Combination Therapy for Use in the Treatment of Non-Small Cell Lung Cancer - Patent application

Abstract

The present disclosure generally relates to combination therapy comprising an anti-clusterin antibody or an antigen-binding fragment thereof and a taxane, and its use in treating subjects with non-small cell lung cancer (NSCLC). The combination therapy may be used to treat NSCLC patients, including those who have failed prior therapy comprising an immune checkpoint antibody, those with NSCLC having one or more lesions exhibiting low expression of programmed death-ligand 1 (PD-L1), those with NSCLC who have no evidence of PD-L1 expression, or those who are not eligible for or would not likely benefit from therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

Description

[Technical field]

[0001] The present disclosure relates generally to combination therapies comprising anti-clusterin antibodies or antigen-binding fragments thereof and taxanes, and their uses in treating subjects with non-small cell lung cancer (NSCLC). [Background technology]

[0002] The molecular mechanisms involved in metastatic cancer development are beginning to be elucidated with the identification of key regulators. Increasing evidence points to tumor cell epithelial-mesenchymal (EMT) as a key contributing process to metastatic evolution. The occurrence of EMT during tumor progression allows non-invasive and non-metastatic epithelial tumor cells to migrate from the primary tumor, invade surrounding tissues, enter the bloodstream, and eventually disseminate to and proliferate at secondary sites. In addition, epithelial cancer cells that undergo EMT adopt behaviors that are very similar to cancer stem cells (CSCs), including natural resistance to chemotherapy and immune evasion (Shibue et al., 2017; Terry et al., 2017).

[0003] Despite the short-term effectiveness of first- and second-line therapies such as chemotherapeutic agents and immune checkpoint inhibitors in cancer therapy, a high percentage of subjects become refractory to these therapies due to the resistance of tumor cells to anticancer drugs and the survival of tumor-initiating cells, two events that ultimately lead to increased metastasis and poor subject survival.

[0004] The mechanisms underlying resistance to immune checkpoint inhibitors may be diverse.However, it is generally accepted that checkpoint inhibitors work best against so-called immunologically hot tumors, which are tumors that are invaded by T cells, producing inflammatory tumors.In contrast, immunologically cold tumors respond poorly to immunotherapy, because for unknown reasons, these tumors are not recognized or do not induce strong immune responses, and therefore T cells do not infiltrate into the tumor or its microenvironment.

[0005] Patients who have received a prior first-line immune checkpoint inhibitor as a single agent are given platinum-based chemotherapy in the second line. Single-agent docetaxel can be administered as second- or third-line therapy after failure of immune checkpoint inhibition and platinum doublet chemotherapy administered simultaneously or sequentially.

[0006] Because most patients eventually progress after immunochemotherapy, and because docetaxel has very limited efficacy in this setting, new therapies are urgently needed. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2007 / 030930 [Patent Document 2] PCT / CA2006 / 001505 [Patent Document 3] WO2011 / 063523 [Patent Document 4] PCT / CA2010 / 0001882 [Non-patent literature]

[0008] [Non-Patent Document 1] Ojima et al., Expert Opin Ther Pat. 2016: 26(1): 1-20 [Non-Patent Document 2] Zeisber, M. and E. G. Neilson, The Journal of Clin Investig, 119:1429-1437 (2009) [Non-Patent Document 3] Antibody Engineering by Andrew C. R. Martin, Volume 2, Chapter 3 [Non-Patent Document 4] Eisenhauer, EA et al., European Journal of Cancer 45:228-247 (2009) [Non-Patent Document 5] De Petris, L et al. Anticancer Research November 2005, 25:4713-4717 Summary of the Invention

[0009] The present disclosure relates to combination therapies comprising an anti-clusterin antibody, or an antigen-binding fragment thereof, and a taxane, such as docetaxel.

[0010] The present disclosure also relates to methods of treating lung cancer in a subject in need thereof by administering a combination therapy comprising an anti-clusterin antibody, or antigen-binding fragment thereof, and a taxane, such as docetaxel.

[0011] The combination therapy of the present disclosure may be used to treat patients with lung cancer (e.g., lung cancer), and more particularly may provide clinical benefit to patients with non-small cell lung cancer who have failed prior treatment with anti-programmed death 1 (anti-PD-1) or anti-programmed death-ligand 1 (PD-L1) immune checkpoint antibodies and platinum-containing doublet therapy.

[0012] In some embodiments, the combination therapy of the present disclosure is used to treat lung cancer in a subject in need thereof. In certain embodiments, the combination therapy is used to treat non-small cell lung cancer in a subject in need thereof. In another specific embodiment, the combination therapy is used to treat metastatic non-small cell lung cancer in a subject in need thereof.

[0013] In some embodiments, a therapeutically effective combination therapy is administered to a subject in need thereof.

[0014] Administration of the combination therapy results in a reduction in size or stabilization of size of target lesions for most patients during treatment. Complete regression of non-target lesions was also observed in one patient. Surprisingly, clinical benefit was observable after only two cycles of treatment, and in some cases lasted for several weeks.

[0015] Furthermore, current data suggest increased progression-free survival compared with single-agent docetaxel in the same patient population.

[0016] The combination therapy of the present application provides an alternative for NSCLC patients who have failed prior therapy, including immune checkpoint antibodies. Furthermore, evidence of partial response (defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria) has been observed in four patients with tumors with a PD-L1 tumor proportion score (TPS) of ≦15%, including one patient with a KRAS mutation. Evidence of stable disease defined by RECIST 1.1 has also been observed in NSCLC with tumors harboring KRAS mutations.

[0017] The combination therapy of the present disclosure may be an alternative for NSCLC patients who are not eligible for or would likely not benefit from treatments involving immune checkpoint antibodies.

[0018] Additionally, the combination therapy of the present disclosure may be an alternative to immune checkpoint antibody monotherapy or combination treatment for NSCLC patients whose tumors have no evidence of PD-L1 expression or have low expression of PD-L1.

[0019] Although the combination therapy of the present disclosure includes docetaxel, another taxane may be selected by one of skill in the art, such as a physician, investigator, etc. Thus, exemplary embodiments of taxanes include docetaxel, paclitaxel, and derivatives or analogs, including, by way of example and not limitation, Abraxane®, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, and others described in Ojima et al., Expert Opin Ther Pat. 2016: 26(1): 1-20, the entire contents of which are incorporated herein by reference.

[0020] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is selected from those that inhibit epithelial to mesenchymal transition in cancer cells.

[0021] Anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure can include, for example, anti-clusterin antibodies or antigen-binding fragments thereof capable of binding to the C-terminal portion of the β-subunit of human clusterin.

[0022] In some embodiments, an anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure may include, for example, an anti-clusterin antibody or antigen-binding fragment thereof capable of binding to an epitope contained at or within amino acids 421 and 443 of the C-terminal portion of the β-subunit of human clusterin.

[0023] An anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure may comprise, for example, a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0024] An anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure may comprise, for example, a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2), and SEQ ID NO:6 (CDRH3).

[0025] An anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure may comprise, for example, a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2), and SEQ ID NO:9 (CDRH3).

[0026] In another example, an anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure may comprise a light chain variable region having the amino acid sequence set forth in SEQ ID NO:12, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:13.

[0027] In yet another example, an anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure may comprise a light chain having the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain having the amino acid sequence set forth in SEQ ID NO:15.

[0028] Other exemplary embodiments of the anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure include those that can compete with an antibody or antigen-binding fragment thereof comprising a light chain variable region set forth in SEQ ID NO:12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO:13.

[0029] In some embodiments, the combination therapy of the present disclosure may be used to treat a subject with lung cancer (eg, lung cancer).

[0030] More particularly, the combination therapy of the present disclosure may be used to treat subjects with non-small cell lung cancer.

[0031] In some embodiments, the non-small cell lung cancer is metastatic non-small cell lung cancer.

[0032] In some embodiments, the metastatic non-small cell lung cancer is stage III non-small cell lung cancer.

[0033] In some embodiments, the metastatic non-small cell lung cancer is stage IV non-small cell lung cancer.

[0034] In some embodiments, the non-small cell lung cancer is an adenocarcinoma.

[0035] In some embodiments, the non-small cell lung cancer is squamous cell lung cancer.

[0036] In some embodiments, the non-small cell lung cancer is large cell carcinoma.

[0037] In some embodiments, the non-small cell lung cancer is adenosquamous carcinoma.

[0038] In some embodiments, the non-small cell lung cancer (eg, metastatic non-small cell lung cancer) is characterized by having a KRAS mutation.

[0039] Thus, in one embodiment thereof, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and a taxane for use in treating a subject having non-small cell lung cancer, such as metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is as defined herein.

[0040] In some embodiments, the combination therapy of the present disclosure may be used to obtain clinical benefit in subjects with non-small cell lung cancer.

[0041] In other embodiments, the combination therapy of the present disclosure may be used to obtain clinical benefit in subjects with metastatic non-small cell lung cancer.

[0042] Thus, the combination therapy includes an anti-clusterin antibody or antigen-binding fragment thereof and a taxane, for use in obtaining a clinical benefit in a subject having non-small cell lung cancer, such as metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is as defined herein.

[0043] In certain embodiments, the combination therapy is administered in therapeutically effective dosages.

[0044] In certain embodiments, the combination therapy is administered at a safe dosage.

[0045] In certain embodiments, the combination therapy is administered at a dosage that is tolerated.

[0046] In certain embodiments, the combination therapy is administered according to a therapeutically effective dosing schedule.

[0047] In certain embodiments, the combination therapy is administered in any dosing schedule that is tolerated.

[0048] In certain embodiments, the combination therapy is administered according to any dosing schedule that is safe.

[0049] In certain embodiments, the combination therapy is administered according to a therapeutically effective treatment regimen.

[0050] In certain embodiments, the combination therapy is administered according to a treatment regimen that is safe.

[0051] In certain embodiments, the combination therapy is administered in a tolerated therapeutic regimen.

[0052] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 3 mg / kg to about 20 mg / kg.

[0053] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is formulated as an intravenous infusion.

[0054] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is formulated as an injectable solution at a concentration of approximately 10 mg / mL.

[0055] In some embodiments, the taxane may be, by way of example and not limitation, approximately 60 mg / m 2 ~100mg / m 2 , approximately 50 mg / m 2 ~80mg / m 2 , approximately 50 mg / m 2 ~75mg / m 2 , approximately 60 mg / m 2 ~75mg / m 2 etc., approximately 50 mg / m 2 ~ approx. 100 mg / m 2 The compound is formulated for administration at a dose of

[0056] In some embodiments, the taxane is docetaxel, and by way of example and not limitation, the dose is approximately 60 mg / m 2 ~100mg / m 2 , approximately 50 mg / m 2 ~80mg / m 2 , approximately 50 mg / m 2 ~75mg / m 2 , approximately 60 mg / m 2 ~75mg / m 2 etc., approximately 50 mg / m 2 ~ approx. 100 mg / m 2 The compound is formulated for administration at a dose of

[0057] In some embodiments, docetaxel is formulated as an intravenous infusion.

[0058] In some embodiments, docetaxel is formulated as an injectable solution at a concentration of about 10 mg / mL to about 40 mg / mL.

[0059] In an exemplary embodiment, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The compound is formulated for administration at a dose of

[0060] In another exemplary embodiment, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The compound is formulated for administration at a dose of

[0061] In yet another exemplary embodiment, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 12 mg / kg and comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The compound is formulated for administration at a dose of

[0062] In a further exemplary embodiment, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in obtaining a clinical benefit in a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The compound is formulated for administration at a dose of

[0063] In another exemplary embodiment, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in obtaining a clinical benefit in a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2It is formulated for administration at a dose of

[0064] In a further exemplary embodiment, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 12 mg / kg and comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 It is formulated for administration at a dose of

[0065] In a further exemplary embodiment, the combination therapy is for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, the combination therapy comprising administration of an anti-clusterin antibody at a dose of about 3 mg / kg to about 20 mg / kg once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, and administration of an anti-clusterin antibody at a dose of about 50 mg / m once every 2 to 3 weeks. 2 ~100mg / m 2 and for at least two cycles of treatment comprising administration of a taxane at a dose of 0.01 mg / kg / day, and the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0066] In yet a further exemplary embodiment, the combination therapy is for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, the combination therapy comprising administration of an anti-clusterin antibody at a dose of about 12 mg / kg once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, and administration of an anti-clusterin antibody at a dose of about 75 mg / m once every 3 weeks. 2and for at least two cycles of treatment comprising administration of docetaxel at a dose of SEQ ID NO: 13, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0067] In yet a further exemplary embodiment, the combination therapy is for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, the combination therapy comprising administration of an anti-clusterin antibody at a dose of about 12 mg / kg once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, and administration of an anti-clusterin antibody at a dose of about 50 mg / m once every 2 weeks. 2 and for at least two cycles of treatment comprising administration of docetaxel at a dose of SEQ ID NO: 13, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0068] In some embodiments, clinical benefit is defined by RECIST 1.1 guidelines.

[0069] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 6 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 6 weeks after the initial determination of response to treatment.

[0070] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 12 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 12 weeks after an initial determination of response to treatment.

[0071] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 18 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 18 weeks after the initial determination of response to treatment.

[0072] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 24 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 24 weeks after the initial determination of response to treatment.

[0073] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 30 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 30 weeks after an initial determination of response to treatment.

[0074] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 36 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 36 weeks after the first determination of response to treatment. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 42 weeks after the first determination of response to treatment. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 42 weeks after the first determination of response to treatment.

[0075] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 48 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 48 weeks after the initial determination of response to treatment.

[0076] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 54 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 54 weeks after the initial determination of response to treatment.

[0077] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 60 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 60 weeks after the initial determination of response to treatment.

[0078] In some embodiments, the combination therapy is used to obtain clinical benefit for at least 66 weeks. In certain embodiments, the combination therapy is used to obtain clinical benefit for at least 66 weeks after the initial determination of response to treatment.

[0079] According to the present disclosure, the subject matter in need is that described herein.

[0080] Therefore, the present disclosure involves methods involving administration of the combination therapy to a subject in need thereof.

[0081] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once per week.

[0082] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every two weeks.

[0083] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every three weeks.

[0084] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every four weeks.

[0085] According to the present disclosure, docetaxel is administered once per week.

[0086] According to the present disclosure, docetaxel is administered once every two weeks.

[0087] According to the present disclosure, docetaxel is administered once every three weeks.

[0088] According to the present disclosure, docetaxel is administered once every four weeks.

[0089] The frequency of treatment (i.e., once a week, every 2 weeks, every 3 weeks, every 4 weeks, etc.) is not strict and allows for some variation. For example, the physician may decide to administer a dose earlier than scheduled, or to delay a dose by a few days or longer. Similarly, one or more doses may be skipped without affecting treatment.

[0090] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg.

[0091] In some embodiments, the taxane may be, by way of example and not limitation, approximately 60 mg / m 2 ~ approx. 100 mg / m 2 , approximately 50 mg / m 2 ~ approx. 80 mg / m 2 , approximately 50 mg / m 2 ~ approx. 75 mg / m 2 , approximately 60 mg / m 2 ~ approx. 75 mg / m 2 etc., approximately 50 mg / m 2 ~ approx. 100 mg / m 2 is administered at a dose of

[0092] In some embodiments, the taxane is docetaxel, and by way of example and not limitation, the dose is approximately 60 mg / m 2 ~ approx. 100 mg / m 2 , approximately 50 mg / m 2 ~ approx. 80 mg / m 2 , approximately 50 mg / m 2 ~ approx. 75 mg / m 2 , approximately 60 mg / m 2 ~ approx. 75 mg / m 2 etc., approximately 50 mg / m 2 ~ approx. 100 mg / m 2 is administered at a dose of

[0093] In some embodiments, the taxane is docetaxel, and by way of example and not limitation, the dose is 60 mg / m 2 ~100mg / m 2 , 50 mg / m 2 ~80mg / m 2 , 50 mg / m 2 ~75mg / m 2 , 60 mg / m 2 ~75mg / m 2 etc., 50mg / m 2 ~100mg / m 2 is administered at a dose of

[0094] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 12 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0095] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 12 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0096] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 9 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0097] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 9 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0098] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 6 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0099] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 6 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0100] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 3 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0101] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 3 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0102] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 12 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every three weeks. 2 is administered at a dose of

[0103] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 9 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every three weeks. 2 is administered at a dose of

[0104] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 6 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every three weeks. 2 is administered at a dose of

[0105] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 3 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every three weeks. 2 is administered at a dose of

[0106] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 12 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every two weeks. 2 is administered at a dose of

[0107] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 9 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every two weeks. 2 is administered at a dose of

[0108] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 6 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every two weeks. 2 is administered at a dose of

[0109] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 3 mg / kg once weekly (once per week), once every two weeks, or once every three weeks, and docetaxel is administered at a dose of 50 mg / m once every two weeks. 2 is administered at a dose of

[0110] In some embodiments, the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel may be administered on the same day.

[0111] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel may be administered on the same day and separately.

[0112] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel may be administered by injection.

[0113] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered over the course of a treatment period.

[0114] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered with each cycle of treatment.

[0115] Thus, the present disclosure relates to methods of treating a subject with non-small cell lung cancer using the combination therapies disclosed herein.

[0116] The present disclosure also relates to methods of treating a subject with metastatic non-small cell lung cancer using the combination therapies disclosed herein.

[0117] Accordingly, in certain aspects, the disclosure provides a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m2 The method further comprises administering the compound in a dose of

[0118] In an exemplary embodiment, a method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0119] In an exemplary embodiment, a method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0120] In certain embodiments, the disclosure provides for administration of anti-clusterin antibodies at a dose of approximately 12 mg / kg once per week, once every two weeks, once every three weeks, or once every four weeks, and administration of approximately 50 mg / m once every two to three weeks. 2 ~ approx. 75 mg / m 2and administering a combination therapy for at least one cycle of treatment comprising administration of docetaxel at a dose of

[0121] The present disclosure also relates to methods of treating a subject with non-small cell lung cancer with the combination therapies disclosed herein to obtain and / or maintain clinical benefit.

[0122] The present disclosure further relates to methods of treating a subject with metastatic non-small cell lung cancer with the combination therapies disclosed herein to obtain and / or maintain clinical benefit.

[0123] Accordingly, in certain aspects, the disclosure provides a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The method further comprises administering the compound in a dose of

[0124] In an exemplary embodiment, a method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0125] In an exemplary embodiment, a method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0126] The present disclosure also relates to methods of obtaining clinical benefit in subjects with non-small cell lung cancer using the combination therapies disclosed herein.

[0127] The present disclosure further relates to methods of obtaining clinical benefit in subjects with metastatic non-small cell lung cancer using the combination therapies disclosed herein.

[0128] Exemplary embodiments of clinical benefit include, but are not limited to, a reduction in size of a lesion, a stabilization of size of a lesion, regression of a lesion, a complete response (CR) per RECIST 1.1 guidelines, a partial response (PR) per RECIST 1.1 guidelines, a stable disease (SD) per RECIST 1.1 guidelines, an improvement in symptoms associated with the cancer, and / or a reduction or elimination of metabolic activity in a lesion, etc.

[0129] In some cases, a reduction or stabilization in size, or regression, may be observed in the target lesion.

[0130] In some cases, a reduction or stabilization in size, or regression, may be observed in non-target lesions.

[0131] Accordingly, in certain aspects, the disclosure provides a method of obtaining a clinical benefit in a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The method further comprises administering the compound in a dose of

[0132] In an exemplary embodiment, a method is provided for obtaining a clinical benefit in a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0133] In an exemplary embodiment, a method is provided for obtaining a clinical benefit in a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0134] According to the present disclosure, the combination therapy is administered in dosages sufficient to provide a clinical benefit.

[0135] According to the present disclosure, the combination therapy is administered for a period of time sufficient to provide a clinical benefit.

[0136] According to the present disclosure, the combination therapy is administered according to a treatment schedule sufficient to provide a clinical benefit.

[0137] According to the present disclosure, the combination therapy is administered according to a therapeutic regimen sufficient to provide a clinical benefit.

[0138] In an exemplary embodiment, the combination therapy is administered in one or more cycles of treatment, including administration of the anti-clusterin antibody or antigen-binding fragment thereof once per week, once every two weeks, or once every three weeks, and administration of docetaxel once every three weeks. It should be understood that the interval between treatments can be varied without significantly altering the efficacy of the combination therapy.

[0139] In certain embodiments, the combination therapy is administered for at least two cycles of treatment.

[0140] In certain embodiments, the combination therapy is administered for more than two cycles of treatment.

[0141] The disclosure provides that each cycle of treatment comprises administration of an anti-clusterin antibody at a dose of about 3 mg / kg to about 20 mg / kg once per week, once every two weeks, or once every three weeks, and administration of about 50 mg / m once every two to three weeks. 2 ~100mg / m 2 Also provided is a method of obtaining a clinical benefit to a subject with non-small cell lung cancer in a method of treatment comprising administering a combination therapy for at least two cycles of treatment, the combination therapy comprising administration of a taxane at a dose of

[0142] Thus, in other embodiments, the disclosure provides that each cycle of treatment comprises administration of an anti-clusterin antibody at a dose of approximately 12 mg / kg once per week, once every two weeks, or once every three weeks, and administration of approximately 75 mg / m 2 The present invention provides a method of obtaining a clinical benefit to a subject with non-small cell lung cancer in a method of treatment comprising administering a combination therapy for at least two cycles of treatment, including administration of docetaxel at a dose of

[0143] Thus, in other embodiments, the disclosure provides that each cycle of treatment comprises administration of an anti-clusterin antibody at a dose of approximately 12 mg / kg once per week, once every two weeks, or once every three weeks, and administration of an anti-clusterin antibody at a dose of approximately 50 mg / m once every two weeks. 2The present invention provides a method of obtaining a clinical benefit to a subject with non-small cell lung cancer in a method of treatment comprising administering a combination therapy for at least two cycles of treatment, including administration of docetaxel at a dose of

[0144] In some embodiments, the clinical benefit is regression of a target lesion.

