Methods for enabling immune cell infiltration into tumors

Abstract

The present disclosure generally relates to a method for treating a subject with cancer. The method of the present disclosure can be used to allow infiltration of immune cells into the tumor microenvironment and modulate anti-tumor immune responses. The method of the present disclosure is based on the administration of an anti-cancer therapy comprising an anti-clusterin antibody or an antigen-binding fragment thereof. The anti-cancer therapy of the present disclosure can be used as an adjuvant or neoadjuvant therapy. Combination therapies, medicaments, and kits for such use are also provided.

Description

[Technical field]

[0001] The present disclosure generally relates to a method for treating a subject with cancer. The method of the present disclosure can be used to allow infiltration of immune cells into the tumor microenvironment and modulate anti-tumor immune responses. The method of the present disclosure is based on the administration of an anti-cancer therapy comprising an anti-clusterin antibody or an antigen-binding fragment thereof. The anti-cancer therapy of the present disclosure can be used as an adjuvant or neoadjuvant therapy. Combination therapies, medicaments, and kits for such use are also provided. [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 secondary sites where they proliferate. In addition, epithelial cancer cells that undergo EMT acquire behaviors that are very similar to cancer stem cells (CSCs), including intrinsic 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 these tumors are not recognized or do not induce a strong immune response, 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. 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]

[0006] [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]

[0007] [Non-Patent Document 1] Antibody Engineering by Andrew C. R. Martin, Volume 2, Chapter 3 Summary of the Invention

[0008] The applicant has made the unexpected discovery that treatment with an anti-clusterin antibody, such as AB-16B5, or an antigen-binding fragment thereof, leads to increased intratumoral immune infiltration (see International Patent Application No. PCT / CA2021 / 050572, filed April 27, 2021, the entire contents of which are incorporated by reference into this specification).

[0009] Preliminary data from a Phase II clinical trial reported herein show similar findings. The Phase II clinical trial is evaluating a combination treatment including an anti-clusterin antibody (AB-16B5, also known as humanized 16B5) and docetaxel in subjects with metastatic non-small cell lung cancer who had previously experienced disease progression after therapy with an anti-programmed death 1 (PD-1) or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment, administered simultaneously or sequentially (NCT04364620).

[0010] Thus, the anti-cancer therapies of the present disclosure can be used to modulate anti-tumor immune responses, and thus, anti-clusterin antibodies or antigen-binding fragments thereof may enhance the therapeutic effect of other anti-cancer agents or help overcome resistance.

[0011] Thus, the present disclosure, in some aspects and embodiments, relates to anti-cancer therapies comprising anti-clusterin antibodies or antigen-binding fragments thereof.

[0012] The present disclosure also relates to methods of treating a subject having cancer comprising administering to the subject an anti-cancer therapy of the present disclosure.

[0013] The present disclosure also relates to methods of modulating an anti-tumor immune response by administering an anti-cancer therapy of the present disclosure to a subject in need thereof.

[0014] For example, the disclosure encompasses treating a subject with cancer by a method comprising modulating an anti-tumor immune response by administering to the subject an anti-cancer therapy disclosed herein.

[0015] In another example, the disclosure encompasses treating a subject with cancer by a method comprising promoting infiltration of immune cells into the tumor microenvironment by administering to the subject an anti-cancer therapy disclosed herein.

[0016] In some embodiments, the subject may have one or more lesions characterized as immunologically cold.

[0017] In other embodiments, the subject may have one or more lesions that exhibit an epithelial to mesenchymal transition (EMT) signature.

[0018] According to the present disclosure, the anti-cancer therapy consists of an anti-clusterin antibody or antigen-binding fragment thereof provided as a single anti-cancer agent.

[0019] According to the present disclosure, the anti-cancer therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and another anti-cancer agent. Thus, the anti-cancer therapy can be a combination therapy.

[0020] In some embodiments, the combination therapy comprises an anti-clusterin antibody, or an antigen-binding fragment thereof, and radiation therapy.

[0021] In other embodiments, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and chemotherapy.

[0022] Exemplary embodiments of chemotherapy include alkylating agents, antimetabolites, alkaloids, antitumor antibiotics, or combinations thereof.

[0023] In some cases, the alkylating agent may be selected from, for example, altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, or a derivative or analog thereof.

[0024] In some cases, the antimetabolite may be selected from, for example, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, or a derivative or analog thereof.

[0025] In some cases, the alkaloid can be selected from, for example, vincristine, vinblastine, vinorelbine, a taxane, etoposide, teniposide, irinotecan, topotecan, or a derivative or analog thereof.

[0026] 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.

[0027] In some instances, the taxane is docetaxel.

[0028] In some instances, the taxane is paclitaxel.

[0029] In some cases, the antitumor antibiotic may be selected from, for example, daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, valrubicin, derivatives or analogs thereof.

[0030] Thus, the present disclosure provides a method for enabling infiltration of immune cells into a tumor (e.g., a solid tumor) microenvironment, comprising administering an anti-clusterin antibody or antigen-binding fragment thereof to a subject in need thereof.

[0031] According to the present disclosure, anti-clusterin antibodies or antigen-binding fragments thereof may be used to enable infiltration of immune cells into the tumor (e.g., solid tumor) microenvironment in a subject in need thereof, or in the manufacture of a medicament for enabling infiltration of immune cells into the tumor (e.g., solid tumor) microenvironment.

[0032] In some embodiments, the methods of the disclosure include administering an anti-cancer therapy disclosed herein as a neoadjuvant therapy.

[0033] In some embodiments, the methods of the disclosure include administering an anti-cancer therapy disclosed herein as an adjuvant therapy.

[0034] In some embodiments, the methods of the disclosure include administering an anti-cancer therapy prior to tumor removal or surgery.

[0035] In some embodiments, the methods of the disclosure include administering an anti-cancer therapy following tumor removal or surgery.

[0036] In some embodiments, the methods of the present disclosure include administering an anti-cancer therapy both before and after tumor removal or surgery.

[0037] The term "tumor" as used herein refers to a primary tumor or a tumor lesion (lesion). Thus, in some cases, the disclosed method is for enabling the infiltration of immune cells into the primary tumor microenvironment. In other cases, the disclosed method is for enabling the infiltration of immune cells into the microenvironment of one or more lesions.

[0038] The present disclosure also provides a method for treating a subject having cancer (eg, a solid tumor) comprising administering to a subject in need thereof an anti-clusterin antibody, or antigen-binding fragment thereof.

[0039] According to the present disclosure, anti-clusterin antibodies or antigen-binding fragments thereof may be used to treat a subject with cancer or in the manufacture of a medicament for treating a subject with cancer.

[0040] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dosage and / or dosing interval and / or treatment duration sufficient to result in infiltration of immune cells into the tumor (e.g., solid tumor) microenvironment.

[0041] The methods of the present disclosure may also include administering chemotherapy to a subject in need thereof.

[0042] In an exemplary embodiment, the chemotherapy is docetaxel, administered at a dose and / or dosing interval and / or duration sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0043] In an exemplary embodiment, both the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are each administered at a dose and / or dosing interval and / or treatment duration sufficient to enable infiltration of immune cells into the tumor microenvironment and / or chemotherapy-induced immunogenic modulation of the tumor.

[0044] According to the present disclosure, a subject in need is a subject that has a tumor or has cancer and has a functional immune system.

[0045] According to the present disclosure, a subject in need is one who has a tumor or has cancer and has adequate organ and immune function.

[0046] Thus, the present disclosure provides a method of treating a subject with cancer, comprising administering a combination therapy comprising an anti-clusterin antibody or an antigen-binding fragment thereof and docetaxel, wherein the subject has a functional immune system or appropriate organs and immune function.

[0047] According to the present disclosure, anti-clusterin antibody or antigen-binding fragment thereof and docetaxel combination therapy can be used to treat a subject with cancer, or in the manufacture of a medicament for treating a subject with cancer, wherein the subject has a functional immune system or appropriate organs and immune function.

[0048] According to the present disclosure, the methods may result in an increase (in presence or amount) of immune cells in the tumor microenvironment.

[0049] According to the present disclosure, the methods may result in increased activity of immune cells in the tumor microenvironment.

[0050] According to the present disclosure, the methods may result in modulation of the immune response against tumor cells.

[0051] According to the present disclosure, anti-clusterin antibodies or antigen-binding fragments thereof or combination therapies may result in a less immunorefractory tumor microenvironment.

[0052] According to the present disclosure, combination therapy with an anti-clusterin antibody or an antigen-binding fragment thereof and docetaxel may contribute to the creation of a more favorable immune environment with increased anti-tumor cytotoxic T cell activity.

[0053] According to the present disclosure, specific CD8 + The cell killing activity of cytotoxic T cells can be enhanced following treatment with a combination therapy.

[0054] According to the present disclosure, the methods may result in tumors that are more sensitive to chemotherapeutic agents that are normally associated with MDR1 / P-glycoprotein mediated resistance.

