 times the ULN, and a CrCl or GFR equal to or greater than 30 mL / min. In other embodiments, human subjects for whom the methods provided herein can be used also have hemoglobin equal to or greater than 9 g / dL or 5.6 mmol / L, serum bilirubin equal to or less than 1.5 times the ULN, or direct bilirubin equal to or less than the ULN (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, for Gilbert's disease patients, serum bilirubin equal to or less than 3 times the ULN, and ALT and AST equal to or less than 3 times the ULN. In certain embodiments, human subjects for whom the methods provided herein can be used also have hemoglobin at or above 9 g / dL or 5.6 mmol / L, a CrCl or GFR at or above 30 mL / min, and ALT and AST at or below 3 times the ULN. In some embodiments, human subjects for whom the methods provided herein can be used also have either a serum bilirubin at or below 1.5 times the ULN, or a direct bilirubin at or below the ULN (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin at or below 3 times the ULN, a CrCl or GFR at or above 30 mL / min, and ALT and AST at or below 3 times the ULN.In other embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, and either a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 100,000 / μL or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less. In further embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L, and ALT and AST levels of 3 times or less than the ULN. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a serum bilirubin level of 1.5 times or less than the ULN, or a direct bilirubin level of 3 times or less than the ULN (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, for patients with Gilbert's disease, a serum bilirubin level of 3 times or less than the ULN, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects in which the methods provided herein can be used have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, and also an ALT and AST of 3 times the ULN or less.In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a CrCl or GFR of 30 mL / min or greater, and ALT and AST levels of 3 times the ULN or less. In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin level of 1.5 times the ULN or less, or a direct bilirubin level of 3 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin level of 3 times the ULN or less, and a CrCl or GFR of 30 mL / min or greater. In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, and ALT and AST of 3 times the ULN or less. In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a CrCl or GFR of 30 mL / min or greater, and ALT and AST of 3 times the ULN or less. In still other embodiments, the human subjects for which the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less.In further embodiments, the human subjects for which the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease patients, a serum bilirubin of 3 times the ULN or less, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects for whom the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, and ALT and AST of 3 times the ULN or less. In further embodiments, human subjects for whom the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a CrCl or GFR of 30 mL / min or greater, and ALT and AST of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less.In some embodiments, human subjects for whom the methods provided herein can be used also have hemoglobin equal to or greater than 9 g / dL or 5.6 mmol / L, serum bilirubin equal to or less than 1.5 times the ULN, or direct bilirubin equal to or less than the ULN (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, serum bilirubin equal to or less than 3 times the ULN, CrCl or GFR equal to or greater than 30 mL / min, and ALT and AST equal to or less than 3 times the ULN. In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 0.01% or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, for Gilbert's disease patients, a serum bilirubin of 0.01% or less, and a CrCl or GFR of 30 mL / min or greater. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 100,000 / μL or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, and ALT and AST of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L, a CrCl or GFR of 30 mL / min or greater, and ALT and AST of 3 times the ULN or less.In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 100,000 / μL or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less. In certain embodiments, human subjects for whom the methods provided herein can be used also have an absolute neutrophil count of 1500 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less. In some embodiments, the human subjects for whom the methods provided herein can be used also have a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less. The human subjects for whom the methods described herein may be used also have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of either 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and an ALT and AST of 3 times the ULN or less. In some embodiments, a human subject for whom the methods provided herein can be used also has any one of the following conditions: an absolute neutrophil count of 1500 / μL or greater; a platelet count of 100,000 / μL or greater; a hemoglobin of 9 g / dL or greater; a serum bilirubin of 1.5 times the ULN or less; a direct bilirubin of 1.5 times the ULN or less; a total bilirubin level of greater than 1.5 times the ULN; or, for Gilbert's disease patients, a serum bilirubin of 3 times the ULN or less; a CrCl or GFR of 30 mL / min or greater; and an ALT and AST of 3 times the ULN or less. In some embodiments, human subjects for whom the methods provided herein can be used have an absolute neutrophil count of 1500 / μL or greater, a platelet count of 100,000 / μL or greater, a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater, a serum bilirubin of 1.5 times the ULN or less, or a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level greater than 1.5 times the ULN), or in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less, a CrCl or GFR of 30 mL / min or greater, and any two of an ALT and an AST of 3 times the ULN or less, in any combination or permutation.In some embodiments, human subjects for whom the methods provided herein can be used also have any three of the following conditions, in any combination or permutation: an absolute neutrophil count of 1500 / μL or greater; a platelet count of 100,000 / μL or greater; a hemoglobin of 9 g / dL or greater or 5.6 mmol / L; a serum bilirubin not exceeding either 1.5 times the ULN or, for Gilbert's disease patients, 3 times the ULN; a CrCl or GFR of 30 mL / min or greater; and an ALT and AST of 3 times the ULN or less, in any combination or permutation. In some embodiments, the human subject in which the methods provided herein can be used has any four of the following conditions, in any combination or permutation: an absolute neutrophil count of 1500 / μL or greater; a platelet count of 100,000 / μL or greater; a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater; a serum bilirubin of 1.5 times the ULN or less; a direct bilirubin of 1.5 times the ULN or less; a total bilirubin level of greater than 1.5 times the ULN; or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less; a CrCl or GFR of 30 mL / min or greater; and an ALT and AST of 3 times the ULN or less. In some embodiments, a human subject in which the methods provided herein can be used has any five of the following conditions, in any combination or permutation: an absolute neutrophil count of 1500 / μL or greater; a platelet count of 100,000 / μL or greater; a hemoglobin of 9 g / dL or greater or 5.6 mmol / L or greater; a serum bilirubin of 1.5 times the ULN or less; a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less; a CrCl or GFR of 30 mL / min or greater; and an ALT and AST of 3 times the ULN or less.In some embodiments, the human subject for whom the methods provided herein can be used also has all six of the following conditions: an absolute neutrophil count of 1500 / μL or greater; a platelet count of 100,000 / μL or greater; a hemoglobin of 9 g / dL or greater or 5.6 mmol / L; a serum bilirubin of 1.5 times the ULN or less; a direct bilirubin of 1.5 times the ULN or less (wherein the human subject has a total bilirubin level of greater than 1.5 times the ULN), or, in the case of Gilbert's disease, a serum bilirubin of 3 times the ULN or less; a CrCl or GFR of 30 mL / min or greater; and an ALT and AST of 3 times the ULN or less.

[0226] In certain embodiments, the human subject to be used with the methods provided herein may have been surgically or radiotherapeutically treated for prostate cancer at least one year before being treated with any of the methods provided herein, where the subject is not suffering from prostate cancer, and (i) if the subject has undergone or undergone radical prostatectomy, the subject must have undetectable PSA for more than one year before being treated with any of the methods provided herein; (ii) if the subject has undergone radiation, the subject has a PSA doubling time of more than one year (based on at least three values determined at intervals of more than one month) and does not meet the Phoenix criteria for biochemical recurrence (for example, the total PSA value is less than 2.0 ng / mL above the nadir).In certain embodiments, the human subject to be used with the methods provided herein may have untreated low-risk prostate cancer, where the subject is undergoing active surveillance therapy due to a Gleason score of 6 or less and a PSA doubling time of more than one year (based on at least three values determined at intervals of more than one month).

[0227] In other embodiments of the methods provided herein, including the method in the preceding paragraph, the human subject to which the methods provided herein can be used is a human subject who does not have a certain condition. In one embodiment, the human subject to which the methods provided herein are applied has not previously received any treatment with a CPI. A CPI is defined as a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subject to which the methods provided herein are applied has not previously been administered a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor. In certain embodiments, the human subject to which the methods provided herein are applied has not previously been administered atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. In certain embodiments, the human subject to which the methods provided herein are applied has not previously received any treatment with an agent directed against another stimulatory T cell receptor or a co-inhibitory T cell receptor (including, but not limited to, a CD137 agonist, a CTLA4 inhibitor, or an OX-40 agonist). In certain embodiments, the human subject to which the methods provided herein are applied has not previously received any treatment with a CD137 agonist, a CTLA4 inhibitor, or an OX-40 agonist. In one embodiment, the human subject to which the methods provided herein are applied may have sensory or motor neuropathy of Grade 2 or less. In one embodiment, the human subject to which the methods provided herein are applied may not have active central nervous system metastases. In one embodiment, the human subject to which the methods provided herein are applied may not have uncontrolled diabetes. In one embodiment, the human subject to which the methods provided herein are applied has sensory or motor neuropathy of Grade 2 or less and may not have active central nervous system metastases. In some embodiments, the human subject to which the methods provided herein are applied has sensory or motor neuropathy of grade 2 or less and may not have uncontrolled diabetes.In still other embodiments, the human subject to whom the methods provided herein are applied may have sensory or motor neuropathy of Grade 2 or less, no active central nervous system metastases, and no uncontrolled diabetes. In some embodiments, the human subject to whom the methods provided herein are applied may have any one of: sensory or motor neuropathy of Grade 2 or less, no active central nervous system metastases, and no uncontrolled diabetes. In some embodiments, the human subject to whom the methods provided herein are applied may have any two of: sensory or motor neuropathy of Grade 2 or less, no active central nervous system metastases, and no uncontrolled diabetes, in any combination or permutation. In some embodiments, the human subject to whom the methods provided herein are applied may have all three of: sensory or motor neuropathy of Grade 2 or less, no active central nervous system metastases, and no uncontrolled diabetes. In one embodiment of the methods provided in this paragraph, uncontrolled diabetes is determined by a hemoglobin A1c (HbA1c) of 8% or greater. In some embodiments of the methods provided in this paragraph, uncontrolled diabetes is determined by an HbA1c of 7-8% in combination with associated diabetic symptoms that are otherwise unexplained. In further embodiments of the methods provided in this paragraph, the associated diabetic symptoms include or consist of polyuria. In some other embodiments of the methods provided in this paragraph, the associated diabetic symptoms include or consist of polydipsia. In still other embodiments of the methods provided in this paragraph, the associated diabetic symptoms include or consist of both polyuria and polydipsia.