[0145] In some embodiments, the clinical benefit is a reduction in the size of the target lesion.

[0146] In some embodiments, the clinical benefit is a stabilization of the size of the target lesion.

[0147] In some embodiments, the clinical benefit is a reduction in the number of tumor cells in the target lesion.

[0148] In other embodiments, the clinical benefit is regression of non-target lesions.

[0149] In yet other embodiments, the clinical benefit is a reduction in the size of non-target lesions.

[0150] In a further embodiment, the clinical benefit is a stabilization of size of non-target lesions.

[0151] In yet a further embodiment, the clinical benefit is a reduction in the number of tumor cells in non-target lesions.

[0152] In some embodiments, clinical benefit is defined by RECIST 1.1 guidelines.

[0153] In some embodiments, the clinical benefit may be qualitative, such as, for example, improved quality of life (eg, health-related quality of life).

[0154] It should be understood herein that the clinical benefit may last for some period of time. The duration of the clinical benefit may vary from subject to subject.

[0155] According to the present disclosure, the combination therapy may reduce tumor burden.

[0156] It should be understood herein that tumor burden can be assessed by measuring the size of one or more tumor lesions. In other embodiments, tumor burden can be determined by assessing tumor markers in solid biopsies, liquid biopsies, blood samples, serum samples, urine samples, etc. For example, tumor burden is assessed by detecting circulating tumor cells (CTCs). In another example, tumor burden is assessed by detecting circulating tumor DNA.

[0157] In certain embodiments, the method provides a clinical benefit for at least 6 weeks after the initial determination of response to treatment.

[0158] In certain embodiments, the method provides a clinical benefit for at least 12 weeks after an initial determination of response to treatment.

[0159] In certain embodiments, the method provides a clinical benefit for at least 18 weeks after the initial determination of response to treatment.

[0160] In certain embodiments, the methods provide a clinical benefit for at least 24 weeks after an initial determination of response to treatment.

[0161] In certain embodiments, the method provides a clinical benefit for at least 30 weeks after an initial determination of response to treatment.

[0162] In certain embodiments, the method provides a clinical benefit for at least 36 weeks after the initial determination of response to treatment.

[0163] In certain embodiments, the method provides a clinical benefit for at least 42 weeks after the initial determination of response to treatment.

[0164] In certain embodiments, the method provides a clinical benefit for at least 48 weeks after the initial determination of response to treatment.

[0165] In certain embodiments, the method provides a clinical benefit for at least 54 weeks after the initial determination of response to treatment.

[0166] In certain embodiments, the methods provide a clinical benefit for at least 60 weeks after an initial determination of response to treatment.

[0167] In certain embodiments, the methods provide a clinical benefit for at least 66 weeks after an initial determination of response to treatment.

[0168] Once the physician prescribes the combination treatment, the subject's health and condition are monitored. Monitoring may include physical examination, interviewing the subject regarding their quality of life, obtaining biological samples, and / or performing scans to monitor the progression of lung cancer and / or the presence of metastases. Treatment is continued as long as the subject experiences clinical benefit (qualitative or quantitative). Once tumor progression is observed, treatment may be discontinued.

[0169] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is used as an IV infusion.

[0170] In some embodiments, docetaxel is used as an IV infusion.

[0171] In certain embodiments, the combination therapy may promote the infiltration of immune cells into the tumor microenvironment of one or more lesions (target and / or non-target lesions).

[0172] In certain embodiments, the combination therapy may promote lymphocyte infiltration into the tumor microenvironment of one or more lesions (target and / or non-target lesions).

[0173] In certain embodiments, the combination therapy may promote infiltration of T cells into the tumor microenvironment of one or more lesions (target and / or non-target lesions).

[0174] According to the present disclosure, the methods may result in tumors or lesions that are more susceptible to treatment with immunotherapy.

[0175] Therefore, the methods of the present disclosure can also include administering an immunotherapy following the combination therapy disclosed herein.

[0176] In some embodiments, the immunotherapy comprises cellular immunotherapy (CAR-T, TIL, etc.).

[0177] In some embodiments, the immunotherapy comprises an immune checkpoint inhibitor.

[0178] Accordingly, the present disclosure relates to methods of treating NSCLC, such as metastatic NSCLC, by promoting the infiltration of immune cells into one or more lesions.

[0179] In one embodiment, the disclosure encompasses a method of treating NSCLC, such as metastatic NSCLC, by promoting the infiltration of immune cells into one or more lesions that have low expression of PD-L1 or no evidence of PD-L1 expression.

[0180] According to the present disclosure, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 Tumor Proportion Score (TPS) of such lesion is, for example, ≦15%.

[0181] More particularly, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 TPS of such lesion is, for example, <5%.

[0182] More specifically, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 TPS of such lesion is, for example, ≦1%.

[0183] Even more specifically, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 TPS of such lesion is, for example, <1%.

[0184] According to the present disclosure, a lesion is characterized as not having evidence of PD-L1 expression if such lesion has a PD-L1 TPS of 0% or if PD-L1 expression is undetectable.

[0185] In certain embodiments, the combination therapy may facilitate a reduction in the number of tumor cells in one or more lesions.

[0186] In an exemplary embodiment, the combination therapy may result in a decrease in the size of the lesion.

[0187] It should be understood herein that a lesion is considered to be reduced in size if a measurement indicates that it is smaller than a previous measurement or than a baseline measurement.

[0188] In some exemplary embodiments, administration of the combination therapy may result in a reduction in lesion size of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%.

[0189] In another exemplary embodiment, the combination therapy may result in stabilization of lesion size.

[0190] In yet another exemplary embodiment, the combination therapy may result in less than a 20% increase in size of the lesion. It should also be understood herein that an increase in size of the lesion of less than approximately 20% as compared to a previous or baseline measurement is considered stabilization of the growth of the lesion.

[0191] In yet another exemplary embodiment, the combination therapy may result in regression of the lesion. In some cases, the regression may be complete. In other cases, the regression may be partial.

[0192] In some embodiments, the combination therapy may result in a stabilization of lesion size.

[0193] In some cases, the size of the lesion may increase or remain stable, while the number of tumor cells in the lesion decreases. For example, tumor cells may be replaced by fibrous tissue and inflammatory cells, so that no decrease in the size of the lesion is detected. Thus, in some cases, the number of live tumor cells may decrease and the number of immune cells may increase, thereby resulting in pseudoprogression.

[0194] Therefore, in another exemplary embodiment, the combination therapy may result in a reduction in the number of tumor cells in the lesion.

[0195] It should be understood herein that the size of the lesion may be assessed by a number of methods, including, by way of example and not limitation, a CT scan.

[0196] In further exemplary embodiments, the combination therapy may result in the reduction or elimination of metabolic activity in the lesion. It should be understood herein that metabolic activity of the lesion may be assessed by a number of methods, including, by way of example and not limitation, by positron emission tomography (PET) scanning.

[0197] It should also be understood herein that an increase in the size of a lesion coupled with a decrease in the number of tumor cells within that lesion is also considered stabilization of lesion growth.

[0198] It should also be understood herein that a decrease in the metabolic activity of a lesion (with or without growth) is also considered a stabilization of lesion growth.

[0199] In still further exemplary embodiments, the combination therapy may result in amelioration of symptoms associated with lung cancer.

[0200] In another embodiment, administration of the combination therapy may result in a complete response (CR) according to RECIST 1.1 guidelines.

[0201] In additional embodiments, administration of the combination therapy may result in a partial response (PR) according to RECIST 1.1 guidelines.

[0202] In yet another embodiment, administration of the combination therapy may result in stable disease (SD) according to RECIST 1.1 guidelines.

[0203] According to the present disclosure, combination therapy may be used or is for use so long as a clinical benefit is observed.

[0204] According to the present disclosure, the combination therapy is used or intended for use until tumor progression is observed.

[0205] According to the present disclosure, combination therapy is used or intended for use until unmanageable toxicity occurs.

[0206] In some embodiments, administration of the anti-clusterin antibody or antigen-binding fragment thereof can be maintained following cessation of combination therapy.

[0207] In some embodiments, administration of the anti-clusterin antibody or antigen-binding fragment thereof can be maintained after the appearance of clinical benefit.

[0208] It is to be understood herein that clinical benefit may be demonstrated by assessing tumor biomarkers.

[0209] According to the present disclosure, the combination therapy is for use in the subjects described herein.

[0210] According to the present disclosure, the subject is a human subject.

[0211] According to the present disclosure, the subject is an adult (ie, ≧18 years of age).

[0212] In some embodiments, the subject has or is selected for having NSCLC.

[0213] In some embodiments, the subject has, or is selected as having, metastatic NSCLC.

[0214] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC, that would not be eligible for or would likely not benefit from treatment involving an immune checkpoint antibody.

[0215] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has progressed following treatment comprising an immune checkpoint antibody.

[0216] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has progressed following chemotherapy.

[0217] In other embodiments, the subject has or is selected as having NSCLC, such as metastatic NSCLC that has failed prior treatment with an immune checkpoint antibody and chemotherapy combination treatment.

[0218] In other embodiments, the subject has or is selected as having NSCLC, such as metastatic NSCLC that has failed prior treatment with an immune checkpoint antibody and a platinum-containing doublet therapy.

[0219] In additional embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0220] According to the present disclosure, the doublet therapies can be provided simultaneously.

[0221] According to the present disclosure, doublet therapies may be provided sequentially.

[0222] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody.

[0223] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with a PD-L1 immune checkpoint antibody.

[0224] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody.

[0225] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0226] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0227] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0228] In some embodiments, the subject has or is selected as having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab, alone or in combination with platinum-based chemotherapy.

[0229] In some embodiments, the subject has, or is selected as having, NSCLC, such as metastatic NSCLC that has failed prior treatment with pembrolizumab alone or in combination with platinum-based chemotherapy.

[0230] In some embodiments, the subject has, or is selected as having, a PD-L1 Tumor Proportion Score (TPS) of ≧50%.

[0231] In some embodiments, the subject has, or is selected as having, a PD-L1 Tumor Proportion Score (TPS) of <50%.

[0232] In some embodiments, the subject has, or is selected as having, a PD-L1 Tumor Proportion Score (TPS) of 1-49%.

[0233] In some embodiments, the subject has, or is selected as having, a PD-L1 tumor proportion score of <1%.

[0234] In some embodiments, the subject has or is selected to have a tumor with poor immune cell infiltration. The level of immune cell infiltration can be determined by a trained pathologist or scientist. The level of immune cell infiltration can be determined by imaging using computer-based quantification of tumor biopsies.

[0235] In some embodiments, the subject has or is selected to have one or more lesions that have or show signs of an EMT signature. The EMT signature of a tumor can be determined by a trained pathologist or scientist. The EMT signature of a tumor can be determined by imaging using computer-based quantification of the tumor or tumor biopsy.

[0236] In some embodiments, the EMT signature may be assessed by one or more EMT biomarkers. For example, the EMT signature may be associated with the acquisition of mesenchymal markers and / or the attenuation of epithelial markers, which are particularly associated with EMT type 3 (see Zeisber, M. and E. G. Neilson, The Journal of Clin Investig, 119:1429-1437 (2009)).

[0237] EMT biomarkers include, for example, cell surface proteins such as N-cadherin, OB-cadherin, α5β1 integrin, αVβ6 integrin, syndecan-1, cytoskeletal markers such as FSP1, α-SMA, vimentin, B-catenin, α1(I) collagen, α1(III) collagen, fibronectin, laminin 5, transcription factors such as SNAIL1, SNAIL2, ZEB1, CBF-A / KAP-1 complex, Twist, LEF-1, Ets-1, FOXC2, Goosecoid, and microRNAs such as miR10b, miR-21 (acquired markers), E-cadherin, ZO-1, cytokeratin, α1(IV) collagen, laminin-1 (attenuation markers) (Zeisber, M. and E. G. Neilson, The Journal of Clin Investig, 119:1429-1437). (2009).

[0238] According to the present disclosure, a subject in need has a tumor that expresses or secretes clusterin.

[0239] In some embodiments, the subject has, or is selected as having, stage III NSCLC.

[0240] In some embodiments, the subject has, or is selected as having, stage IV NSCLC.

[0241] In some embodiments, the subject is not receiving any concurrent anti-cancer therapy other than the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel.

[0242] In some embodiments, the subject is not or is selected to not be immunosuppressed.

[0243] According to the present disclosure, subjects are selected because they have not or will not have received immunosuppressive medication within 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days prior to treatment.

[0244] In some embodiments, subjects are selected as not having received or will not have received immunosuppressive drugs within 7 days prior to treatment.

[0245] According to the present disclosure, subjects are selected because they have not undergone or have not received prior treatment with docetaxel.

[0246] The methods of the disclosure include administering one or more cycles of treatment to a subject in need.

[0247] In some embodiments, the method includes administering at least one initial cycle of treatment and at least one subsequent cycle of treatment to a subject in need. The initial cycle of treatment and the subsequent cycle of treatment can be the same or different. For example, the initial cycle of treatment can include a given dose of an anti-clusterin antibody or an antigen-binding fragment thereof, while the subsequent cycle of treatment can include a different dose of an anti-clusterin antibody or an antigen-binding fragment thereof. In another example, the initial cycle of treatment can include a given dose of docetaxel, while the subsequent cycle of treatment can include a different dose of docetaxel. In yet another example, the time interval between the anti-clusterin antibody or an antigen-binding fragment thereof and docetaxel can be different in the initial cycle of treatment and in the subsequent cycle of treatment. In some embodiments, the initial cycle of treatment includes at least one dose of an anti-clusterin antibody or an antigen-binding fragment thereof, and at least one dose of a taxane, such as docetaxel. In an exemplary embodiment, the first cycle of treatment includes two doses of an anti-clusterin antibody or antigen-binding fragment thereof, and one dose of a taxane, such as docetaxel. In an exemplary embodiment, the first cycle of treatment includes three doses of an anti-clusterin antibody or antigen-binding fragment thereof, and one dose of a taxane, such as docetaxel. In an exemplary embodiment, the first cycle of treatment includes four doses of an anti-clusterin antibody or antigen-binding fragment thereof, and one dose of a taxane, such as docetaxel.

[0248] In some embodiments, the subsequent cycle of treatment includes at least one dose of an anti-clusterin antibody or antigen-binding fragment thereof, and at least one dose of a taxane, such as docetaxel. In an exemplary embodiment, the subsequent cycle of treatment includes two doses of an anti-clusterin antibody or antigen-binding fragment thereof, and one dose of a taxane, such as docetaxel. In an exemplary embodiment, the subsequent cycle of treatment includes three doses of an anti-clusterin antibody or antigen-binding fragment thereof, and one dose of a taxane, such as docetaxel. In an exemplary embodiment, the subsequent cycle of treatment includes four doses of an anti-clusterin antibody or antigen-binding fragment thereof, and one dose of a taxane, such as docetaxel.

[0249] In some embodiments, the initial cycle of treatment and each subsequent cycle of treatment comprises at least one dose of an anti-clusterin antibody, or antigen-binding fragment thereof, and at least one dose of docetaxel.

[0250] In some embodiments, one cycle of treatment (initial cycle of treatment and / or subsequent cycles of treatment) is about 21 days. In other embodiments, one cycle of treatment is more than 21 days, such as, for example, about one month or more (e.g., about 28-31 days). In other embodiments, one cycle of treatment is less than 21 days, such as, for example, about two weeks (e.g., about 13-16 days).

[0251] According to the present disclosure, a subject is treated for one or more cycles of treatment.

[0252] In some embodiments, one cycle of treatment may last approximately 21 days and may include administration of the anti-clusterin antibody or antigen-binding fragment thereof approximately once every 3 weeks, and administration of docetaxel approximately once every 3 weeks. In such cases, one cycle of treatment would therefore include administration of one dose of the anti-clusterin antibody or antigen-binding fragment thereof, and one dose of docetaxel approximately every 21 days.

[0253] In some embodiments, one cycle of treatment may last approximately 14 days and may include administration of the anti-clusterin antibody or antigen-binding fragment thereof approximately once every two weeks, and administration of docetaxel approximately once every two weeks. In such cases, one cycle of treatment would therefore include administration of one dose of the anti-clusterin antibody or antigen-binding fragment thereof, and one dose of docetaxel approximately every 14 days.

[0254] In some embodiments, one cycle of treatment may last approximately one month and may include approximately one administration of the anti-clusterin antibody or antigen-binding fragment thereof per month, and approximately one administration of docetaxel per month. In such cases, one cycle of treatment would therefore include approximately one dose of the anti-clusterin antibody or antigen-binding fragment thereof, and one dose of docetaxel per month.

[0255] Using the same dosing interval for both drugs may be more convenient and beneficial for compliance, since both drugs may be administered on the same day.

[0256] In some embodiments, one cycle of treatment lasts approximately 21 days and consists of administering the anti-clusterin antibody or antigen-binding fragment thereof once a week and administering docetaxel once every three weeks.

[0257] In some embodiments, the initial cycle of treatment and / or subsequent cycles of treatment each independently comprise administering an anti-clusterin antibody or antigen-binding fragment thereof once per week, once every two weeks, or once every three weeks at a dose of about 3 mg / kg to about 20 mg / kg, and administering an anti-clusterin antibody or antigen-binding fragment thereof once per two weeks or once every three weeks at a dose of about 50 mg / kg to about 50 mg / kg. 2 ~100mg / m 2 The method may include administration of docetaxel at a dose of:

[0258] In an exemplary embodiment, the method comprises administering approximately 75 mg / m once every three weeks. 2and administering an anti-clusterin antibody or antigen-binding fragment thereof once per week, once every two weeks, or once every three weeks.

[0259] In another exemplary embodiment, the method comprises administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks. 2 The method includes administering docetaxel at a dose of

[0260] In yet another exemplary embodiment, the method comprises administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 12 mg / kg once every three weeks, and administering about 75 mg / m once every three weeks. 2 The method includes administering docetaxel at a dose of

[0261] In some embodiments, the method of the present disclosure comprises: a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once per week, and administering about 50 mg / m once every three weeks. 2 ~100mg / m 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once every three weeks, and administering about 50 mg / m once every three weeks. 2 ~100mg / m 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of to a subject in need thereof.

[0262] In another embodiment, the method of the present disclosure comprises: a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks. 2at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once every three weeks, and administering about 75 mg / m once every three weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of to a subject in need thereof.

[0263] In yet another embodiment, the method of the present disclosure comprises: a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 12 mg / kg once every three weeks, and administering about 75 mg / m once every three weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of to a subject in need thereof.

[0264] In an exemplary embodiment, the method comprises administering approximately 50 mg / m once every two weeks. 2 and administering an anti-clusterin antibody or antigen-binding fragment thereof once per week, once every two weeks, or once every three weeks.

[0265] In another exemplary embodiment, the method comprises administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every two weeks. 2 The method includes administering docetaxel at a dose of

[0266] In yet another exemplary embodiment, the method comprises administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 12 mg / kg once every two weeks, and administering about 50 mg / m once every two weeks. 2 The method includes administering docetaxel at a dose of

[0267] In yet another embodiment, the method of the present disclosure comprises: a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every two weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once every two weeks, and administering about 50 mg / m once every two weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of to a subject in need thereof.

[0268] In yet another embodiment, the method of the present disclosure comprises: a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every two weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 12 mg / kg once every two weeks, and administering about 50 mg / m once every two weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of to a subject in need thereof.

[0269] In an exemplary embodiment, the subject is treated for at least one cycle of treatment. In an exemplary embodiment, the subject is treated for at least one initial cycle of treatment and at least one subsequent cycle of treatment.

[0270] In another exemplary embodiment, the subject is treated for at least two cycles of treatment. In an exemplary embodiment, the subject is treated for at least two initial cycles of treatment. In an exemplary embodiment, the subject is treated for at least two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least one initial cycle of treatment and at least two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least two initial cycles of treatment and at least two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least two initial cycles of treatment and more than two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for more than two initial cycles of treatment and more than two subsequent cycles of treatment.

[0271] In additional exemplary embodiments, the subject is treated for at least three cycles of treatment. In exemplary embodiments, the subject is treated for at least three initial cycles of treatment. In exemplary embodiments, the subject is treated for at least three subsequent cycles of treatment. In exemplary embodiments, the subject is treated for at least three initial cycles of treatment and at least three subsequent cycles of treatment. In exemplary embodiments, the subject is treated for at least three initial cycles of treatment and more than three subsequent cycles of treatment.

[0272] In yet additional exemplary embodiments, the subject is treated for at least four cycles of treatment. In exemplary embodiments, the subject is treated for at least four initial cycles of treatment. In exemplary embodiments, the subject is treated for at least four subsequent cycles of treatment. In exemplary embodiments, the subject is treated for at least four initial cycles of treatment and at least four subsequent cycles of treatment. In exemplary embodiments, the subject is treated for at least four initial cycles of treatment and more than four subsequent cycles of treatment.

[0273] In other exemplary embodiments, the subject is treated or undergoes 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more treatment cycles. In yet another exemplary embodiment, the subject is treated or undergoes 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more initial cycles of treatment. In still further exemplary embodiments, the subject is treated or undergoes 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more initial and / or subsequent cycles of treatment. In some embodiments, the treatment cycles are consecutive.

[0274] In some embodiments, the treatment cycle is not interrupted.

[0275] In some embodiments, the treatment cycle is interrupted.

[0276] In some embodiments, the treatment cycle is interrupted for a period of time (ranging from a day to weeks or months). In some embodiments, at least one treatment cycle is interrupted. In other embodiments, more than one treatment cycle is interrupted. In other embodiments, treatment is interrupted after a certain period of time as determined by a physician or clinician.

[0277] According to the present disclosure, the combination therapy is administered for at least two consecutive cycles.