[0055] According to the present disclosure, the methods may result in tumors being more susceptible to treatment with immunotherapy.

[0056] Therefore, the methods of the present disclosure can also include administering an immunotherapy following treatment with an anti-cancer therapy disclosed herein.

[0057] In some embodiments, the immunotherapy comprises cellular immunotherapy (CAR-T, TIL, etc.).

[0058] In some embodiments, the immunotherapy comprises an immune checkpoint inhibitor. An exemplary embodiment of an immune checkpoint inhibitor is an immune checkpoint antibody.

[0059] In other aspects and embodiments, the methods of the present disclosure may result in, for example, regression of a lesion. In some cases, the regression may be complete. In other cases, the regression may be partial. For example, treatment may result in, for example, a decrease in the size of a lesion.

[0060] In still other aspects and embodiments, treatment may result in stabilization of lesion growth, for example.

[0061] 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.

[0062] It should also be understood herein that an increase in size of a lesion of less than approximately 20% compared to a previous or baseline measurement is considered stabilization of lesion growth.

[0063] In some embodiments, the disclosed method may result in an increase in the size of the lesion of about 20% or less than about 20% compared to the baseline measurement. In other embodiments, the disclosed method may result in an increase in the size of the lesion of about 15% or less than about 15% compared to the baseline measurement. In other embodiments, the disclosed method may result in an increase in the size of the lesion of about 10% or less than about 10% compared to the baseline measurement. In yet other embodiments, the disclosed method may result in an increase in the size of the lesion of about 5% or less than about 5% compared to the baseline measurement.

[0064] 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 pseudogrowth.

[0065] 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.

[0066] 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.

[0067] The size or metabolic activity of the lesion may be assessed by several methods known to those skilled in the art, including, by way of example and not limitation, by CT scan or positron emission tomography (PET).

[0068] According to the present disclosure, 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: 9, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 10.

[0069] 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:9, 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:10.

[0070] 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:11, 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:12.

[0071] According to the present disclosure, the antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 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: 41.

[0072] 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 shown in Table 9.

[0073] According to the present disclosure, the method may result in the infiltration of immune cells into the primary tumor microenvironment.

[0074] According to the present disclosure, the method may result in the infiltration of plasma cells into the tumor microenvironment.

[0075] According to the present disclosure, the method can result in the infiltration of T cells into the tumor microenvironment. In some embodiments, the T cells are CD4 + In some embodiments, the T cells are CD8 + In another embodiment, the T cells are CD4 + T cells and CD8 + This includes both T cells.

[0076] According to the present disclosure, the methods may result in the infiltration of B cells into the tumor microenvironment.

[0077] According to the present disclosure, the methods may result in the infiltration of T and B cells into the tumor microenvironment.

[0078] According to the present disclosure, the method may result in necrosis of the tumor.

[0079] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once a week.

[0080] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered twice weekly.

[0081] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every two weeks.

[0082] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every three weeks.

[0083] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every four weeks.

[0084] In some embodiments, docetaxel is administered once weekly.

[0085] In some embodiments, docetaxel is administered once every two weeks.

[0086] In some embodiments, docetaxel is administered once every three weeks.

[0087] In some embodiments, docetaxel is administered once every four weeks.

[0088] 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 ... 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, 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.

[0089] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg.

[0090] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg.

[0091] According to the present disclosure, docetaxel may be administered at a dose of, for example, 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 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 60 mg / m 2 ~ approx. 100 mg / m 2 is administered at a dose of

[0092] In some embodiments, docetaxel is approximately 60 mg / m 2is administered at a dose of

[0093] In some embodiments, docetaxel is approximately 75 mg / m 2 is administered at a dose of

[0094] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once weekly and approximately 75 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0095] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 12 mg / kg once weekly and approximately 60 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0096] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 9 mg / kg once weekly and approximately 75 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0097] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 9 mg / kg once weekly and approximately 60 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0098] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 6 mg / kg once weekly and about 75 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0099] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 6 mg / kg once weekly and approximately 60 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0100] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg once weekly and about 75 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0101] In some embodiments, the subject is administered an anti-clusterin antibody or antigen-binding fragment thereof at a dose of about 3 mg / kg once weekly and about 60 mg / m once every three weeks. 2 The patient is treated with a dose of docetaxel.

[0102] In some embodiments, the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel may be administered on the same day.

[0103] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel may be administered on the same day and separately.

[0104] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel may be administered by infusion over a time frame of approximately one hour.

[0105] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered over the course of a treatment period.

[0106] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered essentially throughout the course of the treatment period.

[0107] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are both administered for the first cycle of the treatment period, and then both are administered for essentially the remaining cycles of the treatment period.

[0108] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are both administered for the first 1, first 2, first 3, first 4, or first 5 cycles of the treatment period, and then both are administered for essentially the remaining cycles of the treatment period.

[0109] In some embodiments, both the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel are administered with each cycle of treatment.

[0110] In some embodiments, the subject in need is receiving no concomitant therapy other than the anti-clusterin antibody or antigen-binding fragment thereof and / or docetaxel.

[0111] In some embodiments, the subject in need does not require any concomitant therapy other than the anti-clusterin antibody, or antigen-binding fragment thereof, and / or docetaxel.

[0112] According to the present disclosure, a subject in need is a human in need.

[0113] According to the present disclosure, a subject in need is a subject having a tumor characterized as metastatic.

[0114] According to the present disclosure, a subject in need is a subject with carcinoma.

[0115] According to the present disclosure, a subject in need is a subject with metastatic cancer.

[0116] According to the present disclosure, a subject in need is a subject who has, or is selected as having, a tumor that is characterized as immunologically cold.

[0117] In some embodiments, a subject in need is a subject who has, or is selected to have, a tumor that is characterized as immunologically warm or hot, that is non-responsive to immunotherapy.

[0118] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed a prior anti-cancer treatment.

[0119] In other embodiments, the subject in need is a subject who has, or is selected as having, a carcinoma that has progressed after primary immune checkpoint therapy.

[0120] In some exemplary embodiments, the subject has not received prior therapy comprising a PD-1 or PD-L1 immune checkpoint inhibitor.

[0121] In some exemplary embodiments, the subject has undergone prior therapy comprising a PD-1 or PD-L1 immune checkpoint inhibitor.

[0122] In some exemplary embodiments, the subject has not received prior therapy involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0123] In another exemplary embodiment, the subject is one who has undergone, or is selected because they have undergone, a prior treatment involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0124] In a further embodiment, the subject has undergone, or is selected because they have undergone, a prior treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and chemotherapy.

[0125] In yet a further embodiment, the subject has undergone, or is selected because they have undergone, a prior treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and a chemotherapy doublet treatment.

[0126] In other embodiments, the subject has, or is selected as having, a carcinoma that has progressed following treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0127] In other embodiments, the subject has, or is selected as having, a carcinoma that has progressed following chemotherapy.

[0128] In additional embodiments, the subject has, or is selected as having, a carcinoma that has progressed following anti-PD-1 or anti-PD-L1 immune checkpoint antibody and chemotherapy doublet treatment.

[0129] In yet other embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0130] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed a prior treatment comprising an anti-PD-1 immune checkpoint antibody.

[0131] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed a prior treatment comprising a PD-L1 immune checkpoint antibody.

[0132] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed a prior treatment involving a CTLA-4 immune checkpoint antibody.

[0133] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior therapy comprising a combination of CTLA-4 and PD-1 immune checkpoint antibodies.

[0134] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0135] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0136] In additional embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0137] In some embodiments, the subject has, or is selected as having, metastatic cancer that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0138] In some embodiments, the doublet therapies may be provided simultaneously.

[0139] In some embodiments, the doublet therapies may be provided sequentially.

[0140] In some embodiments, a PD-L1 tumor proportion score (TPS) is assessed prior to administration of an anti-cancer therapy of the present disclosure. For example, PD-L1 TPS may be determined in one or more tumor lesions. In some embodiments, the anti-cancer therapy is administered to subjects who have low expression of programmed death-ligand 1 (PD-L1), have no evidence of PD-L1 expression, or are untreatable with anti-PD-1 or anti-PD-L1 immune checkpoint antibodies.

[0141] In yet other embodiments, the subject in need is a subject who has, or is selected as having, a carcinoma that has failed prior treatment with immune checkpoint therapy and platinum-containing doublet therapy (e.g., concomitantly or sequentially).

[0142] According to the present disclosure, a subject in need has a tumor that expresses or secretes clusterin.

[0143] In exemplary embodiments, the subject in need may have, for example, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, or melanoma.

[0144] According to the present disclosure, a subject in need is a subject with non-small cell lung cancer (NSCLC).

[0145] In some embodiments, the subject in need is a subject with metastatic NSCLC.