[0228] In certain embodiments, a human subject to whom the methods provided herein are applied may not have ongoing clinically significant toxicity (Grade 2 or higher) associated with a previous treatment. In certain embodiments, a human subject to whom the methods provided herein are applied may not have ongoing clinically significant toxicity (Grade 2 or higher) associated with a previous treatment, where the previous treatment is radiation therapy or surgery. In one embodiment, a human subject to whom the methods provided herein are applied may not have a condition requiring high doses of steroids (e.g., greater than 10 mg / day of prednisone or equivalent) or other immunosuppressants. In one embodiment, a human subject to whom the methods provided herein are applied may not have a condition requiring high doses of steroids or other immunosuppressants, where the steroid or other immunosuppressant is not an inhaled or topical steroid. In certain embodiments, a human subject to whom the methods provided herein are applied may not have previously been treated with enfortumab vedotin or other MMAE-based ADCs for urothelial carcinoma. In certain embodiments, a human subject to whom the methods provided herein are applied may not have a history of another invasive malignancy within three years prior to treatment with the methods provided herein. In certain embodiments, a human subject to which the methods provided herein are applied may have no evidence of residual disease from a previously diagnosed malignancy. In certain embodiments, a human subject to which the methods provided herein are applied may not be receiving systemic antibacterial treatment for an active infection at the time of the first administration of enfortumab vedotin, where the infection is viral, bacterial, or fungal. Systemic antibacterial treatment for an active infection (viral, bacterial, or fungal) at the time of the first administration of enfortumab vedotin. In certain embodiments, a human subject to which the methods provided herein are applied may not have positive hepatitis B surface antigen and / or anti-hepatitis B core antibody. In certain embodiments, a human subject to which the methods provided herein are applied may not have an active hepatitis C infection or a known human immunodeficiency virus (HIV) infection.In certain embodiments, the human subject to which the methods provided herein are applied may not have active tuberculosis. In certain embodiments, the human subject to which the methods provided herein are applied may not have a documented history of cerebrovascular events (e.g., stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms equivalent to NYHA stage IV (including congestive heart failure) within 6 months prior to the first administration of enfortumab vedotin. In certain embodiments, the human subject to which the methods provided herein are applied may not have undergone radiation therapy or major surgery within 2 weeks prior to treatment with the methods provided herein. In certain embodiments, the human subject to which the methods provided herein are applied may not have undergone chemotherapy, biologics, or investigational drug treatment that is not completed within 4 weeks prior to treatment with the methods provided herein. In certain embodiments, a human subject to whom the methods provided herein are applied may not have a known severe (Grade 3 or higher) hypersensitivity to enfortumab vedotin or any excipients contained in a drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20). In certain embodiments, a human subject to whom the methods provided herein are applied may not have a known severe (Grade 3 or higher) hypersensitivity to pembrolizumab or any excipients contained in a drug formulation of pembrolizumab. In certain embodiments, a human subject to whom the methods provided herein are applied may not have active keratitis or a corneal ulcer. In certain embodiments, a human subject to whom the methods provided herein are applied may not have an active autoimmune disease that has required systemic treatment (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressants) within the past two years. In certain embodiments, the human subject to which the methods provided herein are applied may not have an active autoimmune disease that required systemic treatment within the past two years, where the systemic treatment includes a disease-modifying agent, a corticosteroid, or an immunosuppressant. In some embodiments, the systemic treatment is not replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency).In some embodiments, the systemic treatment is not thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency. In certain embodiments, the human subject to whom the methods provided herein are applied may not have a history of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, nor evidence of active pneumonitis by a screening chest CT scan. In certain embodiments, the human subject to whom the methods provided herein are applied may not have previously undergone allogeneic stem cell transplantation or solid organ transplantation. In certain embodiments, the human subject to whom the methods provided herein are applied may not have received a live attenuated vaccine within 30 days prior to treatment with the methods provided herein. In certain embodiments, the live vaccine is a measles vaccine, a mumps vaccine, a rubella vaccine, a varicella / zoster (chickenpox) vaccine, a yellow fever vaccine, a rabies vaccine, a BCG vaccine, or a typhoid vaccine. In certain embodiments, the live attenuated vaccine is a nasal influenza vaccine. In certain embodiments, the human subject to which the methods provided herein are applied may not have an underlying disease that impairs the subject's ability to undergo or tolerate the methods provided herein.

[0229] In some embodiments of the methods provided herein, CrCl is measured by 24-hour urine collection. In other embodiments of the methods provided herein, CrCl is estimated by the Cockcroft-Gault criteria.

[0230] In some embodiments of the methods provided herein, GFR is measured by 24-hour urine collection. In other embodiments of the methods provided herein, GFR is estimated by Cockcroft-Gault criteria. In other embodiments of the methods provided in this paragraph, GFR is measured by Modification of Diet in Renal Disease [MDRD].

[0231] In some embodiments of the methods provided herein, the subject has been treated with one or more other cancer therapies. 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 therapies.

[0232] In some embodiments, the CPIs described herein may include or consist of any CPI as described in this section (Section 5.2.1).

[0233] In all of the methods provided herein, and particularly those described in the preceding paragraph: ADCs that may be used are described in Sections 3, 5.2, 5.3, 5.4, 5.5, and 6; patient selection for treatment is described herein and exemplified in this section (Section 5.2) and Sections 3 and 6; dosing regimens and pharmaceutical compositions for administering therapeutic agents are described in this section (Section 5.2), in Sections 5.4, 5.6, 5.7, and 6 below; and biomarkers that may be used to identify therapeutic agents, select patients, determine the outcome of these methods, and / or serve as criteria in any manner related to these methods are described herein. and are exemplified in this section (Section 5.2, including 5.2.1 and 5.2.2) and Section 6; biomarkers can be determined as described in Section 5.8 or as known in the art; treatment outcomes of the methods provided herein are described in this section (Section 5.2, including Section 5.2.1.4) and Sections 3 and 6; an additional treatment outcome of the methods provided herein can be an improvement in a biomarker described herein, e.g., biomarkers are described and exemplified in this section (Section 5.2, including 5.2.2) and Sections 3 and 6; combination therapies including ADCs and other therapeutic agents are described in this section (Section 5.2) and Section 5.5. Accordingly, one of skill in the art will understand that the methods provided herein include all permutations and combinations of patients, therapeutic agents, dosing regimens, biomarkers, and treatment outcomes as described above and below.

[0234] In certain embodiments, the methods provided herein are used to treat a subject with a urothelial carcinoma that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat a subject with a urothelial carcinoma that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses both 191P4D12 RNA and 191P4D12 protein.

[0235] In certain embodiments, the methods provided herein are used to treat a subject with locally advanced urothelial carcinoma that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat a subject with locally advanced urothelial carcinoma that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses both 191P4D12 RNA and 191P4D12 protein, and who has been previously treated with a CPI.

[0236] In certain embodiments, the methods provided herein are used to treat a subject with a metastatic cancer that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses both 191P4D12 RNA and 191P4D12 protein. In one embodiment, the methods provided herein are used to treat a subject with a metastatic urothelial carcinoma that expresses 191P4D12 RNA, expresses 191P4D12 protein, or expresses both 191P4D12 RNA and 191P4D12 protein.

[0237] In some embodiments, 191P4D12 RNA expression in cancer is determined by polynucleotide hybridization, sequencing (assessing relative abundance of sequences), and / or PCR (including RT-PCR). In some embodiments, 191P4D12 protein expression in cancer is determined by IHC, analysis in fluorescence-activated cell sorting (FACS), and / or Western blotting. In some embodiments, 191P4D12 protein expression in cancer is determined by more than one method. In some embodiments, 191P4D12 protein expression in cancer is determined by two methods: IHC.

[0238] In some embodiments, the locally advanced or metastatic urothelial cancer is histologically, cytologically, or both histologically and cytologically confirmed. In some embodiments, the locally advanced or metastatic bladder cancer is histologically, cytologically, or both histologically and cytologically confirmed.

[0239] In some embodiments, the subject has visceral metastases. In some embodiments, the subject has lymph node-only disease. In some embodiments, the site of disease is the upper urinary tract. In some embodiments, the site of disease is the lower urinary tract.

[0240] In some embodiments, the subject has a PD-L1 expression combined positive score (CPS) of 10 or greater. PD-L1 protein expression is determined by using a combined positive score (CPS) of the number of PD-L1-positive cells (i.e., tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, then multiplied by 100. In some embodiments, the subject has a PD-L1 expression CPS of less than 10. The Nectin H-Score ranges from 0 to 300 based on the following calculation: H-Score = [(0 × % negative cells) + (1 × % weakly positive cells) + (2 × % moderately positive cells) + (3 × % strongly positive cells)]. Urothelial carcinomas generally have a median H-Score of 260 to 270. In some embodiments, the subject has an H-Score for Nectin-4 of 0 to 300. In some embodiments, the subject has an H-Score for Nectin-4 of 0 to 250, 0 to 200, 0 to 150, 0 to 100, or 0 to 50. In some embodiments, the subject has an H-score of 0-200 for Nectin-4.