[0278] According to the present disclosure, the combination therapy is administered for at least three consecutive cycles.

[0279] According to the present disclosure, the combination therapy is administered for at least four consecutive cycles.

[0280] According to the present disclosure, the combination therapy is administered for at least five consecutive cycles.

[0281] According to the present disclosure, the combination therapy is administered for at least six consecutive cycles.

[0282] According to the present disclosure, the combination therapy is administered for at least seven consecutive cycles.

[0283] According to the present disclosure, the combination therapy is administered for at least eight consecutive cycles.

[0284] According to the present disclosure, the combination therapy is administered for at least nine consecutive cycles.

[0285] According to the present disclosure, the combination therapy is administered for at least 10 consecutive cycles.

[0286] According to the present disclosure, the combination therapy is administered for at least 11 consecutive cycles.

[0287] According to the present disclosure, the combination therapy is administered for at least 12 consecutive cycles.

[0288] In some embodiments, clinical benefit may be observed or measured after two cycles of treatment.

[0289] In some embodiments, clinical benefit may be observed or measured after three cycles of treatment.

[0290] In some embodiments, clinical benefit may be observed or measured after four cycles of treatment.

[0291] In some embodiments, clinical benefit may be observed or measured after 5 cycles of treatment.

[0292] In some embodiments, clinical benefit may be observed or measured after more than five cycles of treatment.

[0293] In some embodiments, the combination therapy is administered for as long as a clinical benefit is observed or measured.

[0294] In some embodiments, the combination therapy is administered until tumor progression.

[0295] In some embodiments, the combination therapy is administered until unmanageable toxicity occurs.

[0296] In some embodiments, administration of the anti-clusterin antibody or antigen-binding fragment thereof is maintained after the appearance of clinical benefit.

[0297] The present disclosure also provides kits comprising one or more containers containing at least one dose of an anti-clusterin antibody or antigen-binding fragment thereof, one or more containers containing at least one dose of a taxane, such as docetaxel, for use in combination therapy, and a package insert containing instructions for use to treat a subject as described herein.

[0298] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with NSCLC or metastatic NSCLC. [Brief description of the drawings]

[0299] [Figure 1] Table showing percentage and duration of reduction in target lesions for patients during treatment as best response by RECIST 1.1 (PT; patient, BR; best response, PD-L1; PD-L1 tumor proportion score, PR; partial response, SD; stable disease, PD; progressive disease, AE; adverse event). [Diagram 2] Figure 1. Histological analysis of pre- (a and c) and on-treatment (b and d) biopsies from two patients under study. Tumor sections were stained with hematoxylin and eosin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0300] Further scope, applicability, and advantages of the present disclosure will become apparent from the non-limiting detailed description given below, which should be understood, however, as giving exemplary embodiments of the present disclosure, and is given by way of example only in connection with the accompanying drawings, in which:

[0301] definition Unless otherwise indicated, amino acid numbering shown for dimerization domains is according to the EU numbering system.

[0302] In the context of describing embodiments (particularly in the context of the claims), the use of the terms "a" and "an" and "the" and similar referents should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0303] Unless specifically stated or clear from the context, as used herein, the term "or" is understood to be inclusive, covering both "or" and "and."

[0304] The term "and / or" when used herein should be taken as a specific disclosure of each of the specified features or components without regard to the presence or absence of the other.

[0305] The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms (i.e., meaning "including but not limited to") unless otherwise noted. The term "consisting of" should be construed as closed.

[0306] The term "subject" refers to, without limitation, a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, sheep, horse, or primate) having lung cancer, such as non-small cell lung cancer, metastatic non-small cell lung cancer, and / or a subject having stage III-IV non-small cell lung cancer. The term "subject" is used interchangeably herein with "individual" or "patient."

[0307] The term "antibody" is used in the broadest sense and encompasses various antibody formats and structures, including any immunoglobulin that binds to a specific antigen, monoclonal antibodies, polyclonal antibodies, bivalent antibodies, monovalent antibodies, bispecific antibodies, multispecific (multispecific) antibodies, conventional antibodies, single domain antibodies, single chain antibodies, heavy chain only antibodies, nanobodies, full length antibodies, humanized antibodies, chimeric antibodies, and any antigen-binding fragments that exhibit the desired antigen-binding activity. Antibodies can be naturally occurring (natural) or can be the result of recombinant technology. As used herein, the term "conventional antibody" has the same format as a naturally occurring human antibody. The sequence of a conventional antibody can be derived in part and / or in whole from a non-human animal antibody or from a human antibody, and therefore should be understood herein to include, without limitation, monoclonal, chimeric, human, and humanized antibodies.

[0308] The term "treat" or "treating" for the purposes of this disclosure refers to the act of providing a treatment (such as a combination therapy disclosed herein) to a subject. As used herein, the term "treat" or "treating" refers to any method used to partially or completely alleviate, improve, reduce, inhibit, prevent, delay the onset, reduce the severity, reduce the incidence, stabilize, and / or manage one or more symptoms and / or characteristics of a particular disease, disorder, and / or condition, and / or to obtain or maintain a clinical benefit as defined by the RECIST 1.1 guidelines. It should be understood that a treatment may be effective in some subjects with a particular disease, disorder, and / or condition, but not in others who are nevertheless treated.

[0309] The term "therapeutically effective" refers to a treatment that results in partial or complete alleviation, enhancement, relief, inhibition, prevention, delay in onset, less severity, reduced incidence, stabilization, and / or improved management of one or more symptoms and / or characteristics of a particular disease, disorder, and / or condition, and / or that provides a clinical benefit as defined by RECIST 1.1 guidelines for some subjects.

[0310] As used herein, the term "EMT signature" refers to changes observable at the cellular level and / or observable or measurable at the gene or protein level that indicate a loss of an epithelial phenotype and / or the acquisition of a mesenchymal phenotype.

[0311] The term "about" or "approximately" in reference to a given value means that variation of the value is contemplated. In some embodiments, the term "about" or "approximately" is intended to mean a range generally within ±20 percent, ±10 percent, ±5 percent, ±4 percent, ±3 percent, ±2 percent, or ±1 percent of a given value or range.

[0312] The phrase "over the course of treatment" means that both the anti-clusterin antibody or antigen-binding fragment and docetaxel are administered in each treatment cycle.

[0313] The term "essentially" is used to characterize an action that is performed most of the time, or a condition that occurs most of the time. For example, the phrase "essentially throughout the course of the treatment period" means that both the anti-clusterin antibody or antigen-binding fragment and docetaxel are administered at each treatment cycle and for the entire treatment period, but from time to time, a dose of either the anti-clusterin antibody or antigen-binding fragment or docetaxel, or each dose, may be missed, either intentionally or unintentionally.

[0314] The term "functional immune system" with respect to a subject means that the subject's immune system is essentially unaffected by cancer or by a medication, that the subject is immunocompetent, or that the subject is not immunosuppressed.

[0315] The phrase "treatment comprising an immune checkpoint antibody" refers to treatment with an immune checkpoint antibody, either as a monotherapy or in a combination therapy.

[0316] The phrase "adequate organ and immune function" refers to one or more of the parameters provided in Table 1.

[0317] Exemplary embodiments of combination therapy, methods, uses, dosages, regimens, and schedules The present disclosure provides a combination therapy comprising an anti-clusterin antibody, or antigen-binding fragment thereof, and a taxane.

[0318] More particularly, the present disclosure provides combination therapies comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel.

[0319] The present disclosure provides methods of treating a subject with lung cancer (eg, lung cancer) using the combination therapies disclosed herein.

[0320] More particularly, the present disclosure provides methods of treating a subject with non-small cell lung cancer using the combination therapies disclosed herein.

[0321] More specifically, the present disclosure provides methods of treating a subject with metastatic non-small cell lung cancer using the combination therapies disclosed herein.

[0322] The present disclosure also relates to methods of treating a subject with non-small cell lung cancer to obtain a clinical benefit using the combination therapies disclosed herein.

[0323] The present disclosure further relates to methods of treating a subject with metastatic non-small cell lung cancer to obtain a clinical benefit using the combination therapies disclosed herein.

[0324] The present disclosure also relates to methods of obtaining clinical benefit in subjects with non-small cell lung cancer using the combination therapies disclosed herein.

[0325] The present disclosure further relates to methods of obtaining clinical benefit in subjects with metastatic non-small cell lung cancer using the combination therapies disclosed herein.

[0326] In some embodiments, the methods may include administering a combination therapy in a dosage sufficient to provide a clinical benefit.

[0327] In some embodiments, the methods may include administering the combination therapy for a period of time sufficient to provide a clinical benefit.

[0328] In some embodiments, the methods may include administering the combination therapy according to a treatment schedule sufficient to provide a clinical benefit.

[0329] In some embodiments, the methods may include administering the combination therapy according to a therapeutic regimen sufficient to provide a clinical benefit.

[0330] Thus, in certain aspects, the methods of the disclosure comprise administering a combination therapy comprising an anti-clusterin antibody, or antigen-binding fragment thereof, and a taxane.

[0331] In other aspects, the methods of the disclosure comprise administering a combination therapy comprising an anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel.

[0332] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered in a therapeutically effective dose.

[0333] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered in a safe dose.

[0334] According to the present disclosure, docetaxel is administered in a therapeutically effective dose.

[0335] According to the present disclosure, docetaxel is administered at a safe dose.

[0336] In some embodiments, docetaxel is administered at a dose sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0337] According to the present disclosure, docetaxel is administered at a dosing interval sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0338] In some embodiments, the method includes administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg, and administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 60 mg / m 2 ~100mg / m 2 The method includes administering a combination therapy comprising docetaxel at a dose of

[0339] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof may be administered in a dose range of, for example, about 4 mg / kg to about 20 mg / kg, about 5 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 6 mg / kg to about 18 mg / kg, about 6 mg / kg to about 17 mg / kg, about 6 mg / kg to about 16 mg / kg, about 6 mg / kg to about 15 mg / kg, about 6 mg / kg to about 14 mg / kg, about 6 mg / kg to about 1 3mg / kg, approximately 6mg / kg to approximately 12mg / kg, approximately 7mg / kg to approximately 18mg / kg, approximately 7mg / kg to approximately 17mg / kg, approximately 7mg / kg to approximately 16mg / kg, approximately 7mg / kg to approximately 15mg / kg, approximately 7mg / kg to approximately 14mg / kg, approximately 7mg / kg to approximately 13mg / kg, approximately 7mg / kg to approximately 12mg / kg, approximately 8mg / kg to approximately 18mg / kg, approximately 8mg / kg to approximately 17mg / kg, and 8mg / kg to approximately 16mg / kg, approximately 8mg / kg to approximately 15mg / kg, approximately 8mg / kg to approximately 14mg / kg, approximately 8mg / kg to approximately 13mg / kg, approximately 8mg / kg to approximately 12mg / kg, approximately 9mg / kg to approximately 18mg / kg, approximately 9mg / kg to approximately 17mg / kg, approximately 9mg / kg to approximately 16mg / kg, approximately 9mg / kg to approximately 15mg / kg, approximately 9mg / kg to approximately 14mg / kg, approximately 9mg / kg to approximately 18mg / kg, approximately 9mg / kg to approximately 17mg / kg, approximately 9mg / kg to approximately 16mg / kg, approximately 9mg / kg to approximately 15mg / kg, approximately 9mg / kg to approximately 14mg / kg, approximately 9mg / kg to approximately 18mg / kg, approximately 9mg / kg to approximately 17mg / kg, approximately 9mg / kg to approximately 16mg / kg, approximately 9mg / kg to approximately 17mg / kg, approximately 9mg / kg to approximately 18mg / kg, approximately 9mg / kg to approximately 17 ... The compound may be administered at a dose of about 3 mg / kg to about 20 mg / kg, such as about 13 mg / kg, about 9 mg / kg to about 12 mg / kg, about 10 mg / kg to about 18 mg / kg, about 10 mg / kg to about 17 mg / kg, about 10 mg / kg to about 16 mg / kg, about 10 mg / kg to about 15 mg / kg, about 10 mg / kg to about 14 mg / kg, about 10 mg / kg to about 13 mg / kg, or about 10 mg / kg to about 12 mg / kg.

[0340] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3.0 mg / kg.

[0341] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 3.0 mg / kg.

[0342] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 4.0 mg / kg.

[0343] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 4.0 mg / kg.

[0344] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 5.0 mg / kg.

[0345] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 5.0 mg / kg.

[0346] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6.0 mg / kg.

[0347] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 6.0 mg / kg.

[0348] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 7.0 mg / kg.

[0349] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 7.0 mg / kg.

[0350] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 8.0 mg / kg.

[0351] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 8.0 mg / kg.

[0352] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9.0 mg / kg.

[0353] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 9.0 mg / kg.

[0354] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 10.0 mg / kg.

[0355] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 10.0 mg / kg.

[0356] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 11.0 mg / kg.

[0357] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 11.0 mg / kg.

[0358] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12.0 mg / kg.

[0359] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 12.0 mg / kg.

[0360] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 13.0 mg / kg.

[0361] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 13.0 mg / kg.

[0362] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 14.0 mg / kg.

[0363] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 14.0 mg / kg.

[0364] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 15.0 mg / kg.

[0365] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 15.0 mg / kg.

[0366] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 16.0 mg / kg.

[0367] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 16.0 mg / kg.

[0368] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 17.0 mg / kg.

[0369] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 17.0 mg / kg.

[0370] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 18.0 mg / kg.

[0371] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 18.0 mg / kg.

[0372] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 19.0 mg / kg.

[0373] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 19.0 mg / kg.

[0374] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 20.0 mg / kg.

[0375] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of 20.0 mg / kg.

[0376] According to the present disclosure, docetaxel can be administered at a dose of, for example, 60 mg / m 2 ~ approx. 100 mg / m 2 , approximately 60 mg / m 2 ~ approx. 95 mg / m 2 , approximately 60 mg / m 2 ~ approx. 90 mg / m 2 , approximately 60 mg / m 2 ~ approx. 85 mg / m 2 , approximately 60 mg / m 2 ~ approx. 80 mg / m 2 , approximately 50 mg / m 2 ~ approx. 75 mg / m 2 , approximately 60 mg / m 2 ~ approx. 75 mg / m 2 , approximately 75 mg / m 2 ~ approx. 95 mg / m 2 , approximately 75 mg / m 2 ~ approx. 90 mg / m 2 , approximately 75 mg / m 2 ~ approx. 85 mg / m 2 , approximately 75 mg / m 2 ~ approx. 80 mg / m 2, approximately 70 mg / m 2 ~ approx. 95 mg / m 2 , approximately 70 mg / m 2 ~ approx. 90 mg / m 2 , approximately 70 mg / m 2 ~ approx. 85 mg / m 2 , approximately 70 mg / m 2 ~ approx. 80 mg / m 2 , or approximately 70 mg / m 2 ~ approx. 75 mg / m 2 etc., approximately 50 mg / m 2 ~ approx. 100 mg / m 2 is administered at a dose of

[0377] In some embodiments, docetaxel is approximately 50 mg / m 2 is administered at a dose of

[0378] In some embodiments, docetaxel is approximately 60 mg / m 2 is administered at a dose of

[0379] In some embodiments, docetaxel is approximately 65 mg / m 2 is administered at a dose of

[0380] In some embodiments, docetaxel is approximately 70 mg / m 2 is administered at a dose of

[0381] In some embodiments, docetaxel is approximately 75 mg / m 2 is administered at a dose of

[0382] In some embodiments, docetaxel is approximately 80 mg / m 2 is administered at a dose of

[0383] In some embodiments, docetaxel is approximately 85 mg / m 2 is administered at a dose of

[0384] In some embodiments, docetaxel is approximately 90 mg / m2 is administered at a dose of

[0385] In some embodiments, docetaxel is approximately 95 mg / m 2 is administered at a dose of

[0386] In some embodiments, docetaxel is at approximately 100 mg / m 2 is administered at a dose of

[0387] An exemplary embodiment of the disclosed method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The method comprises administering the compound at a dose of

[0388] Another exemplary embodiment of the methods of the present disclosure is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0389] Another exemplary embodiment of the methods of the present disclosure is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0390] Yet another exemplary embodiment of the disclosed method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The method comprises administering the compound at a dose of

[0391] A further exemplary embodiment of the disclosed method is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0392] Yet a further exemplary embodiment of the disclosed methods is a method of treating a subject having non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The method comprises administering the compound at a dose of

[0393] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once a week.

[0394] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered twice weekly.

[0395] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every two weeks.

[0396] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every three weeks.

[0397] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every four weeks.

[0398] In some embodiments, the docetaxel is administered weekly.

[0399] In some embodiments, docetaxel is administered every two weeks.

[0400] In some embodiments, docetaxel is administered every three weeks.

[0401] In some embodiments, docetaxel is administered every four weeks.

[0402] In some embodiments, docetaxel is administered once per week.

[0403] In some embodiments, docetaxel is administered once every two weeks.

[0404] In some embodiments, docetaxel is administered once every three weeks.

[0405] In some embodiments, docetaxel is administered once every four weeks.

[0406] In some embodiments, docetaxel is administered once every five weeks.

[0407] In some embodiments, docetaxel is administered once every six weeks.

[0408] In some embodiments, a treatment cycle is considered complete after a period of approximately 7 days after a subject has received both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel.

[0409] In some exemplary embodiments, a treatment cycle is approximately 7 days.

[0410] In some exemplary embodiments, essentially every treatment cycle is about 7 days.

[0411] In some exemplary embodiments, each treatment cycle is approximately 7 days.

[0412] According to the present disclosure, a subject may therefore undergo a treatment cycle every seven days.

[0413] In some exemplary embodiments, one treatment cycle is approximately 14 days.

[0414] In some exemplary embodiments, essentially every treatment cycle is about 14 days.

[0415] In some exemplary embodiments, each treatment cycle is approximately 14 days.

[0416] According to the present disclosure, a subject may therefore undergo a treatment cycle every 14 days.

[0417] In some exemplary embodiments, one treatment cycle is approximately 21 days.

[0418] In some exemplary embodiments, essentially every treatment cycle is about 21 days.

[0419] In some exemplary embodiments, each treatment cycle is approximately 21 days.

[0420] According to the present disclosure, a subject may therefore undergo a treatment cycle every 21 days.

[0421] In some exemplary embodiments, a treatment cycle is approximately 28 days.

[0422] In some exemplary embodiments, essentially every treatment cycle is about 28 days.

[0423] In some exemplary embodiments, each treatment cycle is approximately 28 days.

[0424] According to the present disclosure, a subject may therefore undergo a treatment cycle every 28 days.

[0425] In an exemplary embodiment, the combination therapy is administered in one or more cycles of treatment comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof on days 1, 8, and 15, and administration of docetaxel on day 1.

[0426] It should be understood that the interval between administration of the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel can be varied without significantly altering the efficacy of the combination therapy.

[0427] For example, an anti-clusterin antibody or antigen-binding fragment thereof can be administered on days 1, 7, and 14, and docetaxel can be administered on day 1.

[0428] In another example, an anti-clusterin antibody or antigen-binding fragment thereof can be administered on days 1, 7, and 16, and docetaxel can be administered on day 1.

[0429] In yet another example, an anti-clusterin antibody or antigen-binding fragment thereof can be administered on days 1, 8, and 16, and docetaxel can be administered on day 1.

[0430] In an exemplary embodiment, one treatment cycle consists of administration of the anti-clusterin antibody or antigen-binding fragment thereof once per week, and administration of docetaxel every three weeks.

[0431] In an exemplary embodiment, one treatment cycle consists of administering an anti-clusterin antibody or antigen-binding fragment thereof every two weeks, and administering docetaxel every two weeks.

[0432] In an exemplary embodiment, one treatment cycle consists of administration of the anti-clusterin antibody or antigen-binding fragment thereof every two weeks, and docetaxel every three weeks.

[0433] In an exemplary embodiment, one treatment cycle consists of administration of an anti-clusterin antibody or antigen-binding fragment thereof every three weeks, and administration of docetaxel every three weeks.

[0434] In an exemplary embodiment, one treatment cycle consists of one weekly administration of the anti-clusterin antibody or antigen-binding fragment thereof, and monthly administration of docetaxel.

[0435] In an exemplary embodiment, one treatment cycle consists of administration of an anti-clusterin antibody or antigen-binding fragment thereof every two weeks, and monthly administration of docetaxel.

[0436] In an exemplary embodiment, one treatment cycle consists of a monthly administration of the anti-clusterin antibody or antigen-binding fragment thereof, and a monthly administration of docetaxel.

[0437] In an exemplary embodiment, one treatment cycle consists of administration of an anti-clusterin antibody or antigen-binding fragment thereof every two months, and administration of docetaxel every two months.

[0438] In an exemplary embodiment, one treatment cycle consists of administration of an anti-clusterin antibody or antigen-binding fragment thereof every three months, and administration of docetaxel every three months.

[0439] In some embodiments, the method includes administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg every 2 to 3 weeks, and an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 50 mg / m 2 ~ approx. 100 mg / m 2 The method includes administering a combination therapy comprising docetaxel at a dose of

[0440] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and docetaxel is administered at a dose of approximately 75 mg / m every three weeks. 2 is administered at a dose of

[0441] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and docetaxel is administered at a dose of approximately 60 mg / m every three weeks. 2 is administered at a dose of

[0442] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg and docetaxel at a dose of approximately 50 mg / m every two weeks. 2 is administered at a dose of

[0443] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg and docetaxel is administered at a dose of approximately 75 mg / m every three weeks. 2 is administered at a dose of

[0444] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg and docetaxel is administered at a dose of approximately 60 mg / m every three weeks. 2 is administered at a dose of

[0445] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg and docetaxel at a dose of approximately 50 mg / m every two weeks. 2 is administered at a dose of

[0446] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg and docetaxel is administered at a dose of approximately 75 mg / m every three weeks. 2 is administered at a dose of

[0447] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg and the docetaxel is administered at a dose of approximately 60 mg / m every three weeks. 2 is administered at a dose of

[0448] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg and docetaxel is administered at a dose of approximately 50 mg / m every two weeks. 2 is administered at a dose of

[0449] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg and docetaxel is administered at a dose of approximately 75 mg / m every three weeks. 2 is administered at a dose of

[0450] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg and docetaxel is administered at a dose of approximately 60 mg / m every three weeks. 2 is administered at a dose of

[0451] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg and docetaxel at a dose of approximately 50 mg / m every two weeks. 2 is administered at a dose of

[0452] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day, once per week.