[0146] In some embodiments, the subject in need is a subject with stage III or IV NSCLC.

[0147] According to the present disclosure, a subject in need is a subject with breast cancer.

[0148] In some embodiments, the subject in need is a subject with metastatic breast cancer.

[0149] According to the present disclosure, a subject in need is a subject with prostate cancer.

[0150] In some embodiments, the subject in need is a subject with metastatic prostate cancer.

[0151] According to the present disclosure, a subject in need is a subject with gastric cancer.

[0152] In some embodiments, the subject in need is a subject with metastatic gastric cancer.

[0153] According to the present disclosure, a subject in need is a subject with head and neck cancer.

[0154] In some embodiments, a subject in need is a subject with metastatic head and neck cancer.

[0155] According to the present disclosure, a subject in need is a subject with thyroid cancer.

[0156] In some embodiments, a subject in need is a subject with metastatic thyroid cancer.

[0157] According to the present disclosure, a subject in need is a subject with ovarian cancer.

[0158] In some embodiments, a subject in need is a subject with metastatic ovarian cancer.

[0159] According to the present disclosure, a subject in need is a subject with endometrial cancer.

[0160] In some embodiments, a subject in need is a subject with metastatic endometrial cancer.

[0161] According to the present disclosure, a subject in need is a subject with liver cancer.

[0162] In some embodiments, the subject in need is a subject with metastatic liver cancer.

[0163] According to the present disclosure, a subject in need is a subject with colorectal cancer.

[0164] In some embodiments, the subject in need is a subject with metastatic colorectal cancer.

[0165] According to the present disclosure, a subject in need is a subject with pancreatic cancer.

[0166] In some embodiments, a subject in need is a subject with metastatic pancreatic cancer.

[0167] According to the present disclosure, a subject in need is a subject with cholangiocarcinoma.

[0168] In some embodiments, a subject in need is a subject with metastatic cholangiocarcinoma.

[0169] According to the present disclosure, a subject in need is a subject with mesothelioma.

[0170] In some embodiments, a subject in need is a subject with metastatic mesothelioma.

[0171] According to the present disclosure, a subject in need is a subject with melanoma.

[0172] In some embodiments, the subject in need is a subject with metastatic melanoma.

[0173] According to the present disclosure, a subject in need is a subject with bladder cancer.

[0174] According to the present disclosure, a subject in need is a subject with metastatic bladder cancer.

[0175] According to the present disclosure, a subject in need is a subject with cervical cancer.

[0176] According to the present disclosure, a subject in need is a subject with metastatic cervical cancer.

[0177] According to the present disclosure, a subject in need is one who is not immunosuppressed or has not received an immunosuppressant drug within 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day prior to treatment.

[0178] According to the present disclosure, a subject in need is one who has not received prior treatment with docetaxel.

[0179] According to the present disclosure, a subject is treated for one or more cycles of treatment. In some embodiments, one cycle of treatment is approximately 21 days.

[0180] In an exemplary embodiment, the subject is treated for at least one cycle of treatment.

[0181] In another exemplary embodiment, the subject is treated for at least two cycles of treatment.

[0182] In an additional exemplary embodiment, the subject is treated for at least three cycles of treatment.

[0183] In yet an additional exemplary embodiment, the subject is treated for at least 4 cycles of treatment.

[0184] 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.

[0185] In some embodiments, the treatment cycles are continuous.

[0186] 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.

[0187] According to the present disclosure, immune cell infiltration into the tumor microenvironment is confirmed by biopsy.

[0188] According to the present disclosure, infiltration of immune cells into the tumor microenvironment is confirmed by imaging (e.g., magnetic resonance imaging).

[0189] According to the present disclosure, the method includes administering an immunotherapy (such as an immune checkpoint inhibitor, cellular immunotherapy, etc.) after one or more cycles of anti-cancer therapy.

[0190] For example, the method includes administering one or more cycles of an anti-clusterin antibody or antigen-binding fragment thereof as a single agent or in combination therapy with docetaxel, followed by immunotherapy (immune checkpoint inhibitors, cellular immunotherapy).

[0191] In some embodiments, the immunotherapy comprises cellular immunotherapy (CAR-T, TIL, etc.).

[0192] In some embodiments, the immunotherapy comprises an immune checkpoint inhibitor.

[0193] In some embodiments, the method includes administering one or more cycles of an anti-clusterin antibody or antigen-binding fragment thereof, either as a single agent or in combination therapy with docetaxel, followed by ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab.

[0194] In some embodiments, the subject is treated with one or more cycles of anti-cancer therapy and then treated with an immune checkpoint inhibitor that he has not previously received.

[0195] For example, a subject is treated with one or more cycles of an anti-clusterin antibody or antigen-binding fragment thereof, either as a single agent or in combination therapy with docetaxel, and then treated with an immune checkpoint inhibitor to which he has not previously received.

[0196] The present disclosure also provides anti-cancer therapies comprising anti-clusterin antibodies or antigen-binding fragments thereof.

[0197] In some embodiments, the anti-cancer therapy is for use in the methods described herein.

[0198] In some embodiments, the anti-cancer therapy is for use in treating a subject as described herein.

[0199] For example, the anti-cancer therapies of the present disclosure may be used to treat subjects with early stage cancer.

[0200] In another example, the anti-cancer therapies of the present disclosure may be used to treat subjects with late stage cancer.

[0201] In some embodiments, anti-cancer therapies may be used to enable infiltration of immune cells into the tumor (e.g., solid tumor) microenvironment in a subject with cancer.

[0202] The anti-cancer therapy can be used in methods of treating a subject with cancer, for example, by promoting infiltration of immune cells into the tumor microenvironment.

[0203] In some embodiments, the anti-cancer therapy of the present disclosure may be used as a neoadjuvant therapy, for example, the anti-cancer therapy may be used prior to tumor removal.

[0204] The anti-cancer therapy of the present disclosure can be used as an adjuvant therapy, for example, the anti-cancer therapy of the present disclosure can be used following tumor removal.

[0205] In some embodiments, anti-cancer therapy may be used before and after tumor removal.

[0206] Thus, the anti-cancer therapy may be used in subjects with resectable tumors. In some embodiments, the anti-cancer therapy is a combination therapy described herein.

[0207] In some embodiments, the anti-cancer therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof in combination with docetaxel for the treatment of a subject with cancer, wherein the subject has a functional immune system or appropriate organs and immune function.

[0208] 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.

[0209] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is formulated as an intravenous infusion for delivery of a dose of approximately 3 mg / kg to approximately 20 mg / kg.

[0210] In some embodiments, docetaxel is formulated as an injectable solution at a concentration of about 10 mg / mL to about 40 mg / mL.

[0211] In some embodiments, docetaxel is approximately 60 mg / m 2 ~ approx. 100 mg / m 2 It has been formulated as an intravenous infusion for delivery of a dose of

[0212] The present disclosure provides pharmaceutical compositions comprising an anti-clusterin antibody or antigen-binding fragment thereof formulated for administration at a dose of about 3 mg / kg to about 20 mg / kg, and a pharmaceutical composition comprising an anti-clusterin antibody or antigen-binding fragment thereof formulated for administration at a dose of about 60 mg / kg 2 ~100mg / m 2 and a pharmaceutical composition comprising docetaxel formulated for administration at a dose of

[0213] According to the present disclosure, an anti-clusterin antibody or antigen-binding fragment thereof comprises the CDRs, variable regions, or light and heavy chains described herein.

[0214] According to the present disclosure, the combination therapy is used or for use in treating a subject in need thereof.

[0215] According to the present disclosure, the combination therapy is used or for use in treating a subject with a cancer described herein.

[0216] In some exemplary embodiments, the combination therapy is used or is for use in treating a subject with carcinoma.

[0217] In some exemplary embodiments, the combination therapy is used or is for use in treating a subject with metastatic cancer.

[0218] According to the present disclosure, the combination therapy is used or for use in treating a subject who has or is selected as having a carcinoma that has progressed after first-line immune checkpoint therapy.

[0219] According to the present disclosure, the combination therapy is used or for use in treating a subject having, or selected as having, a carcinoma that has failed prior treatment with a platinum-containing doublet therapy and an immune checkpoint therapy (e.g., simultaneously or sequentially).

[0220] According to the present disclosure, the combination therapy is used or for use in treating a subject having, or selected as having, a carcinoma that has failed prior treatment with a platinum-containing doublet therapy and an anti-PD1 or PD-L1 immune checkpoint antibody (e.g., simultaneously or sequentially).

[0221] In some exemplary embodiments, the combination therapy is used or is for use in treating a subject with non-small cell lung cancer, hi some embodiments, the subject has metastatic NSCLC or stage III-IV NSCLC.

[0222] In some exemplary embodiments, the combination therapy is used or is for use in treating a subject with breast cancer, prostate cancer, gastric cancer, head and neck cancer, thyroid cancer, or ovarian cancer.