[0241] 5.2.1.3 Combination therapy with checkpoint inhibitors and pembrolizumab Checkpoint inhibitors In some embodiments, subjects that can be treated with the methods provided herein have certain phenotypic or genotypic characteristics, hi some embodiments, subjects have any permutation or combination of the phenotypic or genotypic characteristics described herein.

[0242] In some embodiments, phenotypic or genotypic characteristics are determined histologically, cytologically, or both histologically and cytologically. In some embodiments of the methods provided herein, histological and / or cytological determination of phenotypic and / or genotypic characteristics is performed based on recently analyzed tissue as described in the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines, the entire contents of which are incorporated herein by reference. In some embodiments, phenotypic or genotypic characteristics are determined by sequencing, including next-generation sequencing (e.g., NGS from Illumina, Inc.), DNA hybridization, and / or RNA hybridization.

[0243] In various aspects or embodiments of the methods provided herein, including the methods provided in this section (Section 5.2), such as those provided in this and the previous paragraph, the human subject to whom the methods are provided herein has not previously received any treatment with a CPI. A CPI is defined as a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab). In some embodiments, the human subject to whom the methods provided herein are applied has not previously received treatment with a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor. In certain embodiments, the human subject to whom the methods provided herein are applied has not previously received treatment with atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab. As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" (CPI) refers to a molecule that reduces, inhibits, antagonizes, or modulates one or more checkpoint proteins, either in whole or in part. Numerous checkpoint proteins are known, including CTLA-4 and its ligands CD80 and CD86; and PD-1 and its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). Other exemplary checkpoint proteins include LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. These proteins appear to be involved in costimulatory or inhibitory interactions in T cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance as well as the duration and magnitude of physiological immune responses. Immune checkpoint inhibitors include or are derived from antibodies.

[0244] In certain embodiments, the checkpoint inhibitors used in the methods provided herein may be inhibitors or activators of checkpoint proteins that are upregulated in cancer. In some specific embodiments, the checkpoint inhibitors used in the methods provided herein may be inhibitors or activators of checkpoint proteins, including LAG-3, B7, TIM3 (HAVCR2), OX40 (CD134), GITR, CD137, CD40, VTCN1, IDO1, CD276, PVRIG, TIGIT, CD25 (IL2RA), IFNAR2, IFNAR1, CSF1R, VSIR (VISTA), or HLA. In some embodiments, the checkpoint inhibitor for the methods provided herein can be an inhibitor or activator 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 OX40 (CD134) inhibitor, a GITR agonist, a CD137 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 an HLA-targeted therapeutic agent. Such inhibitors, activators, or therapeutic agents are further described below.

[0245] 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 U.S. 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 by reference 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 sold under the trade name Yervoy™.

[0246] In certain embodiments, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of PD-1 / PD-L1 inhibitors include, but are not limited to, those described in U.S. Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; and 8,217,149, as well as PCT Patent Application Publication Nos. WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, all of which are incorporated by reference in their entireties.

[0247] "PD-1 antagonist" refers to any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or natural killer T cells), and in a specific embodiment, also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any of the therapeutic methods, medicaments, and uses of the invention in which a human individual is treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and in a specific embodiment, blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found at NCBI locus number: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus numbers: NP_054862 and NP_079515, respectively.

[0248] In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist. In one embodiment, the PD-1 inhibitor or antagonist is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), or pembrolizumab (also known as MK-3475, SCH900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody and is sold under the trade name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is sold under the trade name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. CT-011 administered alone failed to elicit a response in the treatment of relapsed acute myeloid leukemia (AML). In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody specifically designed for binding to Fc gamma receptor I and possesses a unique binding signature for PD-1 with high affinity and excellent target specificity. In one embodiment, the PD-1 antibody is cemiplimab. In another embodiment, the PD-1 antibody is camrelizumab. In a further embodiment, the PD-1 antibody is sintilimab. In some embodiments, the PD-1 antibody is tislelizumab. In a specific embodiment, 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.

[0249] In certain embodiments, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and Tecentriq®). In a further embodiment, the PD-L1 inhibitor is avelumab.

[0250] 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.

[0251] 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.

[0252] In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).

[0253] In one embodiment, the checkpoint inhibitor is a TIM3 (T-cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp. Med., 2010, 207, 2187-94).

[0254] In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

[0259] In one embodiment, the checkpoint inhibitor is a VTCN inhibitor. In one embodiment, the VTCN inhibitor is FPA150.

[0260] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod. In one embodiment, the IDO inhibitor is epacadostat. In another embodiment, the IDO inhibitor is BMS986205. In yet another embodiment, the IDO inhibitor is navoximod. In one embodiment, the IDO inhibitor is PF-06840003. In another embodiment, the IDO inhibitor is KHK2455. In yet another embodiment, the IDO inhibitor is RG70099. In one embodiment, the IDO inhibitor is IOM-E. In another embodiment, the IDO inhibitor is IOM-D.

[0261] In some embodiments, the checkpoint inhibitor is a TIGIT inhibitor. In certain embodiments, the TIGIT inhibitor is an anti-TIGIT antibody. In one embodiment, the TIGIT inhibitor is MTIG7192A. In another embodiment, the TIGIT inhibitor is BMS-986207. In yet another embodiment, the TIGIT inhibitor is OMP-313M32. In one embodiment, the TIGIT inhibitor is MK-7684. In another embodiment, the TIGIT inhibitor is AB154. In yet another embodiment, the TIGIT inhibitor is CGEN-15137. In one embodiment, the TIGIT inhibitor is SEA-TIGIT. In another embodiment, the TIGIT inhibitor is ASP8374. In yet another embodiment, the TIGIT inhibitor is AJUD008.

[0262] In some embodiments, the checkpoint inhibitor is a VSIR inhibitor. In certain embodiments, the VSIR inhibitor is an anti-VSIR antibody. In one embodiment, the VSIR inhibitor is MTIG7192A. In another embodiment, the VSIR inhibitor is CA-170. In yet another embodiment, the VSIR inhibitor is JNJ61610588. In one embodiment, the VSIR inhibitor is HMBD-002.

[0263] 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.

[0264] 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.

[0265] In some embodiments, the checkpoint inhibitor is an IFNAR1 inhibitor. In certain embodiments, the IFNAR1 inhibitor is an anti-IFNAR1 antibody. In one embodiment, the IFNAR1 inhibitor is anifrolumab. In another embodiment, the IFNAR1 inhibitor is sifalimumab.

[0266] In some embodiments, the checkpoint inhibitor is a CSF1R inhibitor. In certain embodiments, the CSF1R inhibitor is an anti-CSF1R antibody. In one embodiment, the CSF1R inhibitor is pexidartinib. In another embodiment, the CSF1R inhibitor is emactuzumab. In yet another embodiment, the CSF1R inhibitor is caviralizumab. 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.

[0267] In some embodiments, the checkpoint inhibitor is an HLA-targeted therapeutic agent. In certain embodiments, the HLA-targeted therapeutic agent is an anti-HLA antibody. In one embodiment, the HLA-targeted therapeutic agent is GSK01. In another embodiment, the HLA-targeted therapeutic agent is IMC-C103C. In yet another embodiment, the HLA-targeted therapeutic agent is IMC-F106C. In one embodiment, the HLA-targeted therapeutic agent is IMC-G107C. In another embodiment, the HLA-targeted therapeutic agent is ABBV-184.

[0268] The methods described herein can be used in combination with one or more second active agents described herein, where appropriate for the treatment of a disease as described herein and understood in the art.

[0269] PD-1 antagonist and pembrolizumab Provided herein are methods for treating various cancers in subjects, including those with unresectable locally advanced or metastatic urothelial carcinoma (1a / mUC) who cannot receive cisplatin-based chemotherapy, using an antibody-drug conjugate (ADC) that binds to 191P4D12 in combination with pembrolizumab. In certain embodiments, the treatment is a first-line treatment. In other embodiments, the treatment is a second-line treatment.

[0270] "Pembrolizumab" (formerly known as MK-3475, SCH900475, and lambrolizumab), alternatively referred to herein as "pembro," is a humanized IgG4 mAb whose structure is set forth in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013), and contains the heavy and light chain amino acid sequences and CDRs set forth in Table 4. Pembrolizumab is approved by the U.S. FDA as set forth in the KEYTRUDA™ package insert (Merck & Co., Inc., Rahway, NJ, USA; first approved in the U.S. in 2014, revised March 2021).

[0271] As used herein, a "pembrolizumab variant" or "variant thereof" with respect to a pembrolizumab sequence refers to a monoclonal antibody comprising heavy and light chain sequences substantially identical to those of pembrolizumab, except that it has three, two, or one conservative amino acid substitutions at positions located outside the light chain CDRs and six, five, four, three, two, or one conservative amino acid substitutions at positions located outside the heavy chain CDRs, e.g., the variant positions are located in the FR or constant region, and optionally, the "pembrolizumab variant" or "variant thereof" has a deletion of the C-terminal lysine residue of the heavy chain. In other words, pembrolizumab and pembrolizumab variants contain the same CDR sequences, but their full-length light chain sequences and full-length heavy chain sequences differ from each other by having conservative amino acid substitutions at no more than three or no more than six other positions. Pembrolizumab variants are substantially identical to pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of PD-1 to PD-L1 and PD-L2, respectively.