[0453] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day, once per week.

[0454] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day every two weeks.

[0455] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day every three weeks.

[0456] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day every four weeks.

[0457] In some embodiments, the method includes administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once per week, and about 50 mg / m once every 2-3 weeks. 2 ~100mg / m 2 The method includes administering a combination therapy comprising docetaxel at a dose of

[0458] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg once weekly and docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0459] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg once weekly and docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0460] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg once weekly and docetaxel is administered at a dose of approximately 50 mg / m once every three weeks. 2 is administered at a dose of

[0461] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg once weekly and docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0462] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg once weekly and docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0463] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg once weekly and docetaxel is administered at a dose of approximately 50 mg / m once every three weeks. 2 is administered at a dose of

[0464] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg once weekly and docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0465] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg once weekly and docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0466] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg once weekly and docetaxel is administered at a dose of approximately 50 mg / m once every three weeks. 2 is administered at a dose of

[0467] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg once weekly and docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0468] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg once weekly and docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0469] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg once weekly and docetaxel is administered at a dose of approximately 50 mg / m once every three weeks. 2 is administered at a dose of

[0470] In some embodiments, the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel may be administered on the same day. However, they can be administered on different days.

[0471] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel may be administered on the same day and separately.

[0472] The anti-clusterin antibody or antigen-binding fragment thereof and docetaxel may be administered sequentially.

[0473] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel may be administered by injection.

[0474] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered over the course of a treatment period.

[0475] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered with each cycle of treatment.

[0476] Both the anti-clusterin antibody or its antigen-binding fragment and docetaxel are generally administered in each treatment cycle. However, one or more doses of the anti-clusterin antibody or its antigen-binding fragment and / or docetaxel can be omitted without negatively affecting the treatment. One or more additional doses of the anti-clusterin antibody or its antigen-binding fragment and / or docetaxel can also be administered without negatively affecting the treatment.

[0477] According to the present disclosure, a subject may undergo at least one cycle of treatment.

[0478] According to the present disclosure, a subject may undergo at least two cycles of treatment.

[0479] According to the present disclosure, a subject may receive at least three cycles of treatment.

[0480] According to the present disclosure, a subject may receive at least four cycles of treatment.

[0481] According to the present disclosure, a subject may undergo four or more cycles of treatment.

[0482] According to the present disclosure, a subject may receive at least five treatment cycles.

[0483] According to the present disclosure, a subject may receive at least six treatment cycles.

[0484] According to the present disclosure, a subject may receive at least seven treatment cycles.

[0485] According to the present disclosure, a subject may receive at least eight treatment cycles.

[0486] According to the present disclosure, a subject may receive at least nine treatment cycles.

[0487] According to the present disclosure, a subject may receive at least 10 treatment cycles.

[0488] According to the present disclosure, a subject may receive at least 11 treatment cycles.

[0489] According to the present disclosure, a subject may receive at least 12 treatment cycles.

[0490] According to the present disclosure, a subject may receive at least 13 treatment cycles.

[0491] According to the present disclosure, a subject may receive at least 14 treatment cycles.

[0492] According to the present disclosure, a subject may receive at least 15 treatment cycles.

[0493] According to the present disclosure, a subject may receive at least 16 treatment cycles.

[0494] According to the present disclosure, a subject may receive at least 17 treatment cycles.

[0495] According to the present disclosure, a subject may receive at least 18 treatment cycles.

[0496] According to the present disclosure, a subject may receive at least 19 treatment cycles.

[0497] According to the present disclosure, a subject may receive at least 20 treatment cycles.

[0498] According to the present disclosure, a subject may undergo more than 20 cycles of treatment.

[0499] According to the present disclosure, a subject may receive at least one treatment cycle comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof once per week, and administration of docetaxel once every three weeks.

[0500] According to the present disclosure, a subject may receive at least two treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0501] According to the present disclosure, a subject may receive at least three treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0502] According to the present disclosure, a subject may receive at least four treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0503] According to the present disclosure, a subject may receive four or more treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0504] According to the present disclosure, a subject may receive at least five treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0505] According to the present disclosure, a subject may receive at least six treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0506] According to the present disclosure, a subject may receive at least seven cycles of treatment, with each cycle comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0507] According to the present disclosure, a subject may receive at least eight treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0508] According to the present disclosure, a subject may receive at least nine treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0509] According to the present disclosure, a subject may receive at least 10 treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0510] According to the present disclosure, a subject may receive at least 11 treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0511] According to the present disclosure, a subject may receive at least 12 treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0512] According to the present disclosure, a subject may receive up to 12 treatment cycles, each comprising one administration of an anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks.

[0513] According to the present disclosure, the treatment cycle is continuous.

[0514] According to the present disclosure, all treatment cycles are sequential.

[0515] According to the present disclosure, the treatment cycle is not interrupted.

[0516] According to the present disclosure, all treatment cycles are uninterrupted.

[0517] The method or use may also involve discontinuing treatment (monotherapy or combination therapy) for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, at least 10 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, at least 6 months, at least 10 months, at least 1 year, 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, at least 10 cycles). Treatment may then be resumed.

[0518] In some embodiments, at least one treatment cycle is discontinued.

[0519] In other embodiments, more than one treatment cycle is discontinued.

[0520] In some embodiments, the interruption lasts from 1 day to 1 week. In some embodiments, the interruption lasts from 1 day to 2 weeks. In some embodiments, the interruption lasts from 1 day to 3 weeks. In some embodiments, the interruption lasts from 1 day to 1 month. In some embodiments, the interruption lasts from 1 day to 2 months. In some embodiments, the interruption lasts from 1 day to 3 months. In some embodiments, the interruption lasts from 1 day to 4 months. In some embodiments, the interruption lasts from 1 day to 5 months. In some embodiments, the interruption lasts from 1 day to 6 months. In some embodiments, the interruption lasts for more than 1 day to 6 months.

[0521] In some embodiments, the method specifically involves administering an anti-clusterin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2), and SEQ ID NO:6 (CDRH3).

[0522] In other embodiments, the method specifically involves administering an anti-clusterin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2), and SEQ ID NO:9 (CDRH3).

[0523] In yet another embodiment, the method comprises: a. a light chain variable region having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 13; or b. a light chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:15. The method particularly involves administering to the patient an anti-clusterin antibody or antigen-binding fragment thereof comprising:

[0524] In other embodiments, the method specifically involves administering an anti-clusterin antibody or antigen-binding fragment thereof comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13.

[0525] In a further embodiment, the method specifically involves administering an anti-clusterin antibody or antigen-binding fragment thereof comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15.

[0526] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered by infusion over a time frame of approximately one hour.

[0527] In some embodiments, the docetaxel is administered by infusion over a time frame of approximately one hour.

[0528] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered by infusion over approximately a one hour time frame, and docetaxel is subsequently administered by infusion on the same day over approximately a one hour time frame.

[0529] In some embodiments, docetaxel is administered by infusion over approximately a one hour time frame, and the anti-clusterin antibody or antigen-binding fragment thereof is then administered by infusion on the same day over approximately a one hour time frame.

[0530] According to the present disclosure, the combination therapy or medicament may be used in subjects with non-small cell lung cancer, such as metastatic NSCLC or stage III-IV NSCLC.

[0531] According to the present disclosure, both the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered essentially throughout the course of the treatment period.

[0532] According to the present disclosure, combination therapy may be used in NSCLC patients who have progressed after treatment with immune checkpoint antibodies, either alone or in combination with chemotherapy.

[0533] Also, according to the present disclosure, the combination therapy may be used in NSCLC patients with no evidence of PD-L1 expression (e.g., Tumor Proportion Score (TPS) < 1%) or with low expression of PD-L1 (e.g., Tumor Proportion Score (TPS) ≦ 15%, including < 5%, ≦ 1%, < 1%, and 0%).

[0534] According to the present disclosure, combination therapy may be used in NSCLC that is not eligible for or would likely not benefit from treatment involving immune checkpoint antibodies.

[0535] The present disclosure relates to combination therapies for use in methods of treating NSCLC, such as metastatic NSCLC, by promoting the infiltration of immune cells into one or more lesions.

[0536] Accordingly, the present disclosure relates to combination therapies for use in methods of treating NSCLC, such as metastatic NSCLC, by promoting the infiltration of immune cells into one or more lesions that have low expression of PD-L1 or no evidence of PD-L1 expression.

[0537] Exemplary embodiments of anti-clusterin antibodies or antigen-binding fragments thereof In some embodiments, the anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure may inhibit epithelial to mesenchymal transition.

[0538] In some embodiments, the anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure can bind to an epitope contained at or within amino acids 421 and 443 of the C-terminal portion of the β-subunit of human clusterin (SEQ ID NO: 41, see PCT / CA2006 / 001505, published under WO2007 / 030930, and International Application No. PCT / CA2010 / 0001882, published under WO2011 / 063523, the entire contents of which are incorporated herein by reference). Such anti-clusterin antibodies or antigen-binding fragments thereof include those illustrated in Table 3 or include the CDRs, variable regions, or full chains illustrated in Table 3. It should be noted that in contrast to WO2011 / 063523, which describes a combination of an anti-clusterin antibody with a taxane, the present application provides evidence that the use of the combination therapy, specific doses or dosages, treatment regimens, and / or administration schedules described herein can induce tumor regression or tumor growth stabilization in NSCLC patients.

[0539] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that can compete with the anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure for binding to clusterin (e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)), or for binding to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:18.

[0540] In some embodiments, CDRs are identified using methods known to those of skill in the art and are outlined in Antibody Engineering, Vol. 2, Chapter 3, by Andrew CR Martin, the entire contents of which are incorporated herein by reference.

[0541] In certain embodiments, all CDRs are identified using the Kabat definition (Wu and Kabat, 1970), which is the most commonly used definition.

[0542] In certain embodiments, all CDRs are identified using the contact definition (MacCallum et al., 1996), which is likely to be most useful for those wishing to perform mutagenesis to alter the affinity of the antibody, since these are the residues that participate in interactions with the antigen.

[0543] According to the present disclosure, an anti-clusterin antibody or antigen-binding fragment thereof comprises the CDRs, light and heavy chain variable regions, or light and heavy chain amino acid sequences set forth in Table 3.

[0544] In certain embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0545] In some exemplary embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRL1 having the amino acid sequence set forth in SEQ ID NO:1, CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and CDRL3 having the amino acid sequence set forth in SEQ ID NO:3.

[0546] In some exemplary embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6.

[0547] In some exemplary embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:7, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:8, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:9.

[0548] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRL1 having the amino acid sequence set forth in SEQ ID NO:1, CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising CDRH1 having the amino acid sequence set forth in SEQ ID NO:4, CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, and CDRH3 having the amino acid sequence set forth in SEQ ID NO:6.

[0549] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRL1 having the amino acid sequence set forth in SEQ ID NO:1, CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, and CDRL3 having the amino acid sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising CDRH1 having the amino acid sequence set forth in SEQ ID NO:7, CDRH2 having the amino acid sequence set forth in SEQ ID NO:8, and CDRH3 having the amino acid sequence set forth in SEQ ID NO:9.

[0550] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 10, and a heavy chain variable region having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0551] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 10, and a heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0552] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:10, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:11.

[0553] In some embodiments, an anti-clusterin antibody or antigen-binding fragment thereof may compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 for binding to clusterin (e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)) or for binding to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0554] According to the present disclosure, an anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to, or identical to, the amino acid sequence set forth in SEQ ID NO:12, and a heavy chain variable region having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to, or identical to, the amino acid sequence set forth in SEQ ID NO:13.

[0555] According to the present disclosure, an anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to, or identical to, the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to, or identical to, the amino acid sequence set forth in SEQ ID NO:15.

[0556] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:12, and a heavy chain variable region having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:13.

[0557] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 13.

[0558] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:12, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:13.

[0559] According to the present disclosure, the antibody or antigen-binding fragment thereof may compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 for binding to clusterin (e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)) or for binding to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0560] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0561] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0562] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:15.

[0563] In some embodiments, an anti-clusterin antibody or antigen-binding fragment thereof may compete with an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15 for binding to clusterin (e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)) or for binding to a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0564] In yet other specific embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises the CDR, variable region, or full-chain amino acid sequence of an antibody or antigen-binding fragment thereof listed in Table 3.

[0565] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5.

[0566] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is a humanized 16B5 biosimilar.

[0567] The amino acid sequences of murine 16B5, humanized 16B5, murine 21B12, and humanized 21B12 are disclosed in International Application No. PCT / CA2010 / 001882, filed November 24, 2010, and published June 3, 2011 under No. WO2011 / 063523, the entire contents of which are incorporated herein by reference.

[0568] In still further specific embodiments, the anti-clusterin antibody or antigen-binding fragment thereof may be capable of competing with one or more of the antibodies or antigen-binding fragments thereof listed in Table 3.

[0569] Exemplary embodiments of antibodies or antigen-binding fragments thereof that compete with AB-16B5 include, by way of example and not limitation, the antibodies identified as 16B5, 21B12, 20E11, 11E2, and 16C11, which are disclosed in International Application No. PCT / CA2006 / 001505, filed Sep. 13, 2006, and published Mar. 22, 2007 under No. WO2007 / 030930, the entire contents of which are incorporated herein by reference. Such anti-clusterin antibodies or antigen-binding fragments thereof are illustrated in Table 3.

[0570] Exemplary embodiments of the subject matter The combination therapies disclosed herein are administered to a subject in need thereof.

[0571] The combination therapies disclosed herein are generally administered to human subjects.

[0572] In some aspects and embodiments of the present disclosure, the subject has cancer.

[0573] In other aspects and embodiments of the present disclosure, the subject has cancer and has a functional immune system.

[0574] In yet other aspects and embodiments of the present disclosure, the subject is a subject with cancer and adequate organ and immune function.

[0575] In some embodiments, the subject has non-small cell lung cancer.

[0576] In some embodiments, the subject has metastatic NSCLC.

[0577] In some embodiments, the subject has stage III-IV NSCLC.

[0578] In other embodiments, the subject has, or is selected as having, NSCLC that has progressed following therapy comprising an immune checkpoint antibody.

[0579] In other embodiments, the subject has, or is selected as having, NSCLC that has progressed following chemotherapy.

[0580] In some embodiments, the subject has undergone prior treatment with chemotherapy.

[0581] In other embodiments, the subject has, or is selected as having, NSCLC that would not be eligible for, or would likely not benefit from, treatment involving an immune checkpoint antibody.

[0582] Subjects may be characterized as ineligible for treatment with a PD-1 or PD-L1 immune checkpoint inhibitor based on objective criteria, such as prior failure of treatment including a PD-1 or PD-L1 immune checkpoint inhibitor, the level of PD-1 or PD-L1 expression, the level of immune cell infiltration into the tumor environment, etc.

[0583] Subjects may be characterized as unlikely to benefit from treatment with a PD-1 or PD-L1 immune checkpoint inhibitor based on subjective criteria, such as a physician's assessment of risks and benefits, the subject's overall clinical condition, etc.

[0584] In yet other embodiments, the subject has, or is selected as having, NSCLC that has failed prior treatment with an immune checkpoint antibody and a platinum-containing doublet therapy.

[0585] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior therapy comprising an anti-PD-1 immune checkpoint antibody.

[0586] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior therapy comprising a PD-L1 immune checkpoint antibody.

[0587] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior therapy comprising an anti-PD-1 or PD-L1 immune checkpoint antibody.

[0588] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0589] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0590] In additional embodiments, the subject has, or is selected as having, NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0591] According to the present disclosure, the doublet therapies can be provided simultaneously.

[0592] According to the present disclosure, doublet therapies may be provided sequentially.

[0593] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0594] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior treatment with an immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab, alone or in combination with platinum-based chemotherapy.

[0595] In some embodiments, the subject has, or is selected as having, NSCLC that has failed prior treatment with pembrolizumab, alone or in combination with platinum-based chemotherapy.

[0596] In other embodiments, the subject has, or is selected as having, metastatic NSCLC that has progressed following therapy comprising an immune checkpoint antibody.

[0597] In other embodiments, the subject has, or is selected as having, metastatic NSCLC that has progressed following chemotherapy.

[0598] In yet other embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an immune checkpoint antibody and chemotherapy treatment.

[0599] In other embodiments, the subject has, or is selected as having, metastatic NSCLC that would be ineligible for, or would likely not benefit from, treatment involving an immune checkpoint antibody.

[0600] In yet other embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an immune checkpoint antibody and a platinum-containing doublet therapy.

[0601] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior therapy comprising an anti-PD-1 immune checkpoint antibody.

[0602] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior therapy comprising a PD-L1 immune checkpoint antibody.

[0603] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior therapy comprising an anti-PD-1 or PD-L1 immune checkpoint antibody.

[0604] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0605] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0606] In additional embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0607] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0608] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with an immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab, alone or in combination with platinum-based chemotherapy.

[0609] In some embodiments, the subject has, or is selected as having, metastatic NSCLC that has failed prior treatment with pembrolizumab, alone or in combination with platinum-based chemotherapy.

[0610] In addition to having or being selected for having NSCLC or metastatic NSCLC, a subject may have or be selected for having one or more characteristics described herein and / or exemplified below.

[0611] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≧50%.

[0612] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of <50%.

[0613] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score between 1% and 49%.

[0614] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦15%.

[0615] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of <5%.

[0616] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦1%.

[0617] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of <1%.

[0618] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of 0%.

[0619] In some embodiments, the tumor proportion score is determined at baseline.

[0620] In some embodiments, the tumor proportion score is determined prior to administration of the combination therapy.

[0621] In some embodiments, the tumor proportion score is determined after primary therapy.

[0622] In some embodiments, the tumor proportion score is determined at the initiation of combination therapy.

[0623] In some embodiments, the PD-L1 tumor proportion score is determined by a scientist or pathologist.

[0624] In some embodiments, the PD-L1 tumor proportion score is determined in accordance with drug regulatory agency guidance (e.g., FDA, EMA, etc.).

[0625] In some embodiments, the subject has, or is selected as having, one or more immunological cold pathologies.

[0626] In some embodiments, the subject has or is selected as having one or more lesions with poor infiltration of immune cells.The level of immune cell infiltration can be determined by a trained pathologist.The level of immune cell infiltration can be determined by computer-based quantification of tumor biopsy imaging.

[0627] In some embodiments, the subject has or is selected to have one or more lesions that have or show signs of an EMT signature. The EMT signature can be determined by a trained pathologist. The EMT signature can be determined by computer-based quantification of tumor or tumor biopsy imaging.

[0628] According to the present disclosure, the subject is a subject with non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, and is selected based on the following non-exhaustive and non-limiting criteria: a) the subject has failed prior therapy with an immune checkpoint antibody, either alone or in combination with chemotherapy; b) the subject has one or more lesions with poor infiltration of immune cells; c) the subject has one or more lesions that have an EMT signature or that are indicative of an EMT signature; d) The subject has one or more of the criteria listed in any one of a)-c).

[0629] Alternatively, according to the present disclosure, the subject is a subject with non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, and is selected based on the following non-exhaustive and non-limiting criteria: a) Subjects have not received prior therapy with an anti-PD-L1 antibody, either alone or in combination with platinum-based chemotherapy; b) the subject has one or more lesions with a PD-L1 tumor proportion score of ≦15%; c) the subject has one or more lesions with poor infiltration of immune cells; d) the subject has one or more lesions that have an EMT signature or that show indicia of an EMT signature; or e) The subject has one or more of the criteria listed in any one of a) through d).

[0630] Subjects may thus be selected based on one or a combination of the criteria disclosed herein.

[0631] In an exemplary embodiment, the subject has a functional immune system and / or appropriate organs and immune function.

[0632] In an exemplary embodiment, the subject has, or is selected as having, NSCLC, such as metastatic non-small cell lung cancer, and has not received prior therapy with an anti-PD-L1 antibody.

[0633] In other exemplary embodiments, the subject has, or is selected as having, NSCLC, such as metastatic non-small cell lung cancer, and one or more lesions with a PD-L1 tumor proportion score of ≦15%.

[0634] In another exemplary embodiment, the subject has, or is selected as having, NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ≦15% and has not received prior therapy with an anti-PD-L1 antibody.

[0635] In other exemplary embodiments, the subject has NSCLC, such as metastatic non-small cell lung cancer, and has, or is selected as having, a PD-L1 tumor proportion score of ≦15% and one or more lesions with poor infiltration of immune cells.

[0636] In other exemplary embodiments, the subject has, or is selected as having, NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of <1%.

[0637] In another exemplary embodiment, the subject has, or is selected as having, NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of <1% and has not received prior therapy with an anti-PD-L1 antibody.

[0638] In other exemplary embodiments, the subject has NSCLC, such as metastatic non-small cell lung cancer, and has, or is selected as having, a PD-L1 tumor proportion score of <1% and one or more lesions with poor infiltration of immune cells.

[0639] In some cases, the subject has or is selected as having NSCLC, such as metastatic non-small cell lung cancer, that has failed prior therapy with an immune checkpoint antibody, either alone or in combination with chemotherapy.

[0640] In some cases, the subject has, or is selected as having, NSCLC, such as metastatic non-small cell lung cancer that has failed first, second, third, or subsequent line therapy.