[0223] In other exemplary embodiments, the combination therapy is used or for use in treating a subject with metastatic breast cancer, metastatic prostate cancer, metastatic gastric cancer, metastatic head and neck cancer, metastatic thyroid cancer, or metastatic ovarian cancer.

[0224] In some exemplary embodiments, the combination therapy is used or is for use in subjects who are not immunosuppressed or who have not received an immunosuppressant within 7 days prior to treatment.

[0225] In some exemplary embodiments, the combination therapy is used in or for use in subjects who have not had prior treatment with docetaxel.

[0226] In some embodiments, both the pharmaceutical composition comprising the anti-clusterin antibody, or antigen-binding fragment thereof, and the pharmaceutical composition comprising docetaxel are administered over the course of a treatment period.

[0227] According to the present disclosure, the anti-clusterin antibodies or antigen-binding fragments thereof are used or for use in the dosages disclosed herein.

[0228] In accordance with the present disclosure, docetaxel is used or for use in the dosages disclosed herein.

[0229] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 12 mg / kg once weekly and docetaxel is used at a dose of 75 mg / m once every three weeks. 2 is used in doses of

[0230] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 12 mg / kg once weekly and docetaxel is used at a dose of 60 mg / m once every three weeks. 2 is used in doses of

[0231] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 9 mg / kg once weekly and docetaxel is used at a dose of 75 mg / m once every three weeks. 2 is used in doses of

[0232] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 9 mg / kg once weekly and docetaxel is used at a dose of 60 mg / m once every three weeks. 2 is used in doses of

[0233] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 6 mg / kg once weekly and docetaxel is used at a dose of 75 mg / m once every three weeks. 2 is used in doses of

[0234] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 6 mg / kg once weekly and docetaxel is used at a dose of 60 mg / kg once every three weeks. 2 is used in doses of

[0235] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 3 mg / kg once weekly and docetaxel is used at a dose of 75 mg / m once every three weeks. 2 is used in doses of

[0236] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is used or for use at a dose of 3 mg / kg once weekly and docetaxel is used at a dose of 60 mg / m once every three weeks. 2 is used in doses of

[0237] The present disclosure also provides kits comprising anti-cancer therapies for use in the methods described herein and for treating the subjects described herein.

[0238] In some embodiments, the kit comprises 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 chemotherapeutic agent for use in combination therapy, and a package insert containing instructions for use for treating a subject in need thereof.

[0239] The present disclosure also 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.

[0240] The kits of the present disclosure comprise an anti-clusterin antibody or antigen-binding fragment thereof disclosed herein.

[0241] In some embodiments, the package insert states that the combination therapy is intended for the treatment of a subject with carcinoma.

[0242] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma that is metastatic.

[0243] In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject in need thereof as disclosed herein.

[0244] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma that has progressed after first-line immune checkpoint therapy.

[0245] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma who have failed prior treatment with immune checkpoint therapy and platinum-containing doublet therapy (e.g., simultaneously or sequentially).

[0246] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma who have failed prior treatment with an anti-PD1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy (e.g., simultaneously or sequentially).

[0247] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with non-small cell lung cancer (NSCLC), such as advanced NSCLC, stage III NSCLC, and / or stage IV NSCLC.

[0248] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with breast cancer.

[0249] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic breast cancer.

[0250] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with prostate cancer.

[0251] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic prostate cancer.

[0252] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with gastric cancer.

[0253] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic gastric cancer.

[0254] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with head and neck cancer.

[0255] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic head and neck cancer.

[0256] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with thyroid cancer.

[0257] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic thyroid cancer.

[0258] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with ovarian cancer.

[0259] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic ovarian cancer.

[0260] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with endometrial cancer.

[0261] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic endometrial cancer.

[0262] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with liver cancer.

[0263] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic liver cancer.

[0264] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with colorectal cancer.

[0265] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic colorectal cancer.

[0266] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with pancreatic cancer.

[0267] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic pancreatic cancer.

[0268] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with cholangiocarcinoma.

[0269] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic cholangiocarcinoma.

[0270] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with mesothelioma.

[0271] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic mesothelioma.

[0272] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with melanoma.

[0273] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic melanoma.

[0274] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with bladder cancer.

[0275] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic bladder cancer.

[0276] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with cervical cancer.

[0277] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic cervical cancer.

[0278] In some embodiments, the package insert states that the combination therapy is intended for treatment of subjects who are not immunosuppressed or have not received an immunosuppressant within 7 days prior to treatment.

[0279] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects who have not received prior treatment with docetaxel.

[0280] In some embodiments, the package insert describes that the combination therapy is for administration essentially over the course of a treatment period (eg, throughout the treatment period).

[0281] The present disclosure also relates to a kit comprising one or more containers containing at least one dose of the pharmaceutical disclosed herein and a package insert disclosed herein containing instructions for use to treat a subject in need thereof, wherein the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are provided in separate containers. [Brief description of the drawings]

[0282] [Figure 1] 4T1 lung metastases are immunologically "cold", preventing immune lymphocyte infiltration. CD3+ and CD8+ T cells are present at the periphery of 4T1 lung metastases due to the creation of a restrictive tumor microenvironment as a result of epithelial to mesenchymal transition, preventing lymphocyte infiltration. [Figure 2A] FIG. 1 shows that inhibition of EMT with 16B5 anti-sCLU mAb results in B (B220) and T (CD3, CD4, CD8) lymphocyte infiltration into 4T1 lung metastases. [Figure 2B] Photographs of human tumor biopsies from patients treated with AB-16B5 as a single agent. [Diagram 3] 1 is a graph of the number of lung nodules in 4T1-implanted animals treated with AB-16B5 in monotherapy or in combination with docetaxel. [Figure 4A] FIG. 4T1 lung metastases from animals treated with AB-16B5 in monotherapy or in combination with docetaxel are infiltrated by B and T lymphocytes. 4T1 lung metastases were dissected 36 days after implantation and treated with collagenase and hyaluronidase for immunophenotyping by flow cytometry. [Figure 4B] FIG. 4T1 lung metastases from animals treated with AB-16B5 in monotherapy or in combination with docetaxel are infiltrated by B and T lymphocytes. 4T1 lung metastases were dissected 36 days after implantation and treated with collagenase and hyaluronidase for immunophenotyping by flow cytometry. [Diagram 5] Diagram showing patient duration on treatment as best response by RECIST 1.1 (PT; patient, BR; best response, PD-L1; PD-L1 tumour proportion score, PR; partial response, SD; stable disease, PD; progressive disease, AE; adverse event). [Figure 6] 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

[0283] 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:

[0284] Detailed Description definition Unless otherwise indicated, amino acid numbering shown for dimerization domains is according to the EU numbering system.

[0285] 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.

[0286] Unless specifically stated or clear from the context, as used herein, the term "or" is understood to be inclusive, covering both "or" and "and."

[0287] 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.

[0288] 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.

[0289] For the purposes of this disclosure, the term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those prone to having the disorder or those in whom the disorder is to be prevented.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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 that 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.

[0294] 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, or that the subject is not immunosuppressed.

[0295] 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.

[0296] The phrase "adequate organ and immune function" refers to one or more of the parameters provided in Table 7.

[0297] Methods and Uses

[0298] In some aspects and embodiments, the present disclosure provides methods for enabling infiltration of immune cells into the tumor microenvironment.

[0299] In some embodiments, the methods of the disclosure are used to treat a subject with cancer.

[0300] In yet other aspects and embodiments, the present disclosure provides a method for treating a subject having cancer comprising promoting infiltration of immune cells into the tumor microenvironment by administering to a subject in need thereof an anti-cancer therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof.

[0301] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof is administered as a single agent to a subject in need thereof.

[0302] In other exemplary embodiments, anti-clusterin antibodies or antigen-binding fragments thereof may be used in combination therapies described herein.

[0303] The methods of the present disclosure may also include administering other therapies to improve the anti-tumor response. In some exemplary embodiments, the methods may include administering cytokines and / or chemokines.

[0304] It should be understood herein that the anti-clusterin antibodies or antigen-binding fragments thereof may be used as single agents for a desired period of time and then used in combination therapy.

[0305] In some embodiments, the methods of the disclosure are for treating a subject as disclosed herein.

[0306] For example, the methods are for treating human subjects. In some cases, the methods are used to treat, for example, adults (i.e., ≧18 years of age).

[0307] In some cases, the methods include administering an anti-cancer therapy comprising an anti-clusterin antibody, or an antigen-binding fragment thereof, in combination with an anti-cancer agent.

[0308] In an exemplary embodiment, the method comprises administering an anti-clusterin antibody, or antigen-binding fragment thereof, in conjunction with radiation therapy or chemotherapy.

[0309] In certain embodiments, the methods comprise administering an anti-clusterin antibody, or antigen-binding fragment thereof, in combination with a chemotherapeutic agent.