[0272] In one embodiment, the PD-1 antagonist useful in the treatments, medicaments, and uses of the present invention comprises a monoclonal antibody (mAb) or antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, 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 comprise a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0273] Examples of mAbs that bind to human PD-1 and are useful in the therapeutic methods, medicaments, and uses of the invention are described in U.S. Patent Nos. US7488802, US7521051, US8008449, US8354509, and US8168757, and International Application Publication Nos. WO2004 / 004771, WO2004 / 072286, WO2004 / 056875, US2011 / 0271358, and WO2008 / 156712. Specific anti-human PD-1 mAbs useful as PD-1 antagonists in the therapeutic methods, medicaments, and uses of the present invention include pembrolizumab (also known as MK-3475), a humanized IgG4 mAb whose structure is set forth in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and comprises the heavy and light chain amino acid sequences set forth in Table 2; These include the mAb nivolumab (BMS-936558); the humanized antibodies h409A11, h409A16 and h409A17 described in WO2008 / 156712, and AMP-514, which is being developed by MedImmune; cemiplimab; camrelizumab; sintilimab; tislelizumab; and toripalimab. Additional anti-PD-1 antibodies contemplated for use herein include MEDI0680 (U.S. Patent No. 8,609,089), BGB-A317 (U.S. Patent Publication No. 2015 / 0079109), INCSHR1210 (SHR-1210) (PCT International Application Publication No. WO2015 / 085847), REGN-2810 (PCT International Application Publication No. WO2015 / 112800), PDR001 (PCT International Application Publication No. WO2015 / 112900), TSR-042 (ANB011) (PCT International Application Publication No. WO2014 / 179664), and STI-1110 (PCT International Application Publication No. WO2014 / 194302).

[0274] Examples of mAbs that bind to human PD-L1 and are useful in the therapeutic methods, medicaments, and uses of the present invention are described in US 8383796. Specific anti-human PD-L1 mAbs useful as PD-1 antagonists in the therapeutic methods, medicaments, and uses of the present invention include BMS-936559, MEDI4736, and MSB0010718C.

[0275] 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. Patent No. 7,332,582), AMP-514 (MedImmune LLC, Gaithersburg, MD, USA), PDR001 (U.S. Patent No. 9,683,048), BGB-A317 (U.S. Patent No. 8,735,553), or MGA012 (MacroGenics, Rockville, MD).

[0276] 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. In some embodiments of the methods, medicaments, and uses of the invention, the PD-1 antagonist is a monoclonal antibody or antigen-binding fragment thereof comprising: (a) a light chain variable region comprising the light chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 24, 25, and 26, respectively; and (b) a heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 29, 30, and 31, respectively.

[0277] In another embodiment of the methods of treatment, 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: 37 or a variant thereof. The variant of the heavy chain variable region sequence is identical to the reference sequence except for up to six conservative amino acid substitutions in the framework regions (i.e., outside the CDRs). The variant of the light chain variable region sequence is identical to the reference sequence except for up to three conservative amino acid substitutions in the framework regions (i.e., outside the CDRs).

[0278] In another embodiment of the methods of treatment, 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 comprising two heavy chains and two light chains, wherein the heavy and light chains comprise the amino acid sequences of SEQ ID NO: 33 and SEQ ID NO: 28, respectively.

[0279] In all of the above methods of treatment, 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 methods of treatment, medicaments, and uses, the PD-1 antagonist is a monoclonal antibody or antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1 and blocks the binding of PD-L1 to PD-1.

[0280] Table 4 below provides a list of amino acid sequences of exemplary anti-PD-1 mAbs for use in the therapeutic methods, medicaments and uses of the invention.

[0281] [Table 4]

[0282] [Table 5] TIFF2025526346000010.tif181165TIFF2025526346000011.tif117165

[0283] 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, e.g., a g1, 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, e.g., a 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 a g4 human heavy chain constant region, and the human light chain constant region can be a kappa human light chain constant region. 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 may be added to the 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 invention requires altered effector function, a heavy chain constant domain other than human IgG1 may be used, or a hybrid IgG1 / IgG4 may be utilized. While human IgG1 antibodies provide long half-life and 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 cases, for example, a human IgG4 constant domain may be used. The present invention encompasses the use of anti-PD-1 antibodies or antigen-binding fragments thereof comprising an IgG4 constant domain. In one embodiment, the IgG4 constant domain may differ from the native human IgG4 constant domain (Swiss-Prot accession number P01861.1) at positions corresponding to position 228 in the EU system and position 241 in the KABAT system, in which native Ser108 is replaced with Pro to prevent a potential interchain disulfide bond between Cys106 and Cys109 (corresponding to positions Cys226 and Cys229 in the EU system, and positions Cys239 and Cys242 in the KABAT system), which may interfere with proper intrachain disulfide bond formation. See Angal et al. (1993) Mol. Immunol. 30:105. In other cases, modified IgG1 constant domains modified to extend half-life or reduce effector function may be used.

[0284] In another embodiment, the PD-1 antagonist is an antibody or antigen binding protein having a variable light chain domain and / or a variable heavy chain domain with at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity to one of the variable light chain domains or variable heavy chain domains described above, and exhibits specific binding to PD-1. In another embodiment of the treatment methods of the invention, the PD-1 antagonist is an antibody or antigen binding protein comprising variable light chain and variable heavy chain domains with up to 1, 2, 3, 4, or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0285] In some embodiments, the checkpoint inhibitor is administered after administration of an ADC provided herein. In other embodiments, the checkpoint inhibitor is administered simultaneously with (e.g., during the same administration period as) an ADC provided herein. In yet other embodiments, the checkpoint inhibitor is administered after administration of an ADC provided herein.

[0286] In some embodiments, the amount of checkpoint inhibitor for the various methods provided herein can be determined by standard clinical techniques. In certain embodiments, the amount of PD-1 antagonist, e.g., pembrolizumab, for the various methods is provided in Section 5.6.

[0287] In some embodiments, subjects that can be treated with the methods provided herein are mammals, hi some embodiments, subjects that can be treated with the methods provided herein are humans.

[0288] 5.2.1.4 Treatment Outcomes of the Methods Provided herein Despite the poor prognosis of cisplatin-ineligible human subjects who are frail as described above and who suffer from multiple comorbidities in addition to their urothelial / bladder cancer, the methods provided herein, including those described in this section (Section 5.2) and Sections 3 and 6, can provide beneficial therapeutic outcomes for these cisplatin-ineligible human subjects. In one embodiment, the human subject exhibits a complete response after treatment with the methods provided herein. In another embodiment, the human subject exhibits a partial response after treatment with the methods provided herein. In another embodiment, the human subject exhibits a complete or partial response after treatment with the methods provided herein.

[0289] In some embodiments, response (complete or partial) is determined by evaluating the tumor or cancer site (lesion). The criteria for determining complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) are listed in Table 10.

[0290] In some embodiments, human subject and patient are used interchangeably, and thus, one of skill in the art will understand that a human subject can be interchangeable with a patient in any of the methods provided herein.

[0291] Thus, the therapeutic outcome of the methods provided herein can be assessed based on any one or more of the response criteria described above.

[0292] In one embodiment, a human subject exhibits a partial response after treatment with the methods provided herein. In another embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by a reduction in the sum of the diameters of the target lesions of at least 30% or about 30% relative to the baseline sum of the diameters. In another embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by a reduction in the sum of the diameters of the target lesions of at least 35% or about 35% relative to the baseline sum of the diameters. In a further embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by a reduction in the sum of the diameters of the target lesions of at least 40% or about 40% relative to the baseline sum of the diameters. In yet another embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by a reduction in the sum of the diameters of the target lesions of at least 45% or about 45% relative to the baseline sum of the diameters. In one embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least a 50% or about a 50% reduction in the sum of the diameters of target lesions relative to the baseline sum of diameters. In another embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least a 55% or about a 55% reduction in the sum of the diameters of target lesions relative to the baseline sum of diameters. In a further embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least a 60% or about a 60% reduction in the sum of the diameters of target lesions relative to the baseline sum of diameters. In yet another embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least a 65% or about a 65% reduction in the sum of the diameters of target lesions relative to the baseline sum of diameters. In one embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where a partial response is defined by at least a 70% or about a 70% reduction in the sum of the diameters of target lesions relative to the baseline sum of the diameters.In another embodiment, the human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least a 75% or about a 75% reduction in the sum of the diameters of the target lesions relative to the baseline sum of the diameters. In a further embodiment, the human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least an 80% or about an 80% reduction in the sum of the diameters of the target lesions relative to the baseline sum of the diameters. In yet another embodiment, the human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least an 85% or about an 85% reduction in the sum of the diameters of the target lesions relative to the baseline sum of the diameters. In one embodiment, the human subject exhibits a partial response after treatment with the methods provided herein, where the partial response is defined by at least a 90% or about a 90% reduction in the sum of the diameters of the target lesions relative to the baseline sum of the diameters. In another embodiment, a human subject exhibits a partial response after treatment with the methods provided herein, where a partial response is defined by a reduction of at least 95% or about 95% in the sum of the diameters of the target lesions relative to the baseline sum of the diameters. In some embodiments, the diameter is determined by the longest diameter of the lesion. In certain embodiments, the diameter is determined by the longest diameter of the lesion in the measurement plane having a minimum size of 10 mm by CT scan. In certain embodiments, the diameter is determined by the longest diameter of the lesion in the measurement plane having a minimum size of 10 mm by CT scan and a CT slice thickness of 5 mm or less.

[0293] The therapeutic outcome of the methods provided herein can also be evaluated based on whether the disease is stable after treatment. In one embodiment, the human subject exhibits stable disease after treatment with the methods provided herein. In another embodiment, the human subject does not have progressive disease after treatment with the methods provided herein.