[0641] In some instances, the combination therapy is administered as a first-line therapy in subjects with NSCLC, such as metastatic non-small cell lung cancer, and who have, or are selected as having, a PD-L1 tumor proportion score of ≦15%.

[0642] In some instances, the combination therapy is administered as a first-line therapy in subjects with NSCLC, such as metastatic non-small cell lung cancer, and who have, or are selected as having, a PD-L1 tumor proportion score of <1%.

[0643] In some cases, the combination therapy is administered as a second-line therapy in subjects with NSCLC, such as metastatic non-small cell lung cancer, who have failed prior therapy with an immune checkpoint antibody, either alone or in combination with chemotherapy.

[0644] In some cases, the combination therapy is administered as a second-line therapy in subjects with NSCLC, such as metastatic non-small cell lung cancer, who have failed prior therapy with an immune checkpoint antibody, either alone or in combination with chemotherapy.

[0645] According to the present disclosure, a subject in need has a tumor that expresses or secretes clusterin.

[0646] According to the present disclosure, a subject in need is one who is not immunosuppressed or has not received an immunosuppressant within 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days prior to treatment. In some embodiments, a subject in need may have received a corticosteroid prior to treatment.

[0647] In some embodiments, the subject is immunocompetent or selected to be immunocompetent.

[0648] In some embodiments, the subject is not or is selected to not be immunosuppressed.

[0649] In some embodiments, subjects are selected as not having received or will not have received immunosuppressive drugs within 7 days prior to treatment.

[0650] According to the present disclosure, a subject in need is one who has not received prior treatment with docetaxel.

[0651] It should be understood herein that treatment failure is often associated with disease progression or unwanted side effects of treatment. Thus, in some embodiments, subjects who have failed a prior treatment include subjects who have progression. In other embodiments, subjects who have failed a prior treatment include subjects who have unwanted side effects associated with the prior treatment.

[0652] In some embodiments, the subject has not received prior treatment with docetaxel.

[0653] PD-L1 expression and immune cell infiltration PD-L1 expression can be determined using methods known to those of skill in the art.

[0654] In an exemplary embodiment, PD-L1 Tumor Proportion Score (TPS) is assessed using the 22C3 antibody (Agilent Technologies, Carpinteria, Calif., code SK006).

[0655] In another exemplary embodiment, PD-L1 TPS is assessed using the 28-8 antibody (Agilent Technologies, Carpinteria, Calif., code SK005; Abcam, Toronto, Canada, catalog number Ab205921).

[0656] In yet another exemplary embodiment, PD-L1 TPS is assessed using the SP263 antibody, Roche Diagnostic, Ref. 740-4907.

[0657] In a further exemplary embodiment, PD-L1 TPS is assessed using the SP142 antibody (Abcam, Toronto, Canada, Catalog No. Ab228462).

[0658] In a further exemplary embodiment, PD-L1 TPS is assessed using the 73-10 antibody (clone MKP1A07310; Merck KgaA, Darmstadt, Germany; Abcam, Toronto, Canada, catalogue no. Ab228415).

[0659] PD-L1 expression can be assessed using an anti-PD-L1 antibody appropriate for the type of carcinoma the subject has.

[0660] PD-L1 expression is usually assessed on tumor cells, however, PD-L1 expression can be assessed on both tumor cells and tumor-infiltrating immune cells.

[0661] In some cases, PD-L1 expression is assessed by immunohistochemistry.

[0662] In other cases, PD-L1 expression is assessed by a fluorescent assay, such as, for example, by quantitative fluorescence or fluorescent in situ hybridization.

[0663] In some embodiments, the assay is an assay approved by at least one regulatory agency.

[0664] According to the present disclosure, the assay is a diagnostic test (Dx) approved by the US Food and Drug Administration (FDA).

[0665] According to this disclosure, the assay is an FDA approved test (Rx) for research purposes.

[0666] In an exemplary embodiment, the assay is based on PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, Calif., code SK006).

[0667] In another exemplary embodiment, the assay is based on PD-L1 IHC 28-8 pharmDx (Agilent Technologies, Carpinteria, Calif., code SK005).

[0668] In yet another exemplary embodiment, the assay is based on Ventana PD-L1 (SP263) (Roche Diagnostics, Ref. 740-4907).

[0669] In some aspects and embodiments, immunohistochemistry assays are performed according to the manufacturer's instructions.

[0670] In some embodiments, the assay uses the Autostainer Link 48 immunohistochemistry platform (Dako).

[0671] In some embodiments, the assay uses the Omnis immunohistochemistry platform (Dako).

[0672] In some embodiments, the assay is performed using the Bond-III immunohistochemistry platform (Leica).

[0673] In some embodiments, the assay uses the BenchMark ULTRA immunohistochemistry platform (Ventana).

[0674] Assay results are interpreted using the manufacturer's interpretation manual.

[0675] Exemplary assays are described in Munari, E. et al., 2021, Marchetti, A. et al., 2017, Yoshikawa, K. et al., 2021, the entire contents of which are incorporated herein by reference.

[0676] In some embodiments, the absence or presence of immune cells in the tumor microenvironment may be confirmed by tumor biopsy.

[0677] In other embodiments, the absence or presence of immune cells in the tumor microenvironment can be confirmed by in vivo imaging (e.g., magnetic resonance imaging, see, e.g., Jiang X. et al., 2020).

[0678] If the tumor microenvironment is not sufficiently infiltrated by immune cells (particularly by lymphocytes) or is not inflamed, the tumor may be characterized as "immunologically cold." In contrast, if infiltration of immune cells (particularly by lymphocytes) into the tumor microenvironment is observed or the tumor shows signs of inflammation, the tumor may be characterized as "immunologically warm" or "immunologically hot."

[0679] Generally, a pathologist, technician, trained scientist, or trained technician equipped with the appropriate reagents and / or equipment may be able to determine the absence or presence of immune cells in the tumor microenvironment and thus assess whether a tumor is "immunologically cold," "immunologically warm," or "immunologically hot."

[0680] Exemplary embodiments of the kit In some aspects and embodiments, the present disclosure provides a kit comprising one or more containers containing at least one dose of an anti-clusterin antibody or antigen-binding fragment thereof, one or more containers containing at least one dose of a taxane for use in combination therapy, and a package insert containing instructions for use to treat a subject in need thereof.

[0681] In other aspects and embodiments, the present disclosure provides a kit comprising one or more containers containing at least one dose of an anti-clusterin antibody or antigen-binding fragment thereof, one or more containers containing at least one dose of docetaxel for use in combination therapy, and a package insert containing instructions for use to treat a subject in need thereof.

[0682] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are provided in separate containers.

[0683] According to the present disclosure, the antibody or antigen-binding fragment thereof is as described herein.

[0684] In some embodiments, the package insert states that the combination therapy is intended for the treatment of a subject described herein.

[0685] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with NSCLC.

[0686] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic NSCLC, such as, for example, stage III-IV NSCLC.

[0687] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with NSCLC that has progressed after therapy including an immune checkpoint antibody.

[0688] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with NSCLC who have failed prior treatment with an immune checkpoint antibody and a platinum-containing doublet therapy.

[0689] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic NSCLC that has progressed after first-line therapy comprising an immune checkpoint antibody.

[0690] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic NSCLC who have failed prior therapy including immune checkpoint antibody and platinum-containing doublet therapy.