[0310] In some cases, the methods of the disclosure can be used to overcome or reduce chemotherapy resistance mediated by MDR1 / P-glycoprotein. Thus, the combination therapy can include a chemotherapy agent that is associated with MDR1 / P-glycoprotein mediated resistance.

[0311] In some exemplary embodiments, the methods may include administering an anti-clusterin antibody or antigen-binding fragment thereof and a chemotherapeutic agent, including, for example, an alkylating agent, an antimetabolite, an alkaloid, an antitumor antibiotic, or a combination thereof.

[0312] In some cases, the method may include administering an anti-clusterin antibody or an antigen-binding fragment thereof and an alkylating agent selected from, for example, altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, or a derivative or analog thereof.

[0313] In other cases, the method may include administering an anti-clusterin antibody or antigen-binding fragment thereof and an antimetabolite selected from, for example, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, or a derivative or analog thereof.

[0314] In yet other cases, the method may include administering an anti-clusterin antibody or antigen-binding fragment thereof and an alkaloid selected from, for example, vincristine, vinblastine, vinorelbine, a taxane, etoposide, teniposide, irinotecan, topotecan, or a derivative or analog thereof.

[0315] In some cases, the method may include administering an anti-clusterin antibody or an antigen-binding fragment thereof and a taxane selected from docetaxel, paclitaxel, and derivatives or analogs including, by way of example and not limitation, Abraxane®, cabazitaxel, larotaxel, mirataxel, ortataxel, tesetaxel, and others.

[0316] In an exemplary embodiment, the method may include administering an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel.

[0317] In another exemplary embodiment, the method may comprise administering an anti-clusterin antibody or antigen-binding fragment thereof and paclitaxel.

[0318] In other cases, the method may include administering an anti-clusterin antibody or antigen-binding fragment thereof and an anti-tumor antibiotic selected from, for example, daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, valrubicin, derivatives or analogs thereof.

[0319] For example, anti-clusterin antibodies or antigen-binding fragments thereof may be used in combination with docetaxel, such as to produce chemotherapy-induced immunogenic modulation.

[0320] In some embodiments, the methods of the disclosure more particularly comprise administering to a subject in need thereof an anti-clusterin antibody or antigen-binding fragment thereof in combination with docetaxel.

[0321] In some exemplary embodiments, the methods are for treating carcinomas including, by way of example and not limitation, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, or melanoma.

[0322] In further exemplary embodiments, the method is for treating metastatic cancer, including, by way of example and not limitation, metastatic endometrial cancer, metastatic breast cancer, metastatic liver cancer, metastatic prostate cancer, metastatic renal cancer, metastatic bladder cancer, cervical cancer, metastatic ovarian cancer, metastatic colorectal cancer, metastatic pancreatic cancer, metastatic lung cancer, metastatic gastric cancer, metastatic head and neck cancer, metastatic thyroid cancer, metastatic cholangiocarcinoma, metastatic mesothelioma, or metastatic melanoma.

[0323] In some embodiments, the methods are for treating a subject with carcinoma or metastatic cancer with one or more lesions that has low expression of PD-L1, has no evidence of PD-L1 expression, or is ineligible for treatment involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0324] In some embodiments, the methods are for treating a subject who is not eligible for, or who would not likely benefit from, a treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint inhibitor.

[0325] Thus, the methods of the disclosure are for treating a subject having a carcinoma or metastatic cancer characterized by one or more lesions that have low expression of PD-L1, have no evidence of PD-L1 expression, or are ineligible for treatment involving anti-PD-1 or anti-PD-L1 immune checkpoint antibodies, wherein the carcinoma or method is as described herein and / or exemplified below.

[0326] In a further aspect, the disclosure also relates to a method of treating a subject having a carcinoma that would not likely benefit from a treatment involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0327] The disclosure also relates to a method for allowing infiltration of immune cells into one or more lesions characterized as immunologically cold and further characterized as having low expression of Programmed Death-Ligand 1 (PD-L1), having no evidence of PD-L1 expression, or being untreatable with an anti-PD-1 or anti-PD-L1 immune checkpoint antibody (e.g., as monotherapy, in combination with chemotherapy, etc.), the method comprising administering to a subject having the one or more lesions an anti-cancer therapy comprising an anti-clusterin antibody or an antigen-binding fragment thereof.

[0328] In some embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of ≧50%.

[0329] In some embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of <50%.

[0330] In some embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of 1-49%.

[0331] In some embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of ≦15%.

[0332] In other embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of <5%.

[0333] In some embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of ≦1%.

[0334] In an additional embodiment, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of <1%.

[0335] In other embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 combined positive score (CPS) of <10%.

[0336] In other embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 combined positive score (CPS) of <5%.

[0337] In yet other embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 combined positive score (CPS) of ≦1%.

[0338] In yet other embodiments, the methods of the disclosure are for treating a subject having a carcinoma having one or more lesions with a PD-L1 combined positive score (CPS) of <1%.

[0339] In a further embodiment, the methods of the disclosure are for treating a subject having a carcinoma in which PD-L1 expression is undetectable or inevaluable.

[0340] In some aspects and embodiments, the methods of the present disclosure may promote the infiltration of immune cells into the tumor microenvironment.

[0341] In some cases, the methods of the disclosure may be used to modulate an anti-tumor immune response.

[0342] In some embodiments, modulation of anti-tumor immune responses may include increasing immune responses to tumor cells. In some cases, the methods of the present disclosure may induce tumor regression. In other cases, the methods of the present disclosure may induce stabilization of tumor growth.

[0343] In some embodiments, the methods of the disclosure are for treating a subject having a carcinoma characterized by having one or more immunologically cold lesions.

[0344] In some cases, immunologically cold lesions may also have low expression of PD-L1 or no evidence of PD-L1 expression.

[0345] In other embodiments, the methods of the disclosure are for treating a subject having a carcinoma characterized by having one or more lesions with an epithelial to mesenchymal transition (EMT) signature.

[0346] In other embodiments, the methods of the disclosure are for treating a subject having a carcinoma characterized by having one or more lesions indicative of an EMT signature.

[0347] In yet other embodiments, the methods of the disclosure are for treating a subject having a carcinoma characterized by having one or more lesions that harbor a KRAS mutation.

[0348] In some embodiments, the method is for treating a subject with non-small cell lung cancer (NSCLC).

[0349] In an exemplary embodiment, the method is for treating a subject with metastatic NSCLC.

[0350] In another exemplary embodiment, the method is for treating a subject with stage III NSCLC.

[0351] In another exemplary embodiment, the method is for treating a subject with stage IV NSCLC.

[0352] In another exemplary embodiment, the method is for treating a subject with stage III-IV NSCLC.

[0353] In some embodiments, the method is for treating a subject with lung adenocarcinoma.

[0354] In some embodiments, the method is for treating a subject with squamous cell lung cancer.

[0355] In some embodiments, the method is for treating a subject with large cell lung cancer.

[0356] In some embodiments, the method is for treating a subject with adenosquamous lung carcinoma.

[0357] In some embodiments, the method is for treating a subject having non-small cell lung cancer characterized by having a KRAS mutation (eg, metastatic non-small cell lung cancer).

[0358] In other embodiments, the method is for treating a subject with breast cancer.

[0359] In yet other embodiments, the method is for treating a subject with metastatic breast cancer.

[0360] In a further embodiment, the method is for treating a subject with prostate cancer.

[0361] In other embodiments, the method is for treating a subject with metastatic prostate cancer.

[0362] In an additional embodiment, the method is for treating a subject with bladder cancer.

[0363] In yet an additional embodiment, the method is for treating a subject with metastatic bladder cancer.

[0364] In an exemplary embodiment, the method is for treating a subject with cervical cancer.

[0365] In another exemplary embodiment, the method is for treating a subject with metastatic cervical cancer.

[0366] In some embodiments, the method is for treating a subject with gastric cancer.

[0367] In other embodiments, the method is for treating a subject with metastatic gastric cancer.

[0368] In an additional embodiment, the method is for treating a subject with head and neck cancer.

[0369] In a further embodiment, the method is for treating a subject with metastatic head and neck cancer.

[0370] In yet a further embodiment, the method is for treating a subject with thyroid cancer.

[0371] In some embodiments, the methods are for treating a subject with metastatic thyroid cancer.

[0372] In some embodiments, the methods are for treating a subject with ovarian cancer.

[0373] In other embodiments, the method is for treating a subject with metastatic ovarian cancer.

[0374] In a further embodiment, the method is for treating a subject with endometrial cancer.

[0375] In yet a further embodiment, the method is for treating a subject with metastatic endometrial cancer.

[0376] In some embodiments, the method is for treating a subject with liver cancer.

[0377] In other embodiments, the method is for treating a subject with metastatic liver cancer.