[0294] Alternatively, treatment outcome based on complete response, partial response, or stable disease can be assessed for a population of human subjects treated with the methods provided herein by evaluating the percentage of subjects in the treated population who experience a complete response, partial response, or stable disease. Thus, in some embodiments, a measure of treatment outcome or efficacy applies to the results achieved by actually treating a population of subjects. In other embodiments, a measure of treatment outcome or efficacy refers to the results or efficacy that can be achieved when a population of human subjects is treated with the methods disclosed herein. In the following sections, treatment of an actual population of human subjects is discussed, but it should be understood that corresponding methods by which a measure of outcome or efficacy can be achieved in a patient population are also encompassed herein. In short, both scenarios described above apply to the following sections, but for simplicity and to avoid redundancy, only one scenario is described below.

[0295] In some embodiments of the methods provided herein, including but not limited to, 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, 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, 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.

[0296] In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a complete response is at least 2% or about 2%. In another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a complete response is at least 5% or about 5%. In a further embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a complete response is at least 10% or about 10%. In a further embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a complete response is at least 10.5% or about 10.5%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a complete response is at least 15% or about 15%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a complete response is at least 20% or about 20%.

[0297] In one embodiment, the complete response rate is at least 10% or about 10% for the population of subjects treated with the method. In another embodiment, the complete response rate is at least 2% or about 2% for the population of subjects treated with the method. In another embodiment, the complete response rate is at least 5% or about 5% for the population of subjects treated with the method. In another embodiment, the complete response rate is at least 10% or about 10% for the population of subjects treated with the method. In another embodiment, the complete response rate is at least 10.5% or about 10.5% for the population of subjects treated with the method. In another embodiment, the complete response rate is at least 15% or about 15% for the population of subjects treated with the method. In another embodiment, the complete response rate is at least 20% or about 20% for the population of subjects treated with the method.

[0298] Similarly, using the percentage of partial responses as a criterion, in one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who exhibit a partial response is at least 25% or about 25%. In another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who exhibit a partial response is at least 30% or about 30%. In a further embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who exhibit a partial response is at least 35% or about 35%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who exhibit a partial response is at least 40% or about 40%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who exhibit a partial response is at least 45% or about 45%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least 50% or about 50%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least 53.9% or about 53.9%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least 54% or about 54%. In another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least 55% or about 55%. In another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least 60% or about 60%. In another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who exhibit a partial response is at least 65% or about 65%.In a further embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least or about 70%. In yet another embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population who experience a partial response is at least or about 75%.

[0299] In one embodiment, the partial response rate is at least 25% or about 25% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 30% or about 30% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 35% or about 35% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 40% or about 40% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 45% or about 45% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 50% or about 50% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 53.9% or about 53.9% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 54% or about 54% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 55% or about 55% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 60% or about 60% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 65% or about 65% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 70% or about 70% for the population of subjects treated with the method. In another embodiment, the partial response rate is at least 75% or about 75% for the population of subjects treated with the method.

[0300] Furthermore, the percentage of subjects exhibiting stable disease can be used as a criterion for evaluating the treatment outcome of human subjects treated by the methods provided herein. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects exhibiting stable disease in the treated population is at least 10% or about 10%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects exhibiting stable disease in the treated population is at least 15% or about 15%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects exhibiting stable disease in the treated population is at least 20% or about 20%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects exhibiting stable disease in the treated population is at least 22% or about 22%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects exhibiting stable disease in the treated population is at least 22.4% or about 22.4%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population exhibiting stable disease is at least 25% or about 25%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population exhibiting stable disease is at least 30% or about 30%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population exhibiting stable disease is at least 35% or about 35%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population exhibiting stable disease is at least 40% or about 40%. In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population exhibiting stable disease is at least 45% or about 45%.In one embodiment, a population of human subjects is treated by the methods provided herein, and the percentage of subjects in the treated population that exhibit stable disease is at least 50% or about 50%.

[0301] In one embodiment, the stable disease rate is at least 10% or about 10% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 15% or about 15% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 20% or about 20% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 22% or about 22% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 22.4% or about 22.4% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 25% or about 25% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 30% or about 30% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 35% or about 35% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least 40% or about 40% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 45% for the population of subjects treated with the method. In one embodiment, the stable disease rate is at least or about 50% for the population of subjects treated with the method.

[0302] Similarly, the objective response rate, which is the sum of the percentage of subjects who experience a complete response and the percentage of subjects who experience a partial response, can be used as a measure of treatment outcome for human subjects treated with the methods provided herein. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the objective response rate in the treated population is at least 30% or about 30%. In one embodiment, a population of human subjects is treated with the methods provided herein, and the objective response rate in the treated population is at least 35% or about 35%. In another embodiment, a population of human subjects is treated with the methods provided herein, and the objective response rate in the treated population is at least 40% or about 40%. In one embodiment, a population of human subjects is treated with the methods provided herein, and the objective response rate in the treated population is at least 45% or about 45%. In a further embodiment, a population of human subjects is treated with the methods provided herein, and the objective response rate in the treated population is at least 50% or about 50%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 52.7% or about 52.7%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 53% or about 53%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 55% or about 55%. In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 60% or about 60%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 64.5% or about 64.5%. In a further embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 65% or about 65%.In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 70% or about 70%. In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 75% or about 75%. In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 75.1% or about 75.1%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 80% or about 80%. In a further embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 85% or about 85%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is at least 90% or about 90%.

[0303] In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 40% to 80%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 40% to 75%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 40% to 70%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 45% to 80%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 45% to 75%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 45% to 70%. In a further embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population is in the range of 50% to 80%. In a further embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 50% to 75%. In another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 52.7% to 75.1%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 55% to 80%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 55% to 75%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 55% to 70%. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 55% to 65%.In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 60% to 80%. In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 60% to 75%. In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 60% to 70%. In one embodiment, a population of human subjects is treated with the methods provided herein and the objective response rate in the treated population ranges from 60% to 65%.

[0304] In one embodiment, the objective response rate is at least 30% or about 30% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 30% or about 30% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 35% or about 35% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 40% or about 40% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 45% or about 45% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 50% or about 50% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 55% or about 55% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 60% or about 60% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 64.5% or about 64.5% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 65% or about 65% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 70% or about 70% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 75% or about 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 80% or about 80% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 85% or about 85% for the population of subjects treated with the method. In another embodiment, the objective response rate is at least 90% or about 90% for the population of subjects treated with the method.

[0305] In one embodiment, the objective response rate is between 40% and 80% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 40% and 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 40% and 70% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 45% and 80% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 45% and 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 45% and 70% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 50% and 80% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 50% and 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 52.7% and 75.1% for the population of subjects treated with the method. In another embodiment, the objective response rate is between 53% and 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is 55% to 80% for the population of subjects treated with the method. In another embodiment, the objective response rate is 55% to 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is 55% to 70% for the population of subjects treated with the method. In another embodiment, the objective response rate is 55% to 65% for the population of subjects treated with the method. In another embodiment, the objective response rate is 60% to 80% for the population of subjects treated with the method. In another embodiment, the objective response rate is 60% to 75% for the population of subjects treated with the method. In another embodiment, the objective response rate is 60% to 70% for the population of subjects treated with the method. In another embodiment, the objective response rate is 60% to 65% for the population of subjects treated with the method.

[0306] Additionally, the therapeutic outcome of the methods provided herein can be assessed based on duration of response as described in Section 6.1.8.2(ii). In one embodiment, the human subject has a duration of response of at least 5 months or about 5 months after treatment. In another embodiment, the human subject has a duration of response of at least 6 months or about 6 months after treatment. In a further embodiment, the human subject has a duration of response of at least 7 months or about 7 months after treatment. In yet another embodiment, the human subject has a duration of response of at least 8 months or about 8 months after treatment. In one embodiment, the human subject has a duration of response of at least 9 months or about 9 months after treatment. In another embodiment, the human subject has a duration of response of at least 10 months or about 10 months after treatment. In yet another embodiment, the human subject has a duration of response of at least 11 months or about 11 months after treatment. In one embodiment, the human subject has a duration of response of at least 12 months or about 12 months after treatment. In another embodiment, the human subject has a duration of response of at least 13 months or about 13 months after treatment. In a further embodiment, the human subject has a duration of response of at least 14 months or about 14 months after treatment. In yet another embodiment, the human subject has a duration of response of at least 15 months or about 15 months after treatment. In one embodiment, the human subject has a duration of response of at least 16 months or about 16 months after treatment. In another embodiment, the human subject has a duration of response of at least 17 months or about 17 months after treatment. In a further embodiment, the human subject has a duration of response of at least 18 months or about 18 months after treatment. In yet another embodiment, the human subject has a duration of response of at least 19 months or about 19 months after treatment. In a further embodiment, the human subject has a duration of response of at least 20 months or about 20 months after treatment. In a further embodiment, the human subject has a duration of response of at least 21 months or about 21 months after treatment. In a further embodiment, the human subject has a duration of response of at least 22 months or about 22 months after treatment. In a further embodiment, the human subject has a duration of response after treatment of at least or about 23 months, hi a further embodiment, the human subject has a duration of response after treatment of at least or about 24 months.In a further embodiment, the human subject has a duration of response of at least 25 months or about 25 months after treatment. In a further embodiment, the human subject has a duration of response of at least 26 months or about 26 months after treatment. In a further embodiment, the human subject has a duration of response of at least 27 months or about 27 months after treatment. In a further embodiment, the human subject has a duration of response of at least 28 months or about 28 months after treatment. In a further embodiment, the human subject has a duration of response of at least 29 months or about 29 months after treatment. In a further embodiment, the human subject has a duration of response of at least 30 months or about 30 months after treatment.