[0691] In addition to the embodiments described and provided in this disclosure, the following non-limiting embodiments are specifically contemplated. 1. A method of treating a subject having lung cancer comprising administering a combination therapy disclosed herein. 2. A method of treating a subject with non-small cell lung cancer comprising administering a combination therapy disclosed herein. 3. A method of treating a subject with non-small cell lung cancer comprising administering a combination therapy disclosed herein to achieve and / or maintain clinical benefit. 4. The method of any one of embodiments 1 to 3, wherein the combination therapy comprises an anti-clusterin antibody, or an antigen-binding fragment thereof, and a taxane. 5. A method of obtaining a clinical benefit to a subject with non-small cell lung cancer comprising administering a combination therapy disclosed herein. 6. Each cycle of treatment consists of administration of an anti-clusterin antibody at a dose of about 3 mg / kg to about 20 mg / kg once per week, and about 60 mg / m once every 3 weeks. 2 ~100mg / m 2 A method of treatment comprising administering a combination therapy for at least two cycles of treatment, comprising administration of a taxane at a dose of from about 100 to about 150 mg / kg, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining region (CDR) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDR of the heavy chain variable region set forth in SEQ ID NO: 13, to obtain a clinical benefit to a subject with non-small cell lung cancer. 7. Each cycle of treatment consists of administration of an anti-clusterin antibody at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every 3 weeks. 2 A method of obtaining a clinical benefit to a subject with non-small cell lung cancer in a method of treatment comprising administering a combination therapy for at least two cycles of treatment, including administration of docetaxel at a dose of 8. A method of treating a subject with non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and a taxane, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 9. A method of treating a subject with non-small cell lung cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and a taxane to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 10. The method of any one of the preceding embodiments, wherein the taxane is docetaxel or paclitaxel. 11. Each cycle of treatment comprises administration of an anti-clusterin antibody at a dose of about 3 mg / kg to about 20 mg / kg once per week, once every 2 weeks, or once every 3 weeks, and about 50 mg / m once every 2 to 3 weeks. 2 ~ approx. 100 mg / m 2 1. A method of treating non-small cell lung cancer in a subject in need thereof comprising administering a combination therapy for at least two cycles of treatment, comprising administration of docetaxel at a dose of 12. The method of any one of embodiments 1 to 11, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg to approximately 20 mg / kg. 13. The method of any one of embodiments 1 to 12, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg to approximately 20 mg / kg. 14. The method of any one of embodiments 1 to 13, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg to approximately 15 mg / kg. 15. The method of any one of embodiments 1 to 14, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg to approximately 14 mg / kg. 16. The method of any one of embodiments 1 to 15, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg to approximately 13 mg / kg. 17. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of between approximately 6 mg / kg and approximately 12 mg / kg. 18. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of between approximately 7 mg / kg and approximately 12 mg / kg. 19. The method of any one of embodiments 1 to 18, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 8 mg / kg to approximately 12 mg / kg. 20. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg to approximately 12 mg / kg. 21. The method of any one of embodiments 1 to 20, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 10 mg / kg to approximately 12 mg / kg. 22. The method of any one of embodiments 1 to 21, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 11 mg / kg to approximately 12 mg / kg. 23. The method of any one of embodiments 1 to 22, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg. 24. The method of any one of embodiments 1 to 23, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg. 25. The method of any one of embodiments 1 to 24, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg. 26. The method of any one of embodiments 1 to 25, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg. 27. The method of any one of the preceding embodiments, wherein the taxane is docetaxel. 28. The taxane is docetaxel, approximately 50 mg / m 2 ~ approx. 100 mg / m 2 28. The method according to any one of the preceding embodiments, wherein the dose is 29. The taxane is docetaxel, approximately 60 mg / m 2 ~ approx. 100 mg / m 2 29. The method of any one of the preceding embodiments, wherein the dose is administered. 30. Docetaxel is approximately 60 mg / m 2 ~ approx. 95 mg / m 2 30. The method of any one of the preceding embodiments, wherein the dose is administered. 31. Docetaxel is approximately 60 mg / m 2 ~ approx. 90 mg / m 2 31. The method of any one of the preceding embodiments, wherein the dose is administered. 32. Docetaxel is approximately 60 mg / m 2 ~ approx. 85 mg / m 2 32. The method of any one of the preceding embodiments, wherein the dose is administered. 33. Docetaxel is approximately 60 mg / m 2 ~ approx. 80 mg / m 2 33. The method of any one of the preceding embodiments, wherein the dose is administered. 34. Docetaxel is approximately 50 mg / m 2 ~ approx. 75 mg / m 2 34. The method of any one of the preceding embodiments, wherein the dose is administered. 35. Docetaxel is approximately 60 mg / m 2~ approx. 75 mg / m 2 35. The method of any one of the preceding embodiments, wherein the dose is administered. 36. Docetaxel is approximately 75 mg / m 2 ~ approx. 80 mg / m 2 36. The method of any one of the preceding embodiments, wherein the dose is 37. The taxane is docetaxel, approximately 50 mg / m 2 37. The method of any one of the preceding embodiments, wherein the dose is administered. 38. The taxane is docetaxel, approximately 60 mg / m 2 38. The method of any one of the preceding embodiments, wherein the dose is administered. 39. The taxane is docetaxel, approximately 75 mg / m 2 39. The method of any one of the preceding embodiments, wherein the dose is administered. 40. The taxane is docetaxel, approximately 100 mg / m 2 40. The method of any one of the preceding embodiments, wherein the dose is administered. 41. The method of any one of embodiments 1 to 40, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered once a week (once per week). 42. The method of any one of embodiments 1 to 41, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered once every two weeks. 43. The method of any one of embodiments 1 to 42, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered once every three weeks. 44. The method of any one of embodiments 1 to 43, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered once every 4 weeks. 45. The method of any one of embodiments 1-44, wherein docetaxel is administered once a week. 46. ​​The method of any one of embodiments 1-45, wherein docetaxel is administered once every two weeks. 47. The method of any one of embodiments 1-46, wherein docetaxel is administered once every three weeks. 48. The method of any one of embodiments 1-47, wherein docetaxel is administered once every 4 weeks. 49. Anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, and approximately 50 mg / m once every 2 to 3 weeks. 2 ~ approx. 75 mg / m 2 A method of treating a subject with non-small cell lung cancer, comprising administering a combination therapy comprising docetaxel at a dose of 0.01 mg / kg / day to achieve clinical benefit, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 50. Each cycle of treatment consists of administration of an anti-clusterin antibody at a dose of approximately 12 mg / kg once per week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, and administration of approximately 50 mg / m once every 2 to 3 weeks. 2 ~ approx. 75 mg / m 2 1. A method of treating non-small cell lung cancer in a subject in need thereof comprising administering a combination therapy for at least two cycles of treatment, comprising administration of docetaxel at a dose of 51. The method of any one of embodiments 1 to 50, wherein the subject is as described herein. 52. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day. 53. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on different days. 54. The method of any one of embodiments 1 to 53, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an immune checkpoint antibody. 55. The method of any one of embodiments 1-54, wherein the subject has, or is selected because, has NSCLC that has failed prior treatment with chemotherapy. 56. The method of any one of embodiments 1 to 55, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an immune checkpoint antibody with or without chemotherapy. 57. The method of any one of embodiments 1 to 56, wherein the subject has, or is selected for having, NSCLC that has failed prior therapy comprising an anti-PD-1 immune checkpoint antibody. 58. The method of any one of embodiments 1 to 57, wherein the subject has, or is selected for having, NSCLC that has failed prior therapy comprising a programmed death-ligand 1 (PD-L1) immune checkpoint antibody. 59. The method of any one of embodiments 1 to 58, wherein the subject has, or is selected for having, NSCLC that has failed prior therapy comprising an anti-PD-1 or PD-L1 immune checkpoint antibody. 60. The method of any one of embodiments 1 to 59, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an immune checkpoint antibody and chemotherapy. 61. The method of any one of embodiments 1 to 60, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy. 62. The method of any one of embodiments 1 to 61, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy. 63. The method of any one of embodiments 1 to 62, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy. 64. The method of any one of embodiments 1 to 63, wherein the immune checkpoint antibody is selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab. 65. The method of any one of embodiments 1 to 64, wherein the immune checkpoint antibody is pembrolizumab. 66. The method of any one of embodiments 1 to 65, wherein the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score (TPS) of ≧50%. 67. The method of any one of embodiments 1 to 66, wherein the subject has, or is selected for having, one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of <50%. 68. The method of any one of the preceding embodiments, wherein the subject has, or is selected for having, one or more lesions with a PD-L1 tumor proportion score (TPS) of between 1% and 49%. 69. The method of any one of embodiments 1 to 68, wherein the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦15%. 70. The method of any one of embodiments 1 to 69, wherein the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of <5%. 71. The method of any one of embodiments 1 to 70, wherein the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦1%. 72. The method of any one of embodiments 1 to 71, wherein the subject has, or is selected for having, one or more lesions with a PD-L1 tumor proportion score of <1%. 73. The method of any one of embodiments 1 to 72, wherein the subject has, or is selected as having, one or more lesions that do not have evidence of PD-L1 expression. 74. The method of any one of embodiments 1 to 73, wherein the subject has, or is selected for having, NSCLC that is ineligible for therapy comprising an immune checkpoint antibody. 75. The method of any one of embodiments 1 to 74, wherein the subject has, or is selected because he has, NSCLC that would likely not benefit from a treatment comprising an immune checkpoint antibody. 76. The method of any one of the preceding embodiments, wherein the tumor proportion score is determined prior to administration of the combination therapy. 77. The method of any one of the preceding embodiments, wherein the subject has, or is selected for having, NSCLC characterized as having a KRAS mutation. 78. The method of any one of the preceding embodiments, wherein the subject has, or is selected for having, NSCLC, including one or more lesions with a KRAS mutation. 79. The method of any one of the preceding embodiments, wherein the subject has or is selected as having a tumor with poor infiltration of immune cells. 80. The method of any one of the preceding embodiments, wherein the subject has, or is selected because, one or more lesions having an EMT signature. 81. The method of any one of the preceding embodiments, wherein the subject has, or is selected for having, one or more lesions indicative of an EMT signature. 82. The method of any one of the preceding embodiments, wherein the combination therapy is administered as a cycle of treatment comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof on days 1, 8, and 15, and administration of docetaxel on day 1. 83. The method according to any one of the preceding embodiments, wherein one cycle of treatment lasts one week. 84. The method according to any one of embodiments 1 to 83, wherein one cycle of treatment lasts for 2 weeks. 85. The method according to any one of the preceding embodiments, wherein one cycle of treatment lasts for 3 weeks. 86. The method according to any one of the preceding embodiments, wherein one cycle of treatment lasts for 4 weeks. 87. The method of any one of embodiments 1 to 86, wherein one cycle of treatment lasts for more than 4 weeks. 88. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered by IV infusion. 89. The method of any one of the preceding embodiments, wherein docetaxel is administered by IV infusion. 90. The method of any one of the preceding embodiments, wherein the clinical benefit is regression of the lesion. 91. The method of any one of the preceding embodiments, wherein the clinical benefit is a reduction in the size of the lesion. 92. The method of any one of the preceding embodiments, wherein the clinical benefit is stabilization of lesion size. 93. The method of any one of the preceding embodiments, wherein the clinical benefit is a reduction in the number of tumor cells in the lesion. 94. The method of any one of the preceding embodiments, wherein the reduction in size is at least 5%. 95. The method of any one of the preceding embodiments, wherein the reduction in size is at least 10%. 96. The method of any one of the preceding embodiments, wherein the reduction in size is at least 15%. 97. The method of any one of the preceding embodiments, wherein the reduction in size is at least 20%. 98. The method of any one of the preceding embodiments, wherein the reduction in size is at least 25%. 99. The method of any one of the preceding embodiments, wherein the reduction in size is at least 30%. 100. The method of any one of the preceding embodiments, wherein the reduction in size is at least 35%. 101. The method of any one of the preceding embodiments, wherein the reduction in size is at least 40%. 102. The method of any one of the preceding embodiments, wherein the reduction in size is at least 45%. 103. The method of any one of the preceding embodiments, wherein the reduction in size is at least 50%. 104. The method of any one of embodiments 1 to 103, wherein the clinical benefit is less than a 20% increase in lesion size. 105. The method of any one of embodiments 1 to 104, wherein clinical benefit is defined by RECIST 1.1 guidelines. 106. The method of any one of embodiments 1 to 105, wherein the clinical benefit is an improvement in quality of life. 107. The method according to any one of embodiments 1 to 106, wherein a clinical benefit is achieved for at least 6 weeks after an initial assessment of response to treatment. 108. The method according to any one of the preceding embodiments, wherein a clinical benefit is achieved for at least 12 weeks after the initial assessment of response to treatment. 109. The method according to any one of embodiments 1 to 108, wherein a clinical benefit is achieved for at least 18 weeks after an initial assessment of response to treatment. 110. The method according to any one of embodiments 1 to 109, wherein a clinical benefit is achieved for at least 24 weeks after an initial assessment of response to treatment. 111. The method according to any one of embodiments 1 to 110, wherein a clinical benefit is obtained for at least 30 weeks after an initial assessment of response to treatment. 112. The method according to any one of embodiments 1 to 111, wherein a clinical benefit is achieved for at least 36 weeks after an initial assessment of response to treatment. 113. The method according to any one of embodiments 1 to 112, wherein a clinical benefit is achieved for at least 42 weeks after the initial assessment of response to treatment. 114. The method of any one of embodiments 1 to 113, wherein the clinical benefit is selected from complete response (CR) by RECIST 1.1 guidelines, partial response (PR) by RECIST 1.1 guidelines, or stable disease (SD) by RECIST 1.1 guidelines. 115. The method of any one of embodiments 1 to 114, wherein the clinical benefit is a partial response (PR) according to RECIST 1.1 guidelines. 116. The method of any one of embodiments 1 to 115, wherein the clinical benefit is stable disease (SD) according to RECIST 1.1 guidelines. 117. The method of any one of embodiments 1 to 116, wherein the size of the lesion is assessed according to RECIST 1.1 guidelines. 118. The method of any one of the preceding embodiments, wherein the size of the lesion is measured by CT scan. 119. The method of any one of the preceding embodiments, wherein the clinical benefit is a reduction or elimination of metabolic activity in the lesion. 120. The method of any one of the preceding embodiments, wherein metabolic activity is assessed by PET scanning (e.g., (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)). 121. The method of any one of embodiments 1 to 120, wherein the clinical benefit is assessed using a tumor biomarker. 122. The method of any one of embodiments 1 to 121, wherein the clinical benefit is an improvement in symptoms associated with the cancer. 123. The method of any one of embodiments 1 to 122, wherein the clinical benefit is observed after two cycles of treatment. 124. The method of any one of embodiments 1 to 123, wherein the clinical benefit is observed for at least 12 weeks of treatment. 125. The method of any one of embodiments 1 to 124, wherein the clinical benefit is observed for at least 18 weeks of treatment. 126. The method of any one of embodiments 1 to 125, wherein the clinical benefit is observed for at least 24 weeks of treatment. 127. The method of any one of embodiments 1 to 126, wherein the clinical benefit is observed for at least 30 weeks of treatment. 128. The method of any one of embodiments 1 to 127, wherein the clinical benefit is observed for at least 36 weeks of treatment. 129. The method of any one of embodiments 1 to 128, wherein the clinical benefit is observed for at least 42 weeks of treatment. 130. The method according to any one of embodiments 1 to 129, wherein upon docetaxel-related toxicity, the dose of docetaxel is reduced or treatment with docetaxel is discontinued. 131. The method according to any one of the preceding embodiments, comprising administering at least one initial cycle of treatment and at least one subsequent cycle of treatment, wherein the initial cycle of treatment and the subsequent cycle of treatment are the same or different. 132. The method of any one of the preceding embodiments, wherein the initial cycle of treatment and each of the subsequent cycles of treatment comprise at least one dose of an anti-clusterin antibody or antigen-binding fragment thereof, and at least one dose of docetaxel. 133. The first cycle of treatment and / or subsequent cycles of treatment each independently comprise administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once per week, once every two weeks, or once every three weeks, and administering about 50 mg / m once per two weeks or once every three weeks. 2 ~100mg / m 2 133. The method according to any one of the preceding embodiments, comprising administration of docetaxel at a dose of: Approximately 75 mg / m2 once every 134.3 weeks 2 and administering an anti-clusterin antibody or antigen-binding fragment thereof once per week, once every two weeks, or once every three weeks. 135. Administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks. 2 135. The method of any one of the preceding embodiments, comprising administering docetaxel at a dose of: 136. Administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once every 3 weeks, and approximately 75 mg / m once every 3 weeks. 2 136. The method of any one of the preceding embodiments, comprising administering docetaxel at a dose of 137.a. Administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b. administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once every three weeks, and administering about 75 mg / m once every three weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of 137. The method of any one of the preceding embodiments, comprising administering 138.a. Administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b. administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 12 mg / kg once every three weeks, and administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 75 mg / m once every three weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of 138. The method of any one of the preceding embodiments, comprising administering 139. Approximately 50 mg / m2 once every 2 weeks 2 and administering an anti-clusterin antibody or antigen-binding fragment thereof once per week, once every two weeks, or once every three weeks. 140. Administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every two weeks. 2 140. The method of any one of the preceding embodiments, comprising administering docetaxel at a dose of: 141. Administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once every 2 weeks, and approximately 50 mg / m once every 2 weeks. 2 141. The method of any one of the preceding embodiments, comprising administering docetaxel at a dose of: 142.a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every two weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once every two weeks, and administering about 50 mg / m once every two weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of 142. The method of any one of the preceding embodiments, comprising administering 143.a) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every two weeks. 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b) administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 12 mg / kg once every two weeks, and administering about 50 mg / m once every two weeks. 2 At least one subsequent cycle of treatment comprising administration of docetaxel at a dose of 143. The method of any one of the preceding embodiments, comprising administering 144. The method of any one of embodiments 1 to 143, wherein the combination therapy is administered for two or more treatment cycles, each comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof once every two weeks, and administration of docetaxel once every two weeks. 145. The method of any one of embodiments 1 to 144, wherein the combination therapy is administered for two or more treatment cycles, each comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof once every three weeks, and administration of docetaxel once every three weeks. 146. The method of any one of embodiments 1 to 145, wherein the combination therapy is administered for at least two cycles. 147. The method of any one of embodiments 1 to 146, wherein the combination therapy is administered for at least three cycles. 148. The method of any one of embodiments 1 to 147, wherein the combination therapy is administered for at least 4 cycles. 149. The method of any one of embodiments 1 to 148, wherein the combination therapy is administered for at least 5 cycles. 150. The method of any one of embodiments 1 to 149, wherein the combination therapy is administered for at least 6 cycles. 151. The method of any one of embodiments 1 to 150, wherein the combination therapy is administered for at least 7 cycles. 152. The method of any one of embodiments 1 to 151, wherein the combination therapy is administered for at least 8 cycles. 153. The method of any one of embodiments 1 to 152, wherein the combination therapy is administered for at least 9 cycles. 154. The method of any one of embodiments 1 to 153, wherein the combination therapy is administered for at least 10 cycles. 155. The method of any one of embodiments 1 to 154, wherein the combination therapy is administered for at least 11 cycles. 156. The method of any one of embodiments 1 to 155, wherein the combination therapy is administered for more than 11 cycles. 157. The method of any one of embodiments 1 to 156, wherein the combination therapy is administered for at least 12 cycles. 158. The method of any one of embodiments 1 to 157, wherein the combination therapy is administered for at least 14 cycles. 159. The method of any one of embodiments 1 to 158, wherein the combination therapy is administered for at least 16 cycles. 160. The method of any one of embodiments 1 to 159, wherein the combination therapy is administered for at least 18 cycles. 161. The method of any one of embodiments 1 to 160, wherein the combination therapy is administered for at least 20 cycles. 162. The method of any one of embodiments 1 to 161, wherein the combination therapy is administered for at least 22 cycles. 163. The method of any one of embodiments 1 to 162, wherein the combination therapy is administered for at least one to at least five initial cycles of treatment. 164. The method of any one of embodiments 1 to 163, wherein the combination therapy is administered for two or more subsequent cycles of treatment. 165. The method of any one of the preceding embodiments, wherein the combination therapy is administered for at least one treatment cycle comprising administration of the anti-clusterin antibody or antigen-binding fragment thereof once per week, and administration of docetaxel every three weeks. 166. The method of any one of embodiments 1 to 165, wherein the combination therapy is administered for at least two treatment cycles, each comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof once per week, and administration of docetaxel once every three weeks. 167. The method of any one of embodiments 1 to 166, wherein the combination therapy is administered for at least three treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 168. The method of any one of embodiments 1 to 167, wherein the combination therapy is administered for at least four treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 169. The method of any one of embodiments 1 to 168, wherein the combination therapy is administered for at least four or more treatment cycles, each comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 170. The method of any one of embodiments 1 to 169, wherein the combination therapy is administered for at least five treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 171. The method of any one of embodiments 1 to 170, wherein the combination therapy is administered for at least six treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 172. The method of any one of embodiments 1 to 171, wherein the combination therapy is administered for at least seven treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 173. The method of any one of embodiments 1 to 172, wherein the combination therapy is administered for at least eight treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 174. The method of any one of embodiments 1 to 173, wherein the combination therapy is administered for at least nine treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 175. The method of any one of embodiments 1 to 174, wherein the combination therapy is administered for at least 10 treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 176. The method of any one of embodiments 1 to 175, wherein the combination therapy is administered for at least 11 treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 177. The method of any one of embodiments 1 to 176, wherein the combination therapy is administered for at least 12 treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 178. The method of any one of embodiments 1 to 177, wherein the combination therapy is administered for more than 12 treatment cycles, each cycle comprising one administration of the anti-clusterin antibody or antigen-binding fragment thereof per week, and one administration of docetaxel every three weeks. 179. The method according to any one of the preceding embodiments, wherein the treatment cycle is continuous. 180. The method of any one of embodiments 1 to 179, wherein the combination therapy is administered for as long as a clinical benefit is observed. 181. The method according to any one of the preceding embodiments, wherein the combination therapy is administered until tumor progression. 182. The method of any one of embodiments 1 to 181, wherein the combination therapy is administered until unmanageable toxicity occurs. 183. The method of any one of embodiments 1 to 182, wherein administration of the anti-clusterin antibody or antigen-binding fragment thereof is maintained after the appearance of clinical benefit. 184. The method of any one of embodiments 1 to 183, wherein the anti-clusterin antibody or antigen-binding fragment thereof inhibits epithelial to mesenchymal transition. 185. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is capable of binding to the C-terminal portion of the β-subunit of human clusterin. 186. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is capable of binding to an epitope contained at or within amino acids 421 and 443 of the C-terminal portion of the β-subunit of human clusterin. 187. The method of any one of embodiments 1 to 186, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 188. The method of any one of embodiments 1 to 187, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2), and SEQ ID NO:6 (CDRH3). 189. The method of any one of embodiments 1 to 188, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2), and SEQ ID NO:9 (CDRH3). 190. The anti-clusterin antibody or antigen-binding fragment thereof a. a light chain variable region having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 13; or b. a light chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:15. 190. The method of any one of the preceding embodiments, comprising: 191. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13. 192. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15. 193. The method of any one of embodiments 1 to 192, wherein the subject is not immunosuppressed or has not received an immunosuppressant within 7 days prior to treatment. 194. The method of any one of embodiments 1 to 193, wherein the subject has not received prior treatment with docetaxel. 195. The method of any one of the preceding embodiments, wherein the subject does not receive a concurrent anti-cancer treatment in conjunction with the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel combination treatment. 196. The method of any one of embodiments 1 to 195, wherein the subject is a human subject. 197. The method of any one of embodiments 1 to 196, wherein the subject has a functional immune system. 198. The method of any one of the preceding embodiments, wherein the subject has suitable organ and / or immune function. 199. The method of any one of the preceding embodiments, wherein the NSCLC is metastatic NSCLC. 200. The method of any one of embodiments 1 to 199, wherein the metastatic NSCLC is stage III NSCLC. 201. The method of any one of embodiments 1 to 200, wherein the metastatic NSCLC is stage IV NSCLC. 202. The method according to any one of the preceding embodiments, wherein the metastatic NSCLC is stage III-IV NSCLC. 203. The method according to any one of the preceding embodiments, wherein the subject with NSCLC is a subject with metastatic NSCLC. 204. The method of any one of embodiments 1 to 203, wherein the subject with metastatic NSCLC is a subject with stage III NSCLC. 205. The method of any one of embodiments 1 to 204, wherein the subject with metastatic NSCLC is a subject with stage IV NSCLC. 206. The method of any one of embodiments 1 to 205, wherein the subject has, or is selected for having, stage III-IV NSCLC. 207. The method of any one of embodiments 1 to 206, comprising promoting infiltration of immune cells into the tumor microenvironment of one or more lesions. 208. The method of any one of embodiments 1 to 207, which promotes infiltration of immune cells into the tumor microenvironment of one or more lesions. 209. The method of any one of the preceding embodiments, comprising administering immunotherapy after the combination therapy. 210. The method of any one of the preceding embodiments, wherein the lesion is a tumor metastasis. 211. The method of any one of the preceding embodiments, wherein the lesion is a primary tumor. 212. The method of any one of embodiments 1 to 211, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of ≦15%. 213. The method of any one of embodiments 1 to 212, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of <5%. 214. The method of any one of embodiments 1 to 213, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of ≦1%. 215. The method of any one of embodiments 1 to 214, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of <1%. 216. The method of any one of embodiments 1 to 215, wherein one or more lesions have a PD-L1 combined positive score (CPS) of <10%. 217. The method of any one of embodiments 1 to 216, wherein one or more lesions have a PD-L1 combined positive score (CPS) of <5%. 218. The method of any one of embodiments 1 to 217, wherein one or more lesions have a PD-L1 combined positive score (CPS) of <1%. 219. The method of any one of embodiments 1 to 218, wherein PD-L1 expression is undetectable or unevaluable. 220. The method of any one of the preceding embodiments, wherein the one or more lesions are characterized as immunologically cold. 221. The method of any one of embodiments 1 to 220, wherein the combination therapy is provided as a first-line therapy. 222. The method of any one of embodiments 1 to 221, wherein the combination therapy is provided as a second line therapy. 223. The method of any one of embodiments 1 to 222, wherein the combination therapy is provided as a subsequent therapy. 224. The method of any one of embodiments 1 to 223, wherein the subject is administered a therapeutically effective combination therapy. 225. The method of any one of embodiments 1 to 224, wherein docetaxel is discontinued. 226. The method according to any one of embodiments 1 to 225, wherein upon signs of toxicity, docetaxel is discontinued and treatment with the anti-clusterin antibody or antigen-binding fragment thereof is continued. 227. The method according to any one of the preceding embodiments, wherein docetaxel is stopped during one or more cycles of treatment. 228. The method of any one of embodiments 1 to 227, wherein upon signs of toxicity, docetaxel is stopped for one or more cycles of treatment and treatment with the anti-clusterin antibody or antigen-binding fragment thereof is continued. 229. The method of any one of the preceding embodiments, wherein the anti-clusterin antibody or antigen-binding fragment thereof is a conventional antibody. 230. A combination therapy for use in the method according to any one of embodiments 1 to 229. 231. A combination therapy comprising an anti-clusterin antibody or an antigen-binding fragment thereof and a taxane. 232. A combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and a taxane for the treatment of lung cancer. 233. A therapeutically effective combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and a taxane for use in treating non-small cell lung cancer (NSCLC) in a subject in need thereof. 234. A combination therapy comprising an anti-clusterin antibody, or antigen-binding fragment thereof, and a taxane, for use in treating a subject with non-small cell lung cancer, wherein the anti-clusterin antibody, or antigen-binding fragment thereof, comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 235. A combination therapy comprising an anti-clusterin antibody, or an antigen-binding fragment thereof, and a taxane, for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, wherein the anti-clusterin antibody, or an antigen-binding fragment thereof, comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 236. The combination therapy according to any one of embodiments 230 to 235, wherein the taxane is docetaxel or paclitaxel. 237. The combination therapy of any one of embodiments 230 to 236, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 3 mg / kg to approximately 20 mg / kg. 238. The combination therapy of any one of embodiments 230 to 237, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 6 mg / kg to approximately 20 mg / kg. 239. The combination therapy of any one of embodiments 230 to 238, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 6 mg / kg to approximately 15 mg / kg. 240. The combination therapy of any one of embodiments 230 to 239, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 6 mg / kg to approximately 14 mg / kg. 241. The combination therapy of any one of embodiments 230 to 240, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 6 mg / kg to approximately 13 mg / kg. 242. The combination therapy of any one of embodiments 230 to 241, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 6 mg / kg to approximately 12 mg / kg. 243. The combination therapy of any one of embodiments 230 to 242, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 7 mg / kg to approximately 12 mg / kg. 244. The combination therapy of any one of embodiments 230 to 243, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 8 mg / kg to approximately 12 mg / kg. 245. The combination therapy of any one of embodiments 230 to 244, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 9 mg / kg to approximately 12 mg / kg. 246. The combination therapy of any one of embodiments 230 to 245, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 10 mg / kg to approximately 12 mg / kg. 247. The combination therapy of any one of embodiments 230 to 246, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 11 mg / kg to approximately 12 mg / kg. 248. The combination therapy of any one of embodiments 230 to 247, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 12 mg / kg. 249. The combination therapy according to any one of embodiments 230 to 248, wherein the taxane is docetaxel. 250. The taxane is docetaxel, approximately 50 mg / m 2 ~ approx. 100 mg / m 2 The combination therapy according to any one of embodiments 230 to 249, wherein the combination therapy is formulated for administration at a dose of 251. The taxane is docetaxel, approximately 60 mg / m 2 ~ approx. 100 mg / m 2 The combination therapy according to any one of embodiments 230 to 250, wherein the combination therapy is formulated for administration at a dose of 252. Docetaxel is approximately 60 mg / m 2 ~ approx. 95 mg / m 2 The combination therapy according to any one of embodiments 230 to 251, wherein the combination therapy is formulated for administration at a dose of 253. Docetaxel is approximately 60 mg / m 2 ~ approx. 90 mg / m 2 The combination therapy according to any one of embodiments 230 to 252, wherein the combination therapy is formulated for administration at a dose of 254. Docetaxel is approximately 60 mg / m 2 ~ approx. 85 mg / m 2 The combination therapy according to any one of embodiments 230 to 253, wherein the combination therapy is formulated for administration at a dose of 255. Docetaxel is approximately 60 mg / m 2 ~ approx. 80 mg / m 2 The combination therapy according to any one of embodiments 230 to 254, wherein the combination therapy is formulated for administration at a dose of 256. Docetaxel is approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The combination therapy according to any one of embodiments 230 to 255, wherein the combination therapy is formulated for administration at a dose of 257. Docetaxel is approximately 60 mg / m 2 ~ approx. 75 mg / m 2 The combination therapy according to any one of embodiments 230 to 256, wherein the combination therapy is formulated for administration at a dose of 258. Docetaxel is approximately 75 mg / m 2 ~ approx. 80 mg / m 2 The combination therapy according to any one of embodiments 230 to 257, wherein the combination therapy is formulated for administration at a dose of 259. Docetaxel is approximately 50 mg / m 2 The combination therapy according to any one of embodiments 230 to 258, wherein the combination therapy is formulated for administration at a dose of 260. Docetaxel is approximately 75 mg / m 2 The combination therapy according to any one of embodiments 230 to 259, wherein the combination therapy is formulated for administration at a dose of 261. A combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof is formulated for administration at a dose of approximately 12 mg / kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, and the docetaxel is administered at a dose of approximately 50 mg / m 2 ~ approx. 75 mg / m 2 The combination therapy is formulated for administration at a dose of 262. Each cycle of treatment consists of administration of an anti-clusterin antibody at a dose of about 3 mg / kg to about 20 mg / kg once per week, and about 60 mg / m once every 3 weeks. 2 ~100mg / m 2 1. A combination therapy for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, comprising administration of a taxane at a dose of 263. Each cycle of treatment consists of administration of an anti-clusterin antibody at a dose of approximately 12 mg / kg once per week, and approximately 50 mg / m once every 3 weeks. 2 ~ approx. 75 mg / m 2 1. A combination therapy for use in obtaining a clinical benefit in a subject with non-small cell lung cancer, comprising administration of docetaxel at a dose of 264. The combination therapy according to any one of embodiments 230 to 263, for use in a subject as described herein. 265. The combination therapy according to any one of embodiments 230 to 264, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with an immune checkpoint antibody. 266. The combination therapy according to any one of embodiments 230 to 265, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with chemotherapy. 267. The combination therapy according to any one of embodiments 230 to 266, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with an anti-PD-1 immune checkpoint antibody. 268. The combination therapy according to any one of embodiments 230 to 267, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with a PD-L1 immune checkpoint antibody. 269. The combination therapy according to any one of embodiments 230 to 268, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody. 270. The combination therapy according to any one of embodiments 230 to 269, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with an immune checkpoint antibody and chemotherapy. 270-2. The combination therapy of any one of embodiments 230 to 270, for use in a subject having, or selected as having, NSCLC who has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy. 271. The combination therapy of any one of embodiments 230 to 270-2, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy. 272. The combination therapy of any one of embodiments 230 to 271, for use in a subject with, or selected as having, NSCLC who has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy. 273. The combination therapy according to any one of embodiments 230 to 272, for use in a subject having, or selected as having, a PD-L1 tumor proportion score of ≧50%. 274. The combination therapy according to any one of embodiments 230 to 273, for use in a subject with, or selected as having, a PD-L1 tumor proportion score of <50%. The combination therapy of any one of embodiments 230 to 274, for use in a subject having, or selected as having, a PD-L1 tumor proportion score of between 275.1% and 49%. 276. The combination therapy of any one of embodiments 230 to 275, wherein the subject has, or is selected because they have, one or more lesions with a PD-L1 tumor proportion score of ≦15%. 277. The combination therapy of any one of embodiments 230 to 276, wherein the subject has, or is selected because they have, one or more lesions with a PD-L1 tumor proportion score of <5%. 278. The combination therapy of any one of embodiments 230 to 277, wherein the subject has, or is selected because, one or more lesions with a PD-L1 tumor proportion score of ≦1%. 279. The combination therapy according to any one of embodiments 230 to 278, for use in a subject with, or selected as having, a PD-L1 tumor proportion score of <1%. 280. The combination therapy of any one of embodiments 230 to 279, wherein the subject has, or is selected because they have, one or more lesions that do not have evidence of PD-L1 expression. 281. The combination therapy of any one of embodiments 230 to 280, wherein the subject has, or is selected because he has, NSCLC that is ineligible for treatment comprising an immune checkpoint antibody. 282. The combination therapy of any one of embodiments 230 to 281, wherein the subject has, or is selected because he has, NSCLC that would likely not benefit from a treatment comprising an immune checkpoint antibody. 283. The combination therapy of any one of embodiments 230 to 282, wherein the tumor proportion score is determined at baseline. 284. The combination therapy according to any one of embodiments 230 to 283, wherein the tumor proportion score is determined prior to administration of the combination therapy. 285. The combination therapy according to any one of embodiments 230 to 284, for use in a subject with NSCLC characterized as having a KRAS mutation. 286. The combination therapy according to any one of embodiments 230 to 285, for use in a subject with NSCLC, including one or more lesions with a KRAS mutation. 287. The combination therapy according to any one of embodiments 230 to 286, for use in subjects having or selected as having a tumor with poor infiltration of immune cells. 288. The combination therapy according to any one of embodiments 230 to 287, for use in a subject having, or selected for having, one or more lesions indicative of an EMT signature. 289. The combination therapy according to any one of embodiments 230 to 288, for use in a subject having, or selected for having, one or more lesions indicative of an EMT signature. 290. The combination therapy of any one of embodiments 230 to 289, for administration in a cycle of treatment comprising administration of an anti-clusterin antibody or antigen-binding fragment thereof on days 1, 8, and 15, and administration of docetaxel on day 1. 291. The combination therapy of any one of embodiments 230 to 290, wherein the anti-clusterin antibody or antigen-binding fragment thereof is for use as an IV infusion. 292. The combination therapy of any one of embodiments 230 to 291, wherein docetaxel is for use as an IV infusion. 293. The combination therapy of any one of embodiments 230 to 292, wherein the clinical benefit is regression of lesions. 294. The combination therapy of any one of embodiments 230 to 293, wherein the clinical benefit is a reduction in the size of the lesion. 295. The combination therapy of any one of embodiments 230 to 294, wherein the clinical benefit is stabilization of lesion size. 296. The combination therapy of any one of embodiments 230 to 295, wherein the clinical benefit is stabilization of lesion size. 297. The combination therapy according to any one of embodiments 230 to 296, wherein the clinical benefit is a reduction in the number of tumor cells in the lesion. 298. The combination therapy of any one of embodiments 230 to 297, wherein clinical benefit is defined by RECIST 1.1 guidelines. 299. The combination therapy according to any one of embodiments 230 to 298, wherein the use provides a clinical benefit for at least 6 weeks after an initial determination of response to treatment. 300. The combination therapy of any one of embodiments 230 to 299, wherein the use provides a clinical benefit for at least 12 weeks after an initial determination of response to treatment. 301. The combination therapy of any one of embodiments 230 to 300, wherein the use provides a clinical benefit for at least 18 weeks after an initial determination of response to treatment. 302. The combination therapy of any one of embodiments 230 to 301, wherein the use provides a clinical benefit for at least 24 weeks after an initial determination of response to treatment. 303. The combination therapy of any one of embodiments 230 to 302, wherein the use provides a clinical benefit for at least 30 weeks after an initial determination of response to treatment. 304. The combination therapy of any one of embodiments 230 to 303, wherein the use provides a clinical benefit for at least 36 weeks after an initial determination of response to treatment. 305. The combination therapy of any one of embodiments 230 to 304, wherein the use provides a clinical benefit for at least 42 weeks after an initial determination of response to treatment. 306. The combination therapy of any one of embodiments 230 to 305, wherein the clinical benefit is selected from complete response (CR) according to RECIST 1.1 guidelines, partial response (PR) according to RECIST 1.1 guidelines, or stable disease (SD) according to RECIST 1.1 guidelines. 307. The combination therapy according to any one of embodiments 230 to 306, wherein the clinical benefit is a partial response (PR) according to RECIST 1.1 guidelines. 308. The combination therapy according to any one of embodiments 230 to 307, wherein the clinical benefit is stable disease (SD) according to RECIST 1.1 guidelines. 309. The combination therapy of any one of embodiments 230 to 308, wherein the size of the lesion is assessed according to RECIST 1.1 guidelines. 310. The combination therapy according to any one of embodiments 230 to 309, wherein the clinical benefit is a reduction or elimination of metabolic activity in the lesion. 311. The combination therapy of any one of embodiments 230 to 310, wherein the clinical benefit is an improvement in symptoms associated with said cancer. 312. The combination therapy according to any one of embodiments 230 to 311, for administration as at least two cycles of treatment. 313. The combination therapy according to any one of embodiments 230 to 312, for use as long as a clinical benefit is observed. 314. The combination therapy according to any one of embodiments 230 to 313, for use until tumor progression. 315. The combination therapy according to any one of embodiments 230 to 314, for use until unmanageable toxicity occurs. 316. The combination therapy according to any one of embodiments 230 to 315, wherein the use of the anti-clusterin antibody or antigen-binding fragment thereof is maintained after the appearance of clinical benefit. 317. The combination therapy of any one of embodiments 230 to 316, wherein the anti-clusterin antibody or antigen-binding fragment thereof inhibits epithelial to mesenchymal transition. 318. The combination therapy of any one of embodiments 230 to 317, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2), and SEQ ID NO:6 (CDRH3). 319. The combination therapy of any one of embodiments 230 to 318, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:1 (CDRL1), SEQ ID NO:2 (CDRL2), and SEQ ID NO:3 (CDRL3), and a heavy chain variable region comprising CDRs having the amino acid sequences set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2), and SEQ ID NO:9 (CDRH3). 320. The anti-clusterin antibody or antigen-binding fragment thereof a. a light chain variable region having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 13; or b. a light chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:14, and a heavy chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:15. The combination therapy of any one of embodiments 230 to 319, comprising: 321. The combination therapy of any one of embodiments 230 to 320, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13. 322. The combination therapy of any one of embodiments 230 to 321, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15. 323. The combination therapy according to any one of embodiments 230 to 322, for use in subjects who are not immunosuppressed or have not received an immunosuppressant within 7 days prior to treatment. 324. The combination therapy according to any one of embodiments 230 to 323, for use in subjects who have not received prior treatment with docetaxel. 325. The combination therapy according to any one of embodiments 230 to 324, for use in subjects not receiving concomitant anti-cancer treatment in conjunction with the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel combination treatment. 326. The combination therapy according to any one of embodiments 230 to 325, for use in humans. 327. The combination therapy according to any one of embodiments 230 to 326, for use in a subject having a functional immune system. 328. The combination therapy according to any one of embodiments 230 to 327, for use in subjects with appropriate organ and immune function. 329. The combination therapy according to any one of embodiments 230 to 328, for use as a first-line therapy. 330. The combination therapy according to any one of embodiments 230 to 329, for use as a second-line therapy. 331. The combination therapy according to any one of embodiments 230 to 330, for the treatment of non-small cell lung cancer. 332. The combination therapy according to any one of embodiments 230 to 331, wherein the NSCLC is metastatic NSCLC. 333. The combination therapy according to any one of embodiments 230 to 332, wherein the metastatic NSCLC is stage III NSCLC. 334. The combination therapy of any one of embodiments 230 to 333, wherein the metastatic NSCLC is stage IV NSCLC. 335. The combination therapy according to any one of embodiments 230 to 334, wherein the metastatic NSCLC is stage III to IV NSCLC. 336. The combination therapy according to any one of embodiments 230 to 335, wherein the subject with NSCLC is a subject with metastatic NSCLC. 337. The combination therapy according to any one of embodiments 230 to 336, wherein the subject with metastatic NSCLC is a subject with stage III NSCLC. 338. The combination therapy of any one of embodiments 230 to 337, wherein the subject with metastatic NSCLC is a subject with stage IV NSCLC. 339. The combination therapy of any one of embodiments 230 to 338, wherein the subject has, or is selected because, has stage III-IV NSCLC. 340. The combination therapy according to any one of embodiments 230 to 339, for obtaining a clinical benefit. 341. A combination therapy according to any one of embodiments 230 to 340, which promotes infiltration of immune cells into the tumor microenvironment of one or more lesions. 342. The combination therapy according to any one of embodiments 230 to 341, for increasing the response to immunotherapy after combination therapy. 343. The combination therapy according to any one of embodiments 230 to 342, wherein the lesion is a tumor metastasis. 344. The combination therapy according to any one of embodiments 230 to 343, wherein the lesion is a primary tumor. 345. A combination therapy according to any one of embodiments 230 to 344, for use in a method according to any one of embodiments 1 to 229. 346. The combination therapy of any one of embodiments 230 to 345, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of ≦15%. 347. The combination therapy of any one of embodiments 230 to 346, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of <5%. 348. The combination therapy of any one of embodiments 230 to 347, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of ≦1%. 349. The combination therapy of any one of embodiments 230 to 348, wherein one or more lesions have a PD-L1 Tumor Proportion Score (TPS) of <1%. 350. The combination therapy of any one of embodiments 230 to 349, wherein one or more lesions have a PD-L1 Combined Positive Score (CPS) of <10%. 351. The combination therapy of any one of embodiments 230 to 350, wherein one or more lesions have a PD-L1 Combined Positive Score (CPS) of <5%. 352. The combination therapy of any one of embodiments 230 to 351, wherein one or more lesions have a PD-L1 Combined Positive Score (CPS) of <1%. 353. The combination therapy of any one of embodiments 230 to 352, wherein PD-L1 expression is undetectable or unevaluable. 354. The combination therapy of any one of embodiments 230 to 353, wherein one or more lesions are characterized as immunologically cold. 355. The combination therapy according to any one of embodiments 230 to 354, provided as a first-line therapy. 356. The combination therapy according to any one of embodiments 230 to 355, provided as a second line therapy. 357. The combination therapy according to any one of embodiments 230 to 356, provided as a follow-on therapy. EXAMPLES