[0378] In some embodiments, the method is for treating a subject with colorectal cancer.

[0379] In an additional embodiment, the method is for treating a subject with metastatic colorectal cancer.

[0380] In other embodiments, the method is for treating a subject with pancreatic cancer.

[0381] In other embodiments, the method is for treating a subject with metastatic pancreatic cancer.

[0382] In some embodiments, the method is for treating a subject with cholangiocarcinoma.

[0383] In a further embodiment, the method is for treating a subject with metastatic cholangiocarcinoma.

[0384] In yet a further embodiment, the method is for treating a subject with mesothelioma.

[0385] In some embodiments, the method is for treating a subject with metastatic mesothelioma.

[0386] In an exemplary embodiment, the method is for treating a subject with melanoma.

[0387] In another exemplary embodiment, the method is for treating a subject with metastatic melanoma.

[0388] In some exemplary embodiments, the methods are for treating a subject who has not had prior treatment involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0389] In another exemplary embodiment, the method is for treating a subject who has undergone a prior therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0390] In another exemplary embodiment, the method is for treating a subject who has undergone a prior therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and chemotherapy.

[0391] In another exemplary embodiment, the method is for treating a subject who has undergone a prior therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and a chemotherapy doublet therapy.

[0392] According to the present disclosure, the doublet therapies can be provided simultaneously.

[0393] According to the present disclosure, doublet therapies may be provided sequentially.

[0394] According to the present disclosure, the methods are for treating a subject having a carcinoma that has progressed after prior treatment.

[0395] For example, the methods are for treating a subject having a carcinoma that has progressed after prior therapy including an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0396] According to the disclosure, the methods are for treating a subject having a carcinoma that has progressed after prior therapy including an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0397] In another exemplary embodiment, the method is for treating a subject who has failed a prior therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0398] In another exemplary embodiment, the method is for treating a subject who has failed prior therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and chemotherapy.

[0399] In another exemplary embodiment, the method is for treating a subject whose prior treatment comprises an anti-PD-1 immune checkpoint antibody.

[0400] In another exemplary embodiment, the method is for treating a subject whose prior treatment comprises an anti-PD-L1 immune checkpoint antibody.

[0401] In other exemplary embodiments, the method is for treating a subject where the prior therapy includes, by way of example and not limitation, ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab.

[0402] In another exemplary embodiment, the method is for treating a subject whose prior treatment includes pembrolizumab.

[0403] In other exemplary embodiments, the method is for treating a subject who is not eligible for treatment with ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab.

[0404] In certain embodiments, the methods are for treating a subject who is not eligible for treatment with pembrolizumab.

[0405] In another exemplary embodiment, the method is for treating a subject having appropriate organ and / or immune function.

[0406] In another exemplary embodiment, the method is for treating a subject having a functional immune system.

[0407] In some embodiments, the methods comprise administering an anti-clusterin antibody, or an antigen-binding fragment thereof, capable of inhibiting epithelial to mesenchymal transition of cancer cells.

[0408] In some embodiments, the method comprises administering an anti-clusterin antibody having an amino acid sequence as shown in Table 9, or an antigen-binding fragment thereof.

[0409] In some embodiments, the method comprises administering an anti-clusterin antibody or antigen-binding fragment thereof having a variable region of the humanized 16B5 antibody. According to the present disclosure, the method comprises administering as a first-line therapy an anti-cancer therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof.

[0410] According to the present disclosure, the method includes administering, as a second line therapy, an anti-cancer therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof.

[0411] According to the present disclosure, the method includes administering, as a subsequent therapy (eg, third line or later), an anti-cancer therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof.

[0412] In some embodiments, the methods of the disclosure may include treating a subject with an early stage cancer.

[0413] In other embodiments, the methods of the disclosure may include treating a subject with late stage cancer.

[0414] The present disclosure also relates to a method of treating cancer by administering an anti-cancer therapy as a neoadjuvant therapy, the method comprising administering the anti-cancer therapy prior to tumor removal, according to the present disclosure.

[0415] The present disclosure also relates to a method of treating cancer by administering an anti-cancer therapy as an adjuvant therapy, the method comprising administering the anti-cancer therapy after tumor removal, according to the present disclosure.

[0416] The methods of the present disclosure may include administering an anti-cancer therapy of the present disclosure before and after tumor removal.

[0417] In other aspects and embodiments, the present disclosure relates to the use of an anti-clusterin antibody, or an antigen-binding fragment thereof, to enable infiltration of immune cells into a tumor (e.g., a solid tumor) microenvironment in a subject in need thereof.

[0418] In yet other aspects and embodiments, the present disclosure relates to the use of an anti-clusterin antibody or antigen-binding fragment thereof in the manufacture of a medicament or kit for enabling infiltration of immune cells into a tumor (e.g., a solid tumor) microenvironment in a subject in need thereof.

[0419] In additional aspects and embodiments, the disclosure relates to the use of an anti-clusterin antibody, or an antigen-binding fragment thereof, in treating a subject with cancer (e.g., a solid tumor).

[0420] In still additional aspects and embodiments, the present disclosure relates to the use of an anti-clusterin antibody, or antigen-binding fragment thereof, in the manufacture of a medicament or kit for the treatment of a subject with cancer (e.g., a solid tumor).

[0421] In additional aspects and embodiments, the present disclosure relates to the use of a combination therapy comprising an anti-clusterin antibody, or an antigen-binding fragment thereof, and docetaxel in treating a subject with cancer (e.g., a solid tumor).

[0422] In still additional aspects and embodiments, the present disclosure relates to the use of an anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel in the manufacture of a medicament or kit for treating a subject with cancer (e.g., a solid tumor).

[0423] In some embodiments, the subject in need is a subject with cancer and a functioning immune system.

[0424] In some embodiments, a subject in need is a subject with cancer and adequate organ and immune function.

[0425] In some embodiments, the methods of the present disclosure may result in an increase (in presence or quantity) of immune cells in the tumor microenvironment.

[0426] In some embodiments, the methods or uses of the present disclosure may result in the infiltration of immune cells into the primary tumor microenvironment.

[0427] In some embodiments, the tumor microenvironment may be infiltrated with immune cells, such as plasma cells.

[0428] In some embodiments, the methods or uses of the present disclosure may result in the infiltration of T cells into the tumor microenvironment.

[0429] In some embodiments, the methods or uses of the present disclosure include administering to the tumor microenvironment CD4 + This may result in T cell infiltration.

[0430] In some embodiments, the methods or uses of the present disclosure include administering to the tumor microenvironment CD8 + This may result in T cell infiltration.

[0431] In some embodiments, the methods or uses of the present disclosure may result in the infiltration of B cells into the tumor microenvironment.

[0432] In some embodiments, the absence or presence of immune cells in the tumor microenvironment may be confirmed by tumor biopsy.

[0433] 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).

[0434] "Cold tumors" include, for example, tumors that do not likely induce a strong immune response. Cold tumors tend to be surrounded by cells that can suppress immune responses and prevent T cells from attacking and killing tumor cells. Cold tumors usually do not respond to immunotherapy (National Cancer Institute website).

[0435] 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."

[0436] 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."

[0437] Liquid biopsies can also be a useful method to determine tumor immunogenicity. For example, low tumor immunogenicity can provide an indication that a patient has an immunologically cold tumor.

[0438] Liquid biopsies offer the possibility to assess the total tumor burden by monitoring the levels of circulating tumor DNA (ctDNA) or by quantifying circulating tumor cells (CTCs). Both techniques allow the assessment of tumor genomic instability by determining microsatellite stability or by identifying driver mutations in cancer genes. Tumor cells with microsatellite stability predict a lower number of neoantigens contributing to lower immunogenicity. It is also possible to monitor gene signatures in RNA isolated from CTCs. CTCs with partial EMT or high EMT signatures may predict poor outcome for patients, including those treated with immunotherapy, since EMT contributes to the generation of a "cold" or restrictive tumor microenvironment.

[0439] Thus, following confirmation that a subject has an "immunologically cold tumor," single agent or combination therapy may be administered.

[0440] In addition, detection of immune cells in the tumor microenvironment may reveal that treatment with anti-clusterin antibodies or antigen-binding fragments thereof as single agents or in combination with docetaxel effectively enables infiltration of immune cells into the tumor microenvironment.

[0441] The disclosed methods or uses may result in tumors that are more sensitive to treatment with immunotherapy. Thus, the disclosure includes administering one or more cycles of an anti-clusterin antibody or antigen-binding fragment thereof as a single agent or in combination with docetaxel, followed by immunotherapy.

[0442] Immunotherapies include, for example, immune checkpoint inhibitors (anti-PD1 or anti-PDL-1 antibodies, anti-CTL-A4 antibodies) and cellular immunotherapies (e.g., CAR-T cells, TILs).