[0307] In another embodiment, the human subject has a duration of response ranging from 5 to 30 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 29 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 28 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 27 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 26 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 25 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 24 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 23 months after treatment. In some embodiments, the human subject has a duration of response ranging from 5 to 22 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 21 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 5 to 20 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 5 to 19 months after treatment. In one embodiment, the human subject has a duration of response ranging from 5 to 18 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 17 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 5 to 16 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 5 to 15 months after treatment. In one embodiment, the human subject has a duration of response ranging from 5 to 14 months after treatment. In another embodiment, the human subject has a duration of response ranging from 5 to 13 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 5 to 12 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 30 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 29 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 28 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 27 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 26 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 25 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 24 months after treatment.In another embodiment, the human subject has a duration of response ranging from 6 to 23 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 6 to 22 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 21 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 20 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 6 to 19 months after treatment. In one embodiment, the human subject has a duration of response ranging from 6 to 18 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 17 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 16 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 6 to 15 months after treatment. In one embodiment, the human subject has a duration of response ranging from 6 to 14 months after treatment. In another embodiment, the human subject has a duration of response ranging from 6 to 13 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 12 months after treatment. In one embodiment, the human subject has a duration of response ranging from 7 to 22 months after treatment. In another embodiment, the human subject has a duration of response ranging from 7 to 21 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 7 to 20 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 7 to 19 months after treatment. In one embodiment, the human subject has a duration of response ranging from 7 to 18 months after treatment. In another embodiment, the human subject has a duration of response ranging from 7 to 17 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 7 to 16 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 7 to 15 months after treatment. In one embodiment, the human subject has a duration of response ranging from 7 to 14 months after treatment. In another embodiment, the human subject has a duration of response ranging from 7 to 13 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 7 to 12 months after treatment. In another embodiment, the human subject has a duration of response ranging from 8 to 30 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 9 to 30 months after treatment.In yet another embodiment, the human subject has a duration of response ranging from 10 to 30 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 30 months after treatment. In one embodiment, the human subject has a duration of response ranging from 12 to 30 months after treatment. In another embodiment, the human subject has a duration of response ranging from 13 to 30 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 14 to 30 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 15 to 30 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 16 to 30 months after treatment. In one embodiment, the human subject has a duration of response ranging from 17 to 30 months after treatment. In another embodiment, the human subject has a duration of response ranging from 18 to 30 months after treatment. In another embodiment, the human subject has a duration of response ranging from 8 to 27 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 9 to 27 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 10 to 27 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 27 months after treatment. In one embodiment, the human subject has a duration of response ranging from 12 to 27 months after treatment. In another embodiment, the human subject has a duration of response ranging from 13 to 27 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 14 to 27 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 15 to 27 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 16 to 27 months after treatment. In one embodiment, the human subject has a duration of response ranging from 17 to 27 months after treatment. In another embodiment, the human subject has a duration of response ranging from 18 to 27 months after treatment. In another embodiment, the human subject has a duration of response ranging from 8 to 22 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 9 to 22 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 10 to 22 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 22 months after treatment. In one embodiment, the human subject has a duration of response ranging from 12 to 22 months after treatment.In another embodiment, the human subject has a duration of response ranging from 13 to 22 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 14 to 22 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 15 to 22 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 16 to 22 months after treatment. In one embodiment, the human subject has a duration of response ranging from 17 to 22 months after treatment. In another embodiment, the human subject has a duration of response ranging from 18 to 22 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 6 to 21 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 7 to 20 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 8 to 19 months after treatment. In one embodiment, the human subject has a duration of response ranging from 9 to 18 months after treatment. In another embodiment, the human subject has a duration of response ranging from 10 to 17 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 11 to 16 months after treatment. In yet another embodiment, the human subject has a duration of response ranging from 12 to 15 months after treatment. In a further embodiment, the human subject has a duration of response ranging from 13 to 14 months after treatment.

[0308] In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 5 months or about 5 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 6 months or about 6 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 7 months or about 7 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 8 months or about 8 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 9 months or about 9 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 10 months or about 10 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 11 months or about 11 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 12 months or about 12 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 13 months or about 13 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 14 months or about 14 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 15 months or about 15 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 16 months or about 16 months after treatment.In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 17 months or about 17 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 18 months or about 18 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 19 months or about 19 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 20 months or about 20 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 21 months or about 21 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 22 months or about 22 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 23 months or about 23 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 24 months or about 24 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 25 months or about 25 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 26 months or about 26 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 27 months or about 27 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least 28 months or about 28 months after treatment.In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least or about 29 months after treatment. In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response in the treated population is at least or about 30 months after treatment.

[0309] In certain embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 30 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 29 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 28 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 27 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 26 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 25 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 5 to 24 months. In some embodiments, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 23 months. In certain embodiments, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 22 months. In some embodiments, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 21 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 20 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 19 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 18 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 17 months.In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 16 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 15 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 14 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 13 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 5 to 12 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 30 months. In some embodiments, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 29 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 28 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 27 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 26 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 25 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 24 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 23 months. In further embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 22 months.In some embodiments, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 21 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 20 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 19 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 18 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 17 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 16 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 6 to 15 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 14 months. In one embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 13 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 12 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 30 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 29 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 28 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 27 months.In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 26 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 25 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 24 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 23 months. In yet other embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 22 months. In some embodiments, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 21 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 20 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 19 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 18 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 17 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 16 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 15 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 14 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 13 months.In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 12 months. In one embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6.41 to 22 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 8 to 22 months. In a further embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 9 to 22 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 10 to 22 months. In one embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 11 to 22 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 12 to 12 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 13 to 22 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 14 to 22 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 15 to 22 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 16 to 22 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 17 to 22 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 18 to 22 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 7 to 27 months.In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 8 to 27 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 9 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 10 to 27 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 11 to 27 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 12 to 27 months. In a further embodiment, a population of human subjects is treated with the methods provided herein. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 13 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 14 to 27 months. In one embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 15 to 27 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 16 to 27 months. In a further embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 17 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 18 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 19 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 20 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 21 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 22 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 23 to 27 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 24 to 27 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 30 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 8 to 30 months.In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 9 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 10 to 30 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 11 to 30 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 12 to 30 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 13 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 14 to 30 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 15 to 30 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 16 to 30 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 17 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 18 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 19 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 20 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 21 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 22 to 30 months.In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 23 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 24 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 25 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 26 to 30 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 27 to 30 months. In one embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 6 to 21 months. In another embodiment, a population of human subjects is treated with the methods provided herein, and the duration of response for the treated population ranges from 7 to 20 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 8 to 19 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 9 to 18 months. In one embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 10 to 17 months. In another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 11 to 16 months. In a further embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 12 to 15 months. In yet another embodiment, a population of human subjects is treated with the methods provided herein and the duration of response for the treated population ranges from 13 to 24 months.

[0310] In certain embodiments, the duration of response is at least 5 months or about 5 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 6 months or about 6 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 7 months or about 7 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 8 months or about 8 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 9 months or about 9 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 10 months or about 10 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 11 months or about 11 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 12 months or about 12 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 13 months or about 13 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 14 months or about 14 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 15 months or about 15 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 16 months or about 16 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 17 months or about 17 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 18 months or about 18 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 19 months or about 19 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 20 months or about 20 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least 21 months or about 21 months for the population of subjects treated with the method.In certain embodiments, the duration of response is at least or about 22 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 23 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 24 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 25 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 26 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 27 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 28 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 29 months for the population of subjects treated with the method. In certain embodiments, the duration of response is at least or about 30 months for the population of subjects treated with the method.

[0311] Alternatively, the treatment outcome of the methods provided herein can be assessed based on progression-free survival, as described in Section 6.1.8.2(iv). In one embodiment, the human subject has a progression-free survival of at least 5 months or about 5 months after treatment. In another embodiment, the human subject has a progression-free survival of at least 6 months or about 6 months after treatment. In a further embodiment, the human subject has a progression-free survival of at least 7 months or about 7 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 8 months or about 8 months after treatment. In one embodiment, the human subject has a progression-free survival of at least 9 months or about 9 months after treatment. In another embodiment, the human subject has a progression-free survival of at least 10 months or about 10 months after treatment. In a further embodiment, the human subject has a progression-free survival of at least 11 months or about 11 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 12 months or about 12 months after treatment. In one embodiment, the human subject has a progression-free survival of at least 13 months or about 13 months after treatment. In another embodiment, the human subject has a progression-free survival of at least 14 months or about 14 months after treatment. In a further embodiment, the human subject has a progression-free survival of at least 15 months or about 15 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 16 months or about 16 months after treatment. In one embodiment, the human subject has a progression-free survival of at least 17 months or about 17 months after treatment. In another embodiment, the human subject has a progression-free survival of at least 18 months or about 18 months after treatment. In a further embodiment, the human subject has a progression-free survival of at least 19 months or about 19 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 20 months or about 20 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 21 months or about 21 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 22 months after treatment.In yet another embodiment, the human subject has a progression-free survival of at least 23 months or about 23 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 24 months or about 24 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 25 months or about 25 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 26 months or about 26 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 27 months or about 27 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 28 months or about 28 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 29 months or about 29 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 30 months or about 30 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least 31 months or about 31 months after treatment. In yet another embodiment, the human subject has a progression-free survival of at least or about 32 months after treatment, hi yet another embodiment, the human subject has a progression-free survival of at least or about 33 months after treatment.