[0692] Example 1 Phase II Clinical Study Design Applicants are evaluating the use of an anti-clusterin antibody in combination with docetaxel in previously treated subjects with metastatic non-small cell lung cancer.

[0693] This Phase II study will recruit 40 patients with metastatic non-small cell lung cancer who have failed treatment with a platinum-containing doublet therapy and an anti-PD-1 or PD-L1 immune checkpoint antibody administered concomitantly or sequentially. All recruited patients will receive 75 mg / m once every 3 weeks. 2 The subjects received AB-16B5 (referred to herein as humanized 16B5) at a dose of 12 mg / kg once weekly in combination with docetaxel at a dose of 1 mg / kg once weekly.

[0694] the purpose The primary objective of this study is to determine the objective response rate (ORR) by RECIST 1.1 (Eisenhauer, EA et al., European Journal of Cancer 45:228-247 (2009)) in subjects receiving the combination of AB-16B5 and docetaxel.

[0695] Another primary objective of this study is to determine the safety and tolerability of the combination of AB-16B5 and docetaxel.

[0696] A secondary objective of this study is to determine clinical benefit rates (complete response (CR), partial response (PR), and stable disease (SD)) by RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

[0697] Another secondary objective of this study is to determine duration of response (CR and PR) by RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

[0698] A further secondary objective of this study is to determine the duration of stable disease by RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

[0699] A further secondary objective of this study is to determine progression free survival (PFS) by RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

[0700] Another secondary objective of this study is to determine overall survival (OS) in subjects receiving the combination of AB-16B5 and docetaxel.

[0701] A further secondary objective of this study is to determine the pharmacokinetics of AB-16B5 in this subject population.

[0702] The exploratory objective of this study is to conduct an exploratory pharmacokinetic evaluation of the effect of the combination of AB-16B5 and docetaxel on epithelial to mesenchymal transition (EMT) biomarkers, immune cell biomarkers, and immune checkpoints in tumor biopsies.

[0703] The exploratory objective of this study is to assess disease response using iRECIST in subjects pursuing treatment beyond progression.

[0704] Study design The investigation is an open-label, single-arm, multicenter Phase II study of AB-16B5 in combination with docetaxel in previously treated subjects with metastatic non-small cell lung cancer who have experienced disease progression after treatment with a platinum-containing doublet therapy and an anti-PD-1 or PD-L1 immune checkpoint antibody, administered concomitantly or sequentially. Approximately 40 subjects will be enrolled in the study, with docetaxel administered at 75 mg / m once every 3 weeks on Day 1. 2 Subjects will receive AB-16B5 at a dose of 12 mg / kg once weekly on days 1, 8, and 15 in combination with docetaxel at a dose of 1 mg / kg once weekly on days 1, 8, and 15. One cycle of treatment will consist of 21 days (3 weeks). The safety profile of the AB-16B5 and docetaxel combination will be examined during a safety run-in period with the first 8 subjects completing one cycle of treatment.

[0705] Subjects will be evaluated every 6 weeks with radiological imaging to assess response to treatment using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for determination of objective response rate (ORR) and progression-free survival (PFS). A futility analysis will be performed to minimize subject exposure to ineffective treatment. Paired tumor biopsies (pre- and on-treatment) will be collected in all subjects. Adverse events will be monitored throughout the study and graded for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE). Study treatment will continue until there is evidence of disease progression (defined according to RECIST 1.1), treatment-related adverse events of unacceptable severity, subject request for discontinuation, or investigator determination that further treatment is not in the subject's best interest. Continued treatment after progression will be permitted if the investigator considers the subject to be clinically stable. Subjects who must discontinue docetaxel due to toxicity will continue treatment with AB-16B5.

[0706] Safety introduction period 75 mg / m once every 3 weeks on day 1 2 The safety profile for AB-16B5 at a dose of 12 mg / kg administered weekly on days 1, 8, and 15 in combination with docetaxel at a dose of 1 mg / kg will be examined during a safety run-in period with the first 8 subjects completing one cycle of treatment. The decision to de-escalate the dose of AB-16B5 may be made using a modified toxicity probability interval method (mTPI).

[0707] Investigational treatment will be considered tolerable if 3 or fewer dose-limiting toxicities (DLTs) are observed during the first cycle in the first 8 subjects treated.

[0708] For these purposes, a DLT is defined as a grade ≧3 non-hematological toxicity occurring during cycle 1 of therapy. In addition, the following hematological toxicities are considered DLTs: Grade ≥4 neutropenia or thrombocytopenia for >7 days Grade ≥3 thrombocytopenia with bleeding Febrile neutropenia grade ≥ 3

[0709] Toxicity that is clearly and indisputably attributable to disease progression or to external causes should not be considered a DLT. In addition, the following non-hematologic toxicities should not be considered a DLT: Grade 3 joint or muscle pain that resolves to Grade ≤1 within <7 days with appropriate supportive care Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤1 within <72 hours with appropriate supportive care Grade 3 fatigue lasting <7 days Grade 3 electrolyte abnormalities lasting less than 72 hours and without clinical symptoms Grade 3 amylase or lipase elevation without symptoms or clinical signs of pancreatitis

[0710] If more than three DLTs are observed in the first eight subjects treated, a reduction in AB-16B5 will be performed.

[0711] In such cases, the next 3 subjects will receive 75 mg / m once every 3 weeks on day 1. 2 Each patient will be treated with 9 mg / kg AB-16B5 administered once weekly on days 1, 8, and 15 in combination with docetaxel at a dose of 0. If 0 or 1 DLT is observed during the first cycle in these 3 subjects, the 9 mg / kg dose of AB-16B5 will be considered tolerated.

[0712] If more than one DLT is observed, a final reduction of AB-16B5 to 6 mg / kg will be performed and the safety profile will be evaluated using the same process described above.

[0713] Inclusion criteria Subjects enrolled in the study will meet the following inclusion criteria: Subjects (male or non-pregnant female) ≥ 18 years of age on the date of signing the informed consent. Subjects with a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) (Stage III-IV) with at least one measurable lesion as defined by RECIST 1.1. Subjects who have experienced disease progression following treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy, administered concomitantly or sequentially. Subjects with targetable driver mutations in the EGFR or ALK genes who were admitted to the study after failure of available targeted therapies and have experienced disease progression following treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy, administered simultaneously or sequentially. Subjects with appropriate organ and immune function as shown in Table 1 below:

[0714] [Table 1]

[0715] -Subjects with tumor lesions suitable for biopsy, with no contraindications to biopsy. Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Subjects with a life expectancy of at least 3 months. Subjects who have recovered from toxic effects resulting from their most recent cancer treatment to less than Grade 1. If the subject has undergone major surgery or received radiation therapy, they have recovered from complications and / or toxicities. Female subjects of childbearing potential with a negative urine test or serum pregnancy test within 72 hours prior to the first dose of investigational treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. The serum pregnancy test should preferably be negative for subjects to be eligible. Subjects of reproductive potential (both males and females) willing to practice a highly effective method of contraception throughout the study and for up to 90 days after the last dose of study drug. Abstinence is permitted if this is the subject's usual lifestyle. Female subjects are not considered fertile if they have a history of surgical infertility or evidence of postmenopausal status, defined as any of the following: Age ≥ 45 years and have not had menstruation for more than 2 years. - Amenorrhea for <2 years without hysterectomy and oophorectomy and postmenopausal follicle-stimulating hormone (FSH) levels at screening. Following hysterectomy, oophorectomy, or tubal ligation. A documented hysterectomy or oophorectomy must be confirmed in the medical record of the actual procedure or by ultrasound. A tubal ligation must be confirmed in the medical record of the actual procedure.

[0716] It is to be understood herein that the inclusion criteria are for the purposes of the clinical trial only and should not be considered a limitation of the approved drug for treatment.

[0717] Exclusion criteria Subjects enrolled in the study met the following exclusion criteria: Subjects who have received prior therapy with AB-16B5. Subjects who have received prior docetaxel-based therapy for the treatment of NSCLC. Subjects who are currently participating in a study with an investigational agent or device, or have participated within 21 days prior to the first dose of investigational treatment. The 21-day window should be calculated using the last dose of antineoplastic investigational agent or last use of an investigational device with antineoplastic intent. Subjects who have received any anti-cancer treatment within 3 weeks or radiation therapy within 2 weeks prior to receiving the first dose of study treatment, or have not recovered from an adverse event to Grade 1 or less. Subjects with alopecia are eligible to participate. Subjects who are expected to require any other form of systemic or localized anti-neoplastic therapy during the study, including maintenance therapy with another agent or radiation therapy. Subjects receiving a dose of >10 mg / day prednisone (or equivalent) or any other form of immunosuppressant within 7 days prior to the first dose of study treatment (pre- and / or post-docetaxel corticosteroids are permitted). Subjects requiring treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Subjects may be included if they have alternative treatment with a weak CYP3A4 inhibitor and are willing to switch before randomization. If a subject agrees to switch from a strong inhibitor to a weak CYP3A4 inhibitor, the strong inhibitor must be discontinued at least 7 days before the first dose of study treatment. Subjects with another malignancy that is progressive or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical carcinoma in situ. Subjects with known active central nervous system metastases and / or carcinomatous meningitis. Subjects with previously treated brain metastases may enroll if they are clinically stable for at least 2 weeks prior to the first dose of study treatment, if they have no evidence of new or enlarging brain metastases, and if they have not received a dose of >10 mg / day prednisone (or equivalent) within 7 days prior to the first dose of study treatment. Subjects with clinically significant ECG abnormalities. Subjects who have received or will receive a live vaccine within 30 days prior to the first dose of investigational treatment. Subjects with a known history of human immunodeficiency virus (HIV). -Subjects with active hepatitis B or C infection. -Subjects with active infection requiring antibiotic therapy. Subjects with a known history of alcohol or other substance abuse within the past year. Subjects with known hypersensitivity to docetaxel or drugs formulated with polysorbate 80. Subjects with history or current evidence of any condition, therapy, or laboratory abnormality that may confound the outcome of the study or prevent the subject from participating for the full duration of the study, or where it is not in the subject's best interest to participate in the study. Subjects with medical, social, or psychosocial factors that, in the opinion of the treating investigator, may affect safety or compliance with study procedures. Subjects who are pregnant or lactating, or who expect to conceive or father a child within the planned duration of the study, through 90 days after the last dose of AB-16B5 or the last dose of docetaxel.

[0718] It is to be understood herein that the exclusion criteria are for the purposes of the clinical trial only and should not be considered a limitation of the drug's approval for treatment.

[0719] Investigational Treatment Investigational drugs, doses, and modes of administration AB-16B5 AB-16B5 is a humanized IgG2 monoclonal antibody targeting sCLU for the inhibition of cancer-associated EMT (humanized 16B5). AB-16B5 is provided in 10 mL vials at a protein concentration of 10.0 mg / mL. AB-16B5 is formulated in a citrate buffer solution at pH 6.0. AB-16B5 vials are stored upright at 2-8°C.

[0720] Subjects will receive AB-16B5 by 60 minute IV infusion once weekly on days 1 (prior to docetaxel infusion), 8, and 15 (see Pharmacy Manual for infusion conditions). The dose of AB-16B5 will be determined during a safety run-in period.

[0721] Subjects who experience infusion-related reactions are treated with corticosteroids such as dexamethasone. Antihistamines and acetaminophen may also be used where deemed appropriate.

[0722] Premedication to prevent AB-16B5-related infusion reactions will not be utilized initially. Subjects who have previously experienced an infusion-related reaction will be premedicated as follows: Grade 1 (mild): No premedication before subsequent doses Grade 2 (moderate): Dexamethasone 8 mg PO BID on the day before AB-16B5 infusion, plus acetaminophen 650 mg PO and diphenhydramine 25-50 mg PO 30-60 minutes before AB-16B5 infusion. Grade 3 (severe) and Grade 4 (fatal): Subject is discontinued from further treatment with AB-16B5.

[0723] If at any time during the study, clinically significant infusion-related reactions are observed in multiple subjects, the investigator may decide, in agreement with the sponsor, to pursue premedication for all new subjects.

[0724] Docetaxel Docetaxel was administered at 75 mg / m2 by 60-minute IV infusion on day 1 once every 3 weeks. 2 Docetaxel is prepared and administered in accordance with the approved product label / monograph.

[0725] All subjects should be premedicated with corticosteroids as per standard hospital practice. Venous extravasation and accidental leakage should be managed according to standard hospital practice.

[0726] Treatment duration One cycle of treatment consists of 21 days (3 weeks).

[0727] Study treatment will continue until there is evidence of disease progression, unacceptable toxicity, the subject requests discontinuation of study treatment, or the investigator feels that further treatment is not in the subject's best interest. Subjects who must discontinue docetaxel due to toxicity will continue on AB-16B5.

[0728] Continued treatment after progression will be permitted if the investigator considers the subject to be clinically stable. Site clinical decision making should be based on the subject's clinical stability, as specified below:

[0729] Clinical stability is defined as follows: Absence of symptoms and signs indicating clinically significant progression of disease, including deterioration of laboratory values No decline in ECOG performance status Absence of rapid progression of the disease Absence of progressive neoplasia in critical anatomical locations (e.g., spinal cord compression) requiring urgent alternative medical intervention

[0730] Any subject considered clinically unstable should be discontinued from study treatment upon the first radiological evidence of PD.

[0731] Investigational treatment after safety implementation, dose reduction AB-16B5 dose reduction Subjects who experience any grade > 3 adverse event judged to be possibly, probably, or probably related to AB-16B5 and do not require treatment discontinuation should have a reduction in AB-16B5 by one dose level (Table 2 below).

[0732] Treatment will be resumed at a lower dose only after resolution of adverse events to grade ≦1.

[0733] [Table 2]

[0734] Subjects whose original AB-16B5 dose has been reduced due to toxicity will not be re-escalated.