[0443] Exemplary embodiments of FDA-approved immune checkpoint inhibitors include ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

[0444] In some embodiments, the methods or uses of the present disclosure may result in modulation of the immune response against tumor cells.

[0445] The methods or uses of the present disclosure may result in an increased immune response against tumor cells.

[0446] In some embodiments, the methods or uses of the present disclosure may result in necrosis of the tumor.

[0447] In other aspects and embodiments, the present disclosure relates to methods of treating a subject with cancer by administering an anti-clusterin antibody or antigen-binding fragment thereof. The subject may have a functional immune system.

[0448] In yet other aspects and embodiments, the present disclosure relates to a method of treating a subject with cancer by administering a combination therapy comprising an anti-clusterin antibody or antigen-binding fragment thereof and docetaxel. The subject may have a functional immune system. The subject may have adequate organs and immune function.

[0449] In some embodiments, the methods or uses of the present disclosure do not require concurrent anti-cancer therapy during the treatment period.

[0450] In some embodiments, the methods or uses of the present disclosure do not involve concomitant anti-cancer therapy during the treatment period.

[0451] According to the present disclosure, the method or use comprises administering an anti-clusterin antibody or antigen-binding fragment thereof at a dose of approximately 3 mg / kg to approximately 20 mg / kg.

[0452] Also according to the present disclosure, the method or use comprises 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 ~ approx. 100 mg / m 2 The method includes administering a dose of docetaxel.

[0453] The anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are generally administered on the same day. However, they can be administered on different days.

[0454] The anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are both administered throughout the course of the treatment period, hi some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are both administered in each cycle.

[0455] The anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are both administered essentially throughout the course of the treatment period, hi some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered in every cycle.

[0456] 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.

[0457] 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.

[0458] In some embodiments, at least one treatment cycle is discontinued.

[0459] In other embodiments, more than one treatment cycle is discontinued.

[0460] 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.

[0461] In some embodiments, the method or use may involve treating a subject in need of treatment with one or more cycles of anti-clusterin antibody or antigen-binding fragment thereof and docetaxel combination therapy, and then treating the subject with the anti-clusterin antibody or antigen-binding fragment thereof as a single agent.

[0462] In some embodiments, the method or use may involve treating a subject in need of treatment with an anti-clusterin antibody or antigen-binding fragment thereof as a single agent, and then treating the subject with one or more cycles of anti-clusterin antibody or antigen-binding fragment thereof and docetaxel combination therapy.

[0463] According to the present disclosure, the method or use is for the treatment of carcinoma in a subject in need thereof.

[0464] According to the present disclosure, the method or use is for the treatment of metastatic cancer in a subject in need thereof.

[0465] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In exemplary embodiments, the cancer is metastatic NSCLC, such as stage III-IV NSCLC.

[0466] In some embodiments, the cancer is breast cancer. In an exemplary embodiment, the cancer is metastatic breast cancer.

[0467] In some embodiments, the cancer is prostate cancer. In an exemplary embodiment, the cancer is metastatic prostate cancer.

[0468] In some embodiments, the cancer is gastric cancer. In an exemplary embodiment, the cancer is metastatic gastric cancer.

[0469] In some embodiments, the cancer is head and neck cancer. In exemplary embodiments, the cancer is metastatic head and neck cancer.

[0470] In some embodiments, the cancer is thyroid cancer. In an exemplary embodiment, the cancer is metastatic thyroid cancer.

[0471] In some embodiments, the cancer is ovarian cancer. In an exemplary embodiment, the cancer is metastatic ovarian cancer.

[0472] In other embodiments, the disclosure relates to the use of the anti-cancer therapies disclosed herein as adjuvant therapy.

[0473] In yet other embodiments, the present disclosure relates to the use of the anti-cancer therapies disclosed herein as neoadjuvant therapy.

[0474] Dosage, Treatment Regimens, and Schedules Anti-clusterin antibody According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose sufficient to result in infiltration of immune cells into the tumor microenvironment.

[0475] In some embodiments, the dose of the anti-clusterin antibody or antigen-binding fragment thereof is a therapeutically effective and safe dose.

[0476] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered at intervals sufficient to result in infiltration of immune cells into the tumor microenvironment.

[0477] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered for a therapeutic period sufficient to result in infiltration of immune cells into the tumor microenvironment.

[0478] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose, interval between doses, and / or duration of treatment sufficient to result in infiltration of immune cells into the tumor microenvironment.

[0479] According to an exemplary embodiment of the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once a week.

[0480] According to another exemplary embodiment of the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered twice weekly.

[0481] According to yet another exemplary embodiment of the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered three times per week.

[0482] According to a further exemplary embodiment of the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every two weeks.

[0483] According to yet a further exemplary embodiment of the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every three weeks.

[0484] According to additional exemplary embodiments of the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered once every four weeks.

[0485] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg to about 20 mg / kg.

[0486] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 3.0 mg / kg.

[0487] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 4.0 mg / kg.

[0488] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 5.0 mg / kg.

[0489] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6.0 mg / kg.

[0490] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 7.0 mg / kg.

[0491] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 8.0 mg / kg.

[0492] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9.0 mg / kg.

[0493] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 10.0 mg / kg.

[0494] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 11.0 mg / kg.

[0495] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12.0 mg / kg.

[0496] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 13.0 mg / kg.

[0497] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 14.0 mg / kg.

[0498] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 15.0 mg / kg.

[0499] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 16.0 mg / kg.

[0500] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 17.0 mg / kg.

[0501] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 18.0 mg / kg.

[0502] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 19.0 mg / kg.

[0503] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 20.0 mg / kg.

[0504] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 3 mg / kg to approximately 20 mg / kg.

[0505] According to the present disclosure, humanized 16B5 is administered at a dose of about 4 mg / kg to about 20 mg / kg.

[0506] According to the present disclosure, humanized 16B5 is administered at a dose of about 5 mg / kg to about 20 mg / kg.

[0507] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 20 mg / kg.

[0508] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 18 mg / kg.

[0509] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 17 mg / kg.

[0510] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 16 mg / kg.

[0511] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 15 mg / kg.

[0512] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 14 mg / kg.

[0513] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 13 mg / kg.

[0514] According to the present disclosure, humanized 16B5 is administered at a dose of about 6 mg / kg to about 12 mg / kg.

[0515] According to the present disclosure, humanized 16B5 is administered at a dose of about 7 mg / kg to about 12 mg / kg.

[0516] According to the present disclosure, humanized 16B5 is administered at a dose of about 8 mg / kg to about 12 mg / kg.

[0517] According to the present disclosure, humanized 16B5 is administered at a dose of about 9 mg / kg to about 12 mg / kg.

[0518] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 3.0 mg / kg.

[0519] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 4.0 mg / kg.

[0520] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 5.0 mg / kg.

[0521] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 6.0 mg / kg.

[0522] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 7.0 mg / kg.

[0523] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 8.0 mg / kg.

[0524] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 9.0 mg / kg.

[0525] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 10.0 mg / kg.

[0526] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 11.0 mg / kg.

[0527] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 12.0 mg / kg.

[0528] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 13.0 mg / kg.

[0529] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 14.0 mg / kg.

[0530] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 15.0 mg / kg.

[0531] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 16.0 mg / kg.

[0532] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 17.0 mg / kg.

[0533] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 18.0 mg / kg.

[0534] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 19.0 mg / kg.

[0535] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 20.0 mg / kg.

[0536] Docetaxel According to the present disclosure, docetaxel is administered at a dose sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0537] In some embodiments, the dose of docetaxel is a therapeutically effective and safe dose.

[0538] According to the present disclosure, docetaxel is administered at a dosing interval sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0539] According to the present disclosure, docetaxel is administered for a treatment period sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0540] In some embodiments, docetaxel is administered at a dose and / or dosing interval and / or duration sufficient to allow chemotherapy-induced immunogenic modulation of the tumor.

[0541] According to an exemplary embodiment of the present disclosure, docetaxel is administered once weekly.

[0542] According to another exemplary embodiment of the present disclosure, docetaxel is administered once every two weeks.

[0543] According to yet another exemplary embodiment of the present disclosure, docetaxel is administered once every three weeks.

[0544] According to a further exemplary embodiment of the present disclosure, docetaxel is administered once every four weeks.

[0545] According to a further exemplary embodiment of the present disclosure, docetaxel is administered once every five weeks.

[0546] According to a further exemplary embodiment of the present disclosure, docetaxel is administered once every six weeks.