[0312] In another embodiment, the human subject has a progression-free survival time ranging from 5 to 33 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 32 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 31 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 30 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 29 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 28 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 27 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 26 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 25 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 24 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 23 months after treatment. In some embodiments, the human subject has a progression-free survival time ranging from 5 to 22 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 21 months after treatment. In a further embodiment, the human subject has a progression-free survival time ranging from 5 to 20 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 5 to 19 months after treatment. In one embodiment, the human subject has a progression-free survival time ranging from 5 to 18 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 17 months after treatment. In a further embodiment, the human subject has a progression-free survival time ranging from 5 to 16 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 5 to 15 months after treatment. In one embodiment, the human subject has a progression-free survival time ranging from 5 to 14 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 5 to 13 months after treatment. In a further embodiment, the human subject has a progression-free survival time ranging from 5 to 12 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 33 months after treatment.In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 32 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 31 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 30 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 29 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 28 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 27 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 26 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 25 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 22 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 24 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 23 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 22 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 6 to 21 months after treatment. In a further embodiment, the human subject has a progression-free survival time ranging from 6 to 20 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 19 months after treatment. In one embodiment, the human subject has a progression-free survival time ranging from 6 to 18 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 6 to 17 months after treatment. In a further embodiment, the human subject has a progression-free survival time ranging from 6 to 16 months after treatment. In yet another embodiment, the human subject has a progression-free survival time ranging from 6 to 15 months after treatment. In one embodiment, the human subject has a progression-free survival time ranging from 6 to 14 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 6 to 13 months after treatment. In a further embodiment, the human subject has a progression-free survival time ranging from 6 to 12 months after treatment. In another embodiment, the human subject has a progression-free survival time ranging from 7 to 33 months after treatment.In another embodiment, the human subject has a progression-free survival time ranging from 7 to 32 months after treatment. In another embodiment, the human subject has a progression-free survival time rangin...

Claims

1. 1. A method of treating cancer in a human 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. and administering 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); the anti-PD-1 antibody comprises (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 24, 25, and 26, respectively; and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 29, 30, and 31, respectively; the anti-191P4D12 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a complementarity-determining region (CDR) having the amino acid sequence of the CDR of the heavy chain variable region set forth in SEQ ID NO: 22, and a light chain variable region comprising the CDR having the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO: 23; the subject has urothelial cancer or bladder cancer; the subject has not received immune checkpoint inhibitor (CPI) therapy; the subject is ineligible to receive cisplatin therapy (cisplatin ineligible), The method.

2. The method of claim 1 , wherein the subject has visceral metastases.

3. 10. The method of claim 1, wherein the subject has lymph node-only disease.

4. The method according to any one of claims 1 to 3, wherein the site of disease occurrence is the upper urinary tract.

5. The method according to any one of claims 1 to 3, wherein the site of disease occurrence is the lower urinary tract.

6. The method of any one of claims 1 to 5, wherein the subject has a PD-L1 expression combined positive score (CPS) of 10 or greater.

7. The method of any one of claims 1 to 5, wherein the subject has a PD-L1 expression CPS of less than 10.

8. The method according to any one of claims 1 to 6, wherein the subject has an H score of 0 to 300 for Nectin-4.

9. The method according to any one of claims 1 to 7, wherein the subject has an H score of 0 to 200 for Nectin-4.

10. 10. The method of any one of claims 1 to 9, wherein the subject has an ECOG performance status score of 1 to 2.

11. 10. The method of any one of claims 1-9, wherein the subject has one or more conditions selected from the group consisting of an ECOG performance status score of 2, impaired renal function, and hearing loss of grade 2 or greater.

12. The method of any one of claims 1 to 9, wherein the subject has NYHA grade III heart failure.

13. The subject has an ECOG performance status score of 2, and The subject (i) has hemoglobin of 10 g / dL or greater, (ii) has a GFR of 50 mL / min or greater, and (iii) does not have NYHA Class III heart failure. The method of claim 11.

14. 12. The method of claim 11, wherein the renal impairment is determined by a creatinine clearance (CrCl) of less than 60 mL / min.

15. 12. The method of claim 11, wherein the renal impairment is determined by CrCl less than 60 mL / min but greater than or equal to 30 mL / min.

16. 12. The method of claim 11, wherein the impaired renal function is determined by CrCl less than 30 mL / min but greater than or equal to 15 mL / min.

17. The object is (i) an absolute neutrophil count of 1500 / μL or greater; (ii) a platelet count of 100,000 / μL or greater; (iii) hemoglobin of 9 g / dL or more; (iv) serum bilirubin not exceeding either 1.5 times the upper limit of normal (ULN) or 3 times the ULN in patients with Gilbert's disease; (v) CrCl at 30 mL / min or more; and (vi) alanine aminotransferase and aspartate aminotransferase less than or equal to 3 times the ULN The method according to any one of claims 1 to 16, wherein the method has one or more conditions selected from the group consisting of:

18. The method of claim 17, wherein the subject has all of the conditions (i) to (vi) of claim 15.

19. 19. The method of any one of claims 14 to 18, wherein the CrCl is measured by 24-hour urine collection or estimated by the Cockcroft-Gault criteria.

20. 20. The method of any one of claims 1 to 19, wherein the subject has sensory or motor neuropathy of grade 2 or less.

21. 21. The method of any one of claims 1 to 20, wherein the subject does not have active metastases of the central nervous system.

22. The method of any one of claims 1 to 21, wherein the subject does not have uncontrolled diabetes.

23. 23. The method of claim 22, wherein the uncontrolled diabetes is determined by a hemoglobin A1c (HbA1c) of 8% or greater, or an HbA1c of 7-8% in combination with associated diabetic symptoms that are otherwise unexplained.

24. 24. The method of claim 23, wherein the associated diabetic symptoms include or consist of polyuria, polydipsia, or both polyuria and polydipsia.

25. The method of any one of claims 1 to 24, wherein the subject has locally advanced or metastatic urothelial carcinoma.

26. The method of any one of claims 1 to 25, wherein the subject has locally advanced or metastatic bladder cancer.

27. 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 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; The method according to any one of claims 1 to 26.

28. 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 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; The method according to any one of claims 1 to 26.

29. The method of any one of claims 1 to 28, 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.

30. 30. The method of any one of claims 1 to 29, wherein the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from amino acid 20 (glutamic acid) to amino acid 466 (lysine) of SEQ ID NO: 7, and a light chain comprising the amino acid sequence ranging from amino acid 23 (aspartic acid) to amino acid 236 (cysteine) of SEQ ID NO:

8.

31. The method of any one of claims 1 to 30, wherein the anti-191P4D12 antigen-binding fragment is a Fab, F(ab')2, Fv, or scFv.

32. The method of any one of claims 1 to 30, wherein the anti-191P4D12 antibody is a fully human antibody.

33. The method of any one of claims 1 to 30 and 32, wherein the anti-191P4D12 antibody is an IgG1 and the light chain is a kappa light chain.

34. 34. The method of any one of claims 1 to 33, wherein the anti-191P4D12 antibody or antigen-binding fragment thereof is recombinantly produced.

35. 35. The method of any one of claims 1 to 34, wherein the anti-191P4D12 antibody or antigen-binding fragment is conjugated to each unit of MMAE via a linker.

36. 36. The method of claim 35, wherein the linker is an enzyme-cleavable linker, and the linker forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof.

37. 37. The method of claim 35 or 36, wherein the linker has the formula -Aa-Ww-Yy-, where -A- is an extender unit, a is 0 or 1, -W- is an amino acid unit, w is an integer ranging from 0 to 12, -Y- is a spacer unit, and y is 0, 1, or 2.

38. The extender unit has the structure of formula (1) below, the amino acid unit is valine-citrulline, and the spacer unit is a PAB group having the structure of formula (2) below:

38. The method of claim 37.

39. 39. The method of claim 37 or 38, wherein the extender unit forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof, and the spacer unit is linked to MMAE via a carbamate group.

40. 40. The method of any one of claims 1 to 39, wherein the ADC comprises 1 to 20 units of MMAE per antibody or antigen-binding fragment thereof.

41. The method of any one of claims 1 to 40, wherein the ADC comprises 1 to 10 units of MMAE per antibody or antigen-binding fragment thereof.

42. 42. The method of any one of claims 1 to 41, wherein the ADC comprises 2 to 8 units of MMAE per antibody or antigen-binding fragment thereof.

43. The method of any one of claims 1 to 42, wherein the ADC comprises 3 to 5 units of MMAE per antibody or antigen-binding fragment thereof.

44. The ADC has the following structure: wherein L- represents said anti-191P4D12 antibody or antigen-binding fragment thereof and p is 1-10.

45. 45. The method of claim 44, wherein p is 2 to 8.

46. 46. The method of claim 44 or 45, wherein p is 3 to 5.

47. 47. The method of any one of claims 44 to 46, wherein p is 3 to 4.

48. 48. The method of any one of claims 44 to 47, wherein p is about 4.

49. 48. The method of any one of claims 44-47, wherein the effective amount of the antibody-drug conjugate has a mean p-value of about 3.

8.

50. 50. The method of any one of claims 1-49, 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.

51. 51. The method of any one of claims 1-50, wherein the ADC is administered to the subject at a dose of about 0.25 mg / kg of the subject's body weight, about 0.5 mg / kg of the subject's body weight, about 0.75 mg / kg of the subject's body weight, about 1.0 mg / kg of the subject's body weight, about 1.25 mg / kg of the subject's body weight, about 1.5 mg / kg of the subject's body weight, about 1.75 mg / kg of the subject's body weight, about 2.0 mg / kg of the subject's body weight, about 2.25 mg / kg of the subject's body weight, or about 2.5 mg / kg of the subject's body weight.