[0735] Docetaxel dose reduction Febrile neutropenia <500 cells / mm for >1 week, determined to be related to docetaxel 3 Subjects who experience either neutrophils, severe or cumulative skin reactions, or other grade ≥ 3 non-hematological toxicity should be withheld from treatment until resolution of toxicity, then receive 60 mg / m 2 Based on the subject's condition, treatment with AB-16B5 may be continued for this period.

[0736] 50 mg / m once every 2 weeks 2 The dose is 75 mg / m2 once every 3 weeks as second-line chemotherapy for advanced non-small cell lung cancer. 2 (De Petris, L et al., Anticancer Research November 2005, 25:4713-4717).

[0737] In addition, although not part of the clinical protocol, the literature suggests that in subjects experiencing febrile neutropenia, the dose of docetaxel should be increased by the physician to 65 mg / m 2 or further 50 mg / m 2 It is taught that the concentration can be reduced to as low as

[0738] Subjects who develop grade ≧3 peripheral neuropathy should discontinue docetaxel.

[0739] Example 2 Phase II Clinical Study - Preliminary Results The safety induction treatment period consisted of weekly doses of 12 mg / kg AB-16B5 and 75 mg / m 2 This study confirmed that a dose of docetaxel of 100 mg / kg / day is safe. Therefore, it is expected that lower dosages may also be safe.

[0740] FIG. 1 is a chart showing patient duration on treatment as best response by RECIST 1.1 for 6 patients with partial response (PR), 18 patients with stable disease (SD), and 10 patients with progressive disease (PD) among 34 evaluable patients, and also presents lesion measurements at the indicated time points of treatment by RECIST v1.1.

[0741] Among patients (19 patients) who received AB-16B5 in combination with docetaxel for more than 12 weeks, the best response was 6 partial responses (PR), 12 stable disease (SD), and 1 progressive disease (PD). KRAS mutations were assessed in tumors of several patients before first-line therapy. Among these 19 patients, tumors from 7 patients (4, 7, 12, 17, 18, 21) had KRAS mutations; 5 tumors were KRAS negative (3, 6, 8, 22, and 32), and KRAS status was not determined for the other 7 patients (1, 2, 5, 19, 23, 27, and 30) (Figure 1).

[0742] As can be seen in Figure 1, four of five NSCLC patients (patients 1, 2, 4, and 12) who showed evidence of partial response had low expression of PD-L1 (TPS of ≦15%).

[0743] Biopsies from some patients under treatment were obtained for analysis of various parameters. H&E staining was analyzed by a board-certified pathologist. Detection of tumor cell markers and immune cells was performed on serial histological sections. Slides were digitized and analyzed using algorithms created using the open source software QuPath™.

[0744] Histological analysis of pre- and on-treatment biopsies from two patients under study is illustrated in Figures 2a-d. Tumor sections were stained with hematoxylin and eosin. Pre-treatment samples consisted mostly of neoplastic tumor cells without evidence of inflammatory cells (a and c). In contrast, very few tumor cells could be detected in on-treatment samples (b and d). In addition, cytopathic changes caused by docetaxel (arrows in b and d) as well as active inflammatory infiltrates were observed.

[0745] Patient 1 (PT1) The PD-L1 TPS score determined during first-line therapy was 0%. Results from a scan after 8 cycles of treatment showed a 50% reduction in the size of the target lesions. This patient therefore demonstrated evidence of a partial response.

[0746] Analysis of the pre-treatment biopsies revealed mild lymphocytic infiltration in one specimen, while fibrosis and chronic inflammatory infiltrates were present in the other. However, the largest portion of the other core was replaced by neoplastic tumor cells with extensive necrosis. No residual tumor cells could be found in any of the four cores from the on-treatment biopsies. Fibrotic tissue with chronic lymphoplasmacytic inflammation was observed in the on-treatment tissue core. Lymphocyte and plasmacytic infiltration was found to be prominent in certain areas. On-treatment samples showed no residual tumor cells. Of note, fibrosis and chronic inflammation were present in the on-treatment cores. Tumor cells were only found in the pre-treatment condition.

[0747] Analysis of the Ki-67 proliferation biomarker showed high intensity staining in the pre-treatment state and a strong decrease in the signal in the on-treatment samples. Image analysis revealed a 42% reduction in proliferating tumor cells after the second cycle of treatment.

[0748] Image analysis of E-cadherin staining in the pre-treatment biopsy revealed numerous tumor cells with an H-score of 166. E-cadherin staining could not be observed in the mid-treatment biopsy, suggesting that the treatment was effective in eradicating tumor cells.

[0749] Image analysis of CD3 staining in pretreatment biopsies revealed that tumors were poorly infiltrated by T lymphocytes before the initiation of treatment, however, a 45% increase in CD3 signal was observed in treatment biopsies.

[0750] Image analysis of CD4 staining showed a 100% increase in CD4 T cells in biopsies during treatment, which increased from 4% to 8% of cells in the area of ​​interest.

[0751] Image analysis of CD8 staining showed an 86% increase in CD8 T cells in biopsies during treatment, which increased from 7% to 13% of cells in the area of ​​interest.

[0752] Patient 2 (PT2) The PD-L1 TPS score determined during first-line therapy was 0%. The patient stopped receiving docetaxel at week 33. CT scans were performed after cycles 2, 4, 6, 8, and 10 and showed a reduction in target lesion size from 24% at the end of cycle 2 to 43% at the end of cycle 10. This patient therefore demonstrates evidence of a partial response.

[0753] Analysis of the tumor biopsies revealed that the pre-treatment samples were more basophilic, reflecting the presence of numerous tumor cell aggregates. In contrast, the samples from on-treatment (end of cycle 2) showed large eosinophilic areas, reflecting extensive stromal fibrosis. Higher magnification fields for the pre-treatment condition showed widespread tumor involvement. Of note, tumor nuclei exhibited cytologic abnormalities but no changes suggestive of recent exposure to chemotherapy. There was no inflammatory reaction surrounding the neoplastic lesions. In the on-treatment condition, key findings were reported: cytopathic effects, fibrosis, and chronic lymphoplasmocytic and histiocytic inflammation. There were areas of dense sclerotic tissue with chronic inflammatory cells, and few residual tumor cells with cytopathic changes consistent with chemotherapy agents acting on the cellular spindles. Large aneuploidy and giant cells are reminiscent of changes induced by docetaxel.

[0754] Analysis of the Ki-67 proliferation biomarker showed high intensity staining in the pre-treatment state and a strong decrease in the signal in the on-treatment samples. Image analysis revealed a 67.2% reduction in proliferating cells after the second cycle of treatment.

[0755] Image analysis of E-cadherin staining in the pre-treatment biopsy revealed numerous tumor cells with an H-score of 166. E-cadherin staining could not be observed in the mid-treatment biopsy, suggesting that the treatment was effective in eradicating tumor cells.

[0756] Image analysis of CD3 staining in pretreatment biopsies revealed that tumors were poorly infiltrated by T lymphocytes before the initiation of treatment, however, a 304% increase in CD3 signal was observed in treatment biopsies.

[0757] Image analysis of CD4 staining showed a 100% increase in CD4 T cells in biopsies during treatment, which increased from 4% to 8% of cells in the area of ​​interest.

[0758] Image analysis of CD8 staining showed an 86% increase in CD8 T cells in biopsies during treatment, which increased from 7% to 13% of cells in the area of ​​interest.

[0759] Patient 3 (PT3) The PD-L1 TPS score determined during first-line therapy was 90%. The patient remained on first-line therapy for 14 months until tumor progression. Results from a CT scan after the sixth cycle of treatment showed a 12% reduction in the size of the target lesion. The patient therefore shows evidence of stable disease.

[0760] Patient 4 (PT4) The PD-L1 TPS score determined during first-line therapy was 15%. Results from CT scans showed a 34.6% and 42% reduction in tumor lesion size after two and four cycles of treatment, respectively. This patient therefore shows evidence of a durable partial response (72 weeks at time of disclosure).

[0761] These data indicate that the combination therapies, dosages, treatment regimens, and / or administration schedules of the present disclosure are safe and show indications of efficacy. These data also indicate that the combination therapies, dosages, treatment regimens, and / or administration schedules of the present disclosure are tolerated for several months, with some patients being treated for as long as 66 weeks.

[0762] Indeed, the disclosed combination therapies, dosages, and treatment regimens provide clinical benefit to several patients despite failure of prior treatment with anti-PD-1 or PD-L1 immune checkpoint antibodies and platinum-containing doublet therapy, including some with lesions with PD-L1 tumor proportion scores of <50% and <1%, and some with tumors harboring KRAS mutations.

[0763] Moreover, as can be seen from FIG. 1, in some patients, clinical benefit was observed after only two cycles of treatment and continued for at least six weeks or more after the initial assessment of response to treatment.

[0764] Thus, the combination therapy of the present disclosure may be used, for example, in NSCLC patients who have progressed following treatment involving an immune checkpoint antibody (e.g., alone or in combination with chemotherapy).

[0765] The relatively poor immune cell infiltration combined with low expression of PD-L1 may partially explain the failure of treatments containing immune checkpoint antibodies in NSCLC patients. It is believed that the combination therapy of the present disclosure may benefit NSCLC patients (e.g., metastatic NSCLC patients) who have no evidence of PD-L1 expression or have low expression of PD-L1. Therefore, the combination therapy of the present disclosure may be administered to NSCLC patients with ≦15% PD-L1 TPS instead of treatments containing immune checkpoint inhibitors.

[0766] In addition, the combination therapy of the present disclosure may be administered to NSCLC patients who are not eligible for or would likely not benefit from treatment with immune checkpoint inhibitors.

[0767] Preliminary pharmacokinetic data appears to indicate accumulation of anti-clusterin antibodies over time in treated subjects (not shown). This observation may suggest the feasibility of administering anti-clusterin antibodies every 2 weeks, every 3 weeks, monthly, or using lower doses of anti-clusterin antibodies, such as about 3 mg / kg to about 11 mg / kg. This modification of the treatment regimen may be performed for subsequent cycles of treatment, or for both the initial and subsequent cycles.

[0768] This application claims priority to U.S. Provisional Application No. 63 / 307,533, filed February 7, 2022, and to U.S. Provisional Application No. 63 / 333,597, filed April 22, 2022, the entire contents of which are incorporated herein by reference.

[0769] The embodiments and examples described herein are illustrative and are not intended to limit the scope of the claims. Variations of the foregoing embodiments, including alternatives, modifications, and equivalents, are intended by the inventors to be encompassed by the scope of the claims. The citations cited in this application are incorporated herein by reference.

[0770] References Al-Lazikani et al., Standard conformations for the canonical structures of immunoglobulins. J Mol Biol 273:927-948, 1997. Brochet et al. IMGT / V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucl Acids Res 36:W503-W508, 2008. Andrew C.R. Martin, Antibody Engineering Vol. 2, Chapter 3: Protein Sequence and Structure Analysis of Antibody Variable Domains. R. Kontermann and S. Dubel (eds.), DOI 10.1007 / 978-3-642-01147-4_3, # Springer-Verlag Berlin Heidelberg 2010 Shibue, T., Weinberg, R. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14: 611-629 (2017). Terry, S., Savagner, P., Ortiz-Cuaran, S., Mahjoubi, L., Saintigny, P., Thiery, J.-P. and Chouaib, S., New insights into the role of EMT in tumor immune escape. Mol Oncol, 11: 824-846 (2017). Lenferink, A., Cantin, C., Nantel, A. et al. Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies. Oncogene 29: 831-844 (2010). New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)” E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij; Eur J Cancer, 45 (2009) 228 -247. Cristiano Ferrario, Julie Laurin, Leon Van Kempen, Caroline Lambert, Alan Spatz, Oksana Markova, Gerald Batist, Adrian Langleben, Mario Filion, Jacques Jolivet. Phase 1 first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl): Abstract nr CT098. doi:10.1158 / 1538-7445.AM2017-CT098. Hodge, J.W. Garnett, C.T., Farsaci, B., et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int. J. Cancer. 133: 624-636 (2013). Jiang X, Dudzinski S, Beckermann KE, et al. MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy. Journal for ImmunoTherapy of Cancer 2020;8:e000328. doi:10.1136 / jitc-2019-000328. MacCallum, R. M., Martin, A. C. R. and Thornton, J. T. 'Antibody-antigen interactions: Contact analysis and binding site topography' J. Mol. Biol. 262:732-745, 1996. Ojima I., Brendan, L., Siyeon, L., Wang, C. and Wang, X., Taxane anticancer agents: a patent perspective, Expert Opin Ther Pat. 2016: 26(1): 1-20 Seymour, L. et al., iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics, Lancet Oncol. 18(3)e143-e152, 2017. Tremblay G. B., Filion, M., and Sulea, T., Anti-Clusterin Antibodies and Antigen Binding Fragments and their Use to Reduce Tumor Volume, international application No. PCT / CA2010 / 001882 filed on November 24, 2010 and published on June 3, 2011 under number WO2011 / 063523 A1. Wu and Kabat, An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J Exp Med 132:211-250, 1993. Chi, K. N., et al., Randomized Phase II Study of Docetaxel and Prednisone With or Without OGX-011 in Patients With Metastatic Castration-Resistant Prostate Cancer, J Clin Oncol. 28 :4247-4254, 2010. Zhou, J. et al., Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin, Scientific Reports, 6:29521, 2016. Radvanyl, L.G., Tumor-Infiltrating lymphocyte therapy: addressing prevailing questions, The Cancer Journal 21(6):450-464, 2015. Romeo, E. et al., The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System, Cells : 8(5):460, 2019. Peng, M. et al., The Role of Clusterin in Canacer Metastasis, Cancer Management and Research 11 :2405-2414, 2019. Taki, M. et al., Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition, Clin Can Res., 27:4669-4679, 2021. International application No. PCT / CA2006 / 001505 filed on September 13, 2006 in the name of National Research Council of Canada and published March 22, 2007, under No. WO2007 / 030930 A1. International application No. PCT / CA2021 / 050572 filed on April 27, 2021, in the name of Alethia Biotherapeutics Inc. and published on November 3, 2022, under No. WO2022 / 226623 A1. International application No. PCT / CA2022 / 050632 filed on April 26, 2022, in the name of Alethia Biotherapeutics Inc. and published on November 3, 2022, under No. WO2022 / 226637 A1. Alethia Biotherapeutics Inc. Clinical Trial Protocol entitled “AB-16B5 Combined With Docetaxel in Subjects With Metastatic Non-Small Cell Lung Cancer” identifier number: NTC043634620 published on clinicaltrials.gov on April 28, 2020. De Petris, L et al., Docetaxel Administered Every Two Weeks as Second-line Chemotherapy for Advanced Non-small Cell Lung Cancer: A Phase II Study, Anticancer Research November 2005, 25:4713-4717.

[0771]

Table 3A

[0772]

Table 3B

[0773]

Table 3C

[0774]

Table 3D

[0775]

Table 3E

[0776]

Table 3F

[0777]

Table 3G

Claims

1. A combination pharmaceutical for use in a method for treating a subject with non-small cell lung cancer (NSCLC) to maintain and / or obtain clinical benefit, comprising an anti-clusterin antibody or antigen-binding fragment thereof and a taxane, wherein the anti-clusterin antibody or antigen-binding fragment thereof is capable of binding to the C-terminal portion of the β-subunit of human clusterin.

2. 2. The pharmaceutical combination of claim 1, wherein the taxane is docetaxel, paclitaxel, or a derivative or analog selected from Abraxane®, cabazitaxel, larotaxel, mirataxel, ortataxel, or tesetaxel.

3. The combination medication described in claim 1, wherein the anti-clusterin antibody or its antigen-binding fragment is administered at a dose of approximately 12 mg / kg, the taxane is docetaxel and is administered at a dose of approximately 75 mg / m2, and the combination medication is administered for at least two cycles consisting of administration of the anti-clusterin antibody once per week and administration of docetaxel once every three weeks.

4. 2. The pharmaceutical combination of claim 1, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3 mg / kg to approximately 20 mg / kg, and / or the taxane is docetaxel and is administered at a dose of approximately 50 mg / m2 to approximately 100 mg / m2.

5. The combination pharmaceutical of claim 1, wherein the method comprises administering at least one initial cycle of treatment and at least one subsequent cycle of treatment, wherein the initial cycle of treatment and the subsequent cycle of treatment are the same or different, each comprising at least one dose of an anti-clusterin antibody or an antigen-binding fragment thereof, and at least one dose of docetaxel.

6. The initial cycle of treatment and / or subsequent cycles of treatment each independently comprise administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once per week, once every two weeks, or once every three weeks, and administering about 50 mg / m once per two weeks or once every three weeks. 2 ~100mg / m 2 6. The pharmaceutical combination of claim 5, comprising administration of docetaxel at a dose of:

7. The method comprises: a. administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b. administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg to about 20 mg / kg once every three weeks, and administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 75 mg / m once every three weeks. 2 at least one subsequent cycle of treatment comprising administration of docetaxel at a dose of The method of claim 1, comprising administering

8. The method comprises: a. administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once per week, and approximately 75 mg / m once every three weeks 2 at least one initial cycle of treatment comprising administration of docetaxel at a dose of b. administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once every three weeks, and approximately 75 mg / m once every three weeks 2 at least one subsequent cycle of treatment comprising administration of docetaxel at a dose of The method of claim 1, comprising administering

9. The pharmaceutical combination of claim 1, wherein the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day.

10. The combination pharmaceutical of claim 1, wherein the anti-clusterin antibody or antigen-binding fragment thereof comprises: a) a light chain variable region comprising the complementarity-determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13, or b) is capable of competing with the anti-clusterin antibody or antigen-binding fragment thereof of a).

11. 10. The pharmaceutical combination of claim 1, wherein the subject has or is selected for having NSCLC that has failed prior therapy comprising an immune checkpoint antibody with or without chemotherapy.

12. 12. The combination drug of claim 11, wherein the immune checkpoint antibody is an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

13. 2. The pharmaceutical combination of claim 1, wherein the subject has, or is selected for having, NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

14. 14. The combination pharmaceutical of any one of claims 11 to 13, wherein the immune checkpoint antibody is selected from pembrolizumab, ipilimumab, nivolumab, cemiplimab, atezolizumab, avelumab, or durvalumab.

15. 10. The pharmaceutical combination of claim 1, wherein the subject has or is selected because they have NSCLC characterized as having a KRAS mutation.

16. 2. The pharmaceutical combination of claim 1, wherein the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦15%, <5%, ≦1%, or <1% or with no evidence of PD-L1 expression.

17. 2. The pharmaceutical combination of claim 1, wherein the subject has or is selected as having NSCLC that is ineligible for a therapy comprising an immune checkpoint antibody, or the subject is unlikely to benefit from a therapy comprising an immune checkpoint antibody.

18. The pharmaceutical combination of claim 1, wherein the subject has or is selected because they have one or more lesions characterized as having poor infiltration of immune cells or as immunologically cold.

19. 10. The pharmaceutical combination of claim 1, wherein the subject has or is selected because they have one or more pathologies that have an EMT signature or that exhibit symptoms of an EMT signature.

20. 10. The pharmaceutical combination of claim 1, wherein the anti-clusterin antibody or antigen-binding fragment thereof is administered by IV infusion and / or the docetaxel is administered by IV infusion.

21. 2. The pharmaceutical combination of claim 1, wherein the clinical benefit is a partial response (PR) according to RECIST 1.1 guidelines, stable disease (SD) according to RECIST 1.1 guidelines, a decrease in the size of the lesions assessed according to RECIST 1.1 guidelines, or a complete response (CR) according to RECIST 1.1 guidelines.

22. The combination pharmaceutical of claim 1, wherein the combination pharmaceutical is administered for at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, at least 10 cycles, at least 11 cycles, at least 12 cycles, at least 13 cycles, at least 14 cycles, at least 15 cycles, at least 16 cycles, at least 17 cycles, at least 18 cycles, at least 19 cycles, at least 20 cycles, at least 21 cycles, or at least 22 cycles.

23. The anti-clusterin antibody or antigen-binding fragment thereof is a. a light chain variable region having complementarity determining regions (CDRs) set forth in SEQ ID NO: 12 and an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having complementarity determining regions (CDRs) set forth in SEQ ID NO: 13 and an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 13; or b. A light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12, and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:

13. The combined pharmaceutical composition of claim 1, comprising:

24. The anti-clusterin antibody or antigen-binding fragment thereof is a. a light chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain having an amino acid sequence that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 15; or b. A light chain having the amino acid sequence set forth in SEQ ID NO: 14, and a heavy chain having the amino acid sequence set forth in SEQ ID NO:

15.

24. The pharmaceutical combination of claim 23, comprising:

25. a. The subject is not immunosuppressed or has not received immunosuppressive medication within 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day prior to treatment; b. The subject is a human subject; c. the NSCLC is metastatic; and / or d.NSCLC is stage III-IV NSCLC; The combined pharmaceutical composition of claim 1.

26. The combination medication described in claim 1, wherein the combination medication is for obtaining clinical benefit in subjects with non-small cell lung cancer, and the combination medication is used for at least two cycles of treatment, each cycle of treatment comprising administration of an anti-clusterin antibody at a dose of approximately 3 mg / kg to approximately 20 mg / kg once per week, once every two weeks, once every three weeks, or once every four weeks, and administration of a taxane at a dose of approximately 50 mg / m2 to 100 mg / m2 once every two to three weeks, and the anti-clusterin antibody comprises a light chain variable region comprising the complementarity-determining region (CDR) of the light chain variable region specified in SEQ ID NO: 12 and a heavy chain variable region comprising the CDR of the heavy chain variable region specified in SEQ ID NO:

13.

27. ​​The combination pharmaceutical of claim 26, wherein the clinical benefit is partial response (PR) according to RECIST 1.1 guidelines, stable disease (SD) according to RECIST 1.1 guidelines, a decrease in lesion size assessed according to RECIST 1.1 guidelines, or complete response (CR) according to RECIST 1.1 guidelines.

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