[0547] According to the present disclosure, docetaxel is administered at approximately 60 mg / m 2 ~ approx. 100 mg / m 2 is administered at a dose of

[0548] According to the present disclosure, docetaxel is administered at approximately 60 mg / m 2 ~ approx. 95 mg / m 2 is administered at a dose of

[0549] According to the present disclosure, docetaxel is administered at approximately 60 mg / m 2 ~ approx. 90 mg / m 2 is administered at a dose of

[0550] According to the present disclosure, docetaxel is administered at approximately 60 mg / m 2 ~ approx. 85 mg / m 2 is administered at a dose of

[0551] According to the present disclosure, docetaxel is administered at approximately 60 mg / m 2 ~ approx. 80 mg / m 2 is administered at a dose of

[0552] According to the present disclosure, docetaxel is administered at approximately 60 mg / m 2 ~ approx. 75 mg / m 2 is administered at a dose of

[0553] According to the present disclosure, docetaxel is administered at approximately 70 mg / m 2 ~ approx. 75 mg / m 2 is administered at a dose of

[0554] In some embodiments, docetaxel is approximately 60 mg / m 2 is administered at a dose of

[0555] In some embodiments, docetaxel is approximately 65 mg / m 2 is administered at a dose of

[0556] In some embodiments, docetaxel is approximately 70 mg / m 2 is administered at a dose of

[0557] In some embodiments, docetaxel is approximately 75 mg / m 2 is administered at a dose of

[0558] In some embodiments, docetaxel is approximately 80 mg / m 2 is administered at a dose of

[0559] In some embodiments, docetaxel is approximately 85 mg / m 2 is administered at a dose of

[0560] In some embodiments, docetaxel is approximately 90 mg / m 2 is administered at a dose of

[0561] In some embodiments, docetaxel is approximately 95 mg / m 2 is administered at a dose of

[0562] In some embodiments, docetaxel is at approximately 100 mg / m 2 is administered at a dose of

[0563] combination The present disclosure provides, in some aspects and embodiments, anti-cancer therapies comprising an anti-clusterin antibody, or an antigen-binding fragment thereof, to enable infiltration of immune cells into the tumor (e.g., solid tumor) microenvironment in a subject with cancer.

[0564] In some embodiments, the anti-cancer therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and an anti-cancer agent.

[0565] In some cases, the anti-cancer therapy is a combination therapy.

[0566] Thus, the combination therapy may include an anti-clusterin antibody or antigen-binding fragment thereof and an anti-cancer agent, such as, by way of example and not limitation, radiation therapy or chemotherapy.

[0567] Thus, in some embodiments, the combination therapy comprises an anti-clusterin antibody, or an antigen-binding fragment thereof, and radiation therapy.

[0568] In other embodiments, the combination therapy comprises an anti-clusterin antibody or antigen-binding fragment thereof and chemotherapy.

[0569] In an exemplary embodiment, anti-clusterin antibodies or antigen-binding fragments thereof are used to overcome or reduce chemotherapy resistance mediated by MDR1 / P-glycoprotein.

[0570] Thus, the combination therapy may include chemotherapeutic agents that are associated with MDR1 / P-glycoprotein mediated resistance.

[0571] Exemplary embodiments of chemotherapy include alkylating agents, antimetabolites, alkaloids, antitumor antibiotics, or combinations thereof.

[0572] In some cases, the alkylating agent may be selected from, for example, altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, or a derivative or analog thereof.

[0573] In some cases, the antimetabolite may be selected from, for example, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, or a derivative or analog thereof.

[0574] In some cases, the alkaloid can be selected from, for example, vincristine, vinblastine, vinorelbine, a taxane, etoposide, teniposide, irinotecan, topotecan, or a derivative or analog thereof.

[0575] 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.

[0576] In some instances, the taxane is docetaxel.

[0577] In some instances, the taxane is paclitaxel.

[0578] In some cases, the antitumor antibiotic may be selected from, for example, daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, valrubicin, derivatives or analogs thereof.

[0579] In other aspects and embodiments, the disclosure provides pharmaceutical compositions comprising an anti-clusterin antibody or antigen-binding fragment thereof formulated for administration at a dose of about 3 mg / kg to about 20 mg / kg, and at a dose of about 60 mg / kg to about 70 mg / kg. 2 ~100mg / m 2 and a pharmaceutical composition comprising docetaxel formulated for administration at a dose of

[0580] In some embodiments, the combination therapy is for use in enabling infiltration of immune cells into the tumor (e.g., solid tumor) microenvironment.

[0581] In other embodiments, the combination therapy is for use in treating a subject with cancer.

[0582] In yet other embodiments, the combination therapy is for use in treating a subject with cancer and a functional immune system.

[0583] In yet other embodiments, the combination therapy is for use in treating cancer and a subject with appropriate organ and immune function.

[0584] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are each administered at a dose sufficient to allow infiltration of immune cells into the tumor microenvironment and / or chemotherapy-induced immunogenic modulation of the tumor.

[0585] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are each administered at a dosing interval sufficient to allow infiltration of immune cells into the tumor microenvironment and / or chemotherapy-induced immunogenic modulation of the tumor.

[0586] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are each administered for a therapeutic period sufficient to allow infiltration of immune cells into the tumor microenvironment and / or chemotherapy-induced immunogenic modulation of the tumor.

[0587] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are each administered at a dose, dosing interval, and / or treatment duration sufficient to enable infiltration of immune cells into the tumor microenvironment and / or chemotherapy-induced immunogenic modulation of the tumor.

[0588] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg once weekly and the docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0589] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 12 mg / kg once weekly and the docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0590] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg once weekly and the docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0591] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 9 mg / kg once weekly and the docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0592] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg once weekly and the docetaxel is administered at a dose of approximately 75 mg / m once every three weeks. 2 is administered at a dose of

[0593] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of approximately 6 mg / kg once weekly and the docetaxel is administered at a dose of approximately 60 mg / m once every three weeks. 2 is administered at a dose of

[0594] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg once weekly and the docetaxel is administered at a dose of about 75 mg / m once every three weeks. 2 is administered at a dose of

[0595] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered at a dose of about 3 mg / kg once weekly and the docetaxel is administered at a dose of about 60 mg / m once every three weeks. 2 is administered at a dose of

[0596] The anti-clusterin antibodies or antigen-binding fragments thereof used in the combination therapy are as described herein.

[0597] For example, an anti-clusterin antibody or antigen-binding fragment thereof used in combination therapy may have a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 9, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 10.

[0598] In an exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof used in the combination therapy may have 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.

[0599] In another exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof used in the combination therapy may have 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:35, CDRH2 having the amino acid sequence set forth in SEQ ID NO:36, and CDRH3 having the amino acid sequence set forth in SEQ ID NO:37.

[0600] In yet another exemplary embodiment, the anti-clusterin antibody or antigen-binding fragment thereof used in the combination therapy may have 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 the amino acid sequence set forth in SEQ ID NO:7, 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 the amino acid sequence set forth in SEQ ID NO:8.

[0601] 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:7, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:8.

[0602] In some embodiments, the 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 the amino acid sequence set forth in SEQ ID NO:9, 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 the amino acid sequence set forth in SEQ ID NO:10.

[0603] 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:9, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:10.

[0604] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:11, and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:12.

[0605] 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:11, and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:12.

[0606] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 12 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0607] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 12 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0608] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 9 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0609] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 9 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0610] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 6 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0611] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 6 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0612] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 3 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 is administered at a dose of

[0613] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 3 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 is administered at a dose of

[0614] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of about 3 mg / kg to about 20 mg / kg once weekly, and docetaxel is administered at a dose of about 60 mg / m once every three weeks. 2 ~ approx. 100 mg / m 2 and both are administered essentially over the course of the treatment period.

[0615] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of about 4 mg / kg to about 18 mg / kg once weekly, and docetaxel is administered at a dose of about 60 mg / m once every three weeks. 2 ~ approx. 100 mg / m 2 and both are administered essentially over the course of the treatment period.

[0616] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of about 5 mg / kg to about 16 mg / kg once weekly, and docetaxel is administered at a dose of about 60 mg / m once every three weeks. 2 ~ approx. 100 mg / m 2 and both are administered essentially over the course of the treatment period.

[0617] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of about 6 mg / kg to about 15 mg / kg once weekly, and docetaxel is administered at a dose of about 60 mg / m once every three weeks. 2 ~ approx. 100 mg / m 2 and both are administered essentially over the course of the treatment period.

[0618] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of about 6 mg / kg to about 12 mg / kg once weekly, and docetaxel is administered at a dose of about 60 mg / m once every three weeks. 2 ~ approx. 100 mg / m 2 and both are administered essentially over the course of the treatment period.

[0619] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 12 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2and both are administered essentially over the course of the treatment period.

[0620] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 9 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 and both are administered essentially over the course of the treatment period.

[0621] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 9 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 and both are administered essentially over the course of the treatment period.

[0622] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 6 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 and both are administered essentially over the course of the treatment period.

[0623] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 6 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 and both are administered essentially over the course of the treatment period.

[0624] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 3 mg / kg once weekly, and docetaxel is administered at a dose of 75 mg / m once every three weeks. 2 and both are administered essentially over the course of the treatment period.

[0625] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is humanized 16B5 and is administered at a dose of 3 mg / kg once