52. 52. The method of any one of claims 1 to 51, wherein the ADC is administered to the subject at a dose of about 1 mg / kg of the subject's body weight.

53. 52. The method of any one of claims 1-51, wherein the ADC is administered to the subject at a dose of about 1.25 mg / kg of the subject's body weight.

54. 54. The method of any one of claims 1 to 53, wherein the ADC is administered to the subject by intravenous (IV) injection or infusion.

55. 55. The method of any one of claims 1-54, wherein the ADC is administered to the subject by IV injection or infusion for a maximum of 2 days out of a 21-day treatment cycle.

56. 56. The method of any one of claims 1-55, wherein the ADC is administered to the subject by IV injection or infusion on days 1 and 8 of a 21-day treatment cycle.

57. 57. The method of any one of claims 1-56, wherein the ADC is administered to the subject by IV injection or infusion over about 30 minutes for up to 2 days out of a 21-day treatment cycle.

58. 58. The method of any one of claims 1-57, wherein the ADC is administered by IV injection or infusion over about 30 minutes on days 1 and 8 of a 21-day treatment cycle.

59. 59. The method of any one of claims 1 to 58, wherein the ADC is formulated into a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN-20), and trehalose dehydrate.

60. 60. The method of any one of claims 1 to 59, 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.

61. 60. The method of any one of claims 1 to 59, 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 pharmaceutical composition has a pH of about 6.0 at 25°C.

62. The ADC has the following structure: wherein L- represents the antibody or antigen-binding fragment thereof and p is about 3 to about 4; the anti-191P4D12 antibody comprises a heavy chain comprising the amino acid sequence ranging from amino acid 20 (glutamic acid) to amino acid 466 (lysine) of SEQ ID NO:7 and a light chain comprising the amino acid sequence ranging from amino acid 23 (aspartic acid) to amino acid 236 (cysteine) of SEQ ID NO:8; and the ADC is administered at a dose of about 1.25 mg / kg of the subject's body weight, administered by IV injection or infusion over about 30 minutes on days 1 and 8 of a 21-day treatment cycle.

63. 61. The method of any one of claims 1 to 60, wherein the anti-PD-1 antibody is administered to the subject at a dose of about 100 mg to about 400 mg.

64. 62. The method of any one of claims 1-61, wherein the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg.

65. (a) the anti-PD-1 antibody is administered to the subject at a dose of about 200 mg; 63. The method of claim 62, wherein (b) after step (a), the anti-PD-1 antibody is administered to the subject at a dose of about 400 mg every 42 days.

66. 66. The method of any one of claims 1-65, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on one day of the 21-day treatment cycle.

67. 67. The method of any one of claims 1-66, wherein the anti-PD-1 antibody is administered to the subject by IV infusion on day 1 of each 21-day treatment cycle.

68. 68. The method of any one of claims 1-67, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over about 30 minutes on one day of the 21-day treatment cycle.

69. 67. The method of any one of claims 1-66, wherein the anti-PD-1 antibody is administered to the subject by IV infusion over about 30 minutes on day 1 of each 21-day treatment cycle.

70. 70. The method of any one of claims 1-69, wherein the subject exhibits a complete response after the treatment.

71. 70. The method of any one of claims 1-69, wherein the subject exhibits a partial response after the treatment.

72. 70. The method of any one of claims 1-69, wherein the subject experiences a complete or partial response after the treatment.

73. 70. The method of any one of claims 1-69, wherein the subject exhibits stable disease after the treatment.

74. 70. The method of any one of claims 1-69, wherein the subject has a duration of response of at least 6 months or about 6 months after the treatment.

75. 70. The method of any one of claims 1-69, wherein the subject has a duration of response of at least 12 months or about 12 months after the treatment.

76. 70. The method of any one of claims 1-69, wherein the subject has a duration of response of at least 24 months or about 24 months after the treatment.

77. 70. The method of any one of claims 1-69, wherein the subject has a duration of response of at least or about 27 months after the treatment.

78. 70. The method of any one of claims 1-69, wherein the subject has a progression-free survival of at least 6 months or about 6 months after said treatment.

79. 70. The method of any one of claims 1-69, wherein the subject has a progression-free survival of at least 8 months or about 8 months after said treatment.

80. 70. The method of any one of claims 1-69, wherein the subject has a progression-free survival of at least or about 12 months after said treatment.

81. 70. The method of any one of claims 1-69, wherein the subject has a progression-free survival of at least or about 20 months after said treatment.

82. 70. The method of any one of claims 1-69, wherein the subject has a progression-free survival of at least or about 29 months after said treatment.

83. 70. The method of any one of claims 1-69, wherein the subject has an overall survival of at least or about 22 months after said treatment.

84. 70. The method of any one of claims 1-69, wherein the subject has an overall survival of at least or about 27 months after said treatment.

85. 70. The method of any one of claims 1-69, wherein the subject has an overall survival of at least or about 30 months after said treatment.

86. 70. The method of any one of claims 1-69, wherein said subject has an overall survival after said treatment in the range of 19 to 25 months.

87. 70. The method of any one of claims 1-69, wherein said subject has an overall survival after said treatment in the range of 28 to 32 months.

88. 70. The method of any one of claims 1-69, wherein a population of subjects is treated with said method, and the percentage of subjects in said treated population that exhibit a complete response is at least or about 10%.

89. 70. The method of any one of claims 1-69, wherein a population of subjects is treated with said method, and the percentage of subjects in said treated population who exhibit a partial response is at least or about 54%.

90. 70. The method of any one of claims 1-69, wherein the population of subjects treated with said method has an objective response rate of at least or about 65% of the treated population.

91. 70. The method of any one of claims 1-69, wherein the population of subjects treated with said method has an objective response rate in the treated population ranging from 53% to 75%.

92. 70. The method of any one of claims 1-69, wherein a population of subjects is treated by said method and the percentage of subjects in said treated population that exhibit stable disease is at least or about 22%.

93. 70. The method of any one of claims 1-69, wherein the population of subjects treated with said method has a duration of response of at least 6 months or about 6 months for said treated population.

94. 70. The method of any one of claims 1-69, wherein the population of subjects treated with said method has a duration of response of at least or about 12 months for said treated population.

95. 70. The method of any one of claims 1-69, wherein the population of subjects treated with said method has a duration of response of at least or about 24 months for said treated population.

96. 70. The method of any one of claims 1-69, wherein the population of subjects treated with said method has a duration of response of at least or about 27 months for said treated population.

97. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a progression free survival of at least 6 months or about 6 months for said treated population.

98. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a progression free survival of at least or about 12 months for said treated population.

99. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a progression free survival of at least or about 20 months for said treated population.

100. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a progression free survival of at least or about 29 months for said treated population.

101. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a median overall survival of at least or about 22 months.

102. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a median overall survival of at least or about 27 months.

103. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has a median overall survival of at least or about 30 months.

104. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has an overall survival of said treated population in the range of 19 to 25 months.

105. 70. The method of any one of claims 1-69, wherein the population of subjects treated by said method has an overall survival of said treated population in the range of 30-32 months.

106. 73. The method of any one of claims 1-70 and 72, wherein the complete response rate is at least or about 10% for the population of subjects treated with the method.

107. 73. The method of any one of claims 1-69, 71, and 72, wherein the partial response rate is at least or about 54% for the population of subjects treated with the method.

108. 73. The method of any one of claims 1 to 72, wherein the objective response rate is at least or about 65% for the population of subjects treated with said method.

109. 73. The method of any one of claims 1 to 72, wherein the objective response rate is between 53% and 75% for the population of subjects treated with said method.

110. 74. The method of any one of claims 1-69 and 73, wherein the stable disease rate is at least or about 22% for the population of subjects treated with said method.

111. 80. The method of any one of claims 1-69 and 74-77, wherein the duration of response is at least 6 months or about 6 months for the population of subjects treated with said method.

112. 80. The method of any one of claims 1-69 and 74-77, wherein the duration of response is at least or about 12 months for the population of subjects treated with said method.

113. 78. The method of any one of claims 1-69 and 74-77, wherein the duration of response is at least or about 24 months for the population of subjects treated with said method.

114. 80. The method of any one of claims 1-69 and 74-77, wherein the duration of response is at least or about 27 months for the population of subjects treated with said method.

115. 83. The method of any one of claims 1-69 and 78-82, wherein the progression-free survival is at least 6 months or about 6 months for the population of subjects treated with said method.

116. 83. The method of any one of claims 1-69 and 78-82, wherein the progression-free survival is at least or about 12 months for a population of subjects treated with said method.

117. 83. The method of any one of claims 1-69 and 78-82, wherein the progression-free survival is at least or about 20 months for a population of subjects treated with said method.

118. 83. The method of any one of claims 1-69 and 78-82, wherein the progression-free survival is at least or about 29 months for a population of subjects treated with said method.

119. 88. The method of any one of claims 1-69 and 83-87, wherein the median overall survival is at least or about 22 months for a population of subjects treated with said method.

120. 88. The method of any one of claims 1-69 and 83-87, wherein the median overall survival is at least or about 27 months for a population of subjects treated with said method.

121. 88. The method of any one of claims 1-69 and 83-87, wherein the median overall survival is at least or about 30 months for a population of subjects treated with said method.

122. 81. The method of any one of claims 1-69, 79, and 80, wherein the overall survival is 19-25 months for the population of subjects treated with said method.

123. 81. The method of any one of claims 1-69, 79, and 80, wherein the overall survival is 30-32 months for the population of subjects treated with said method.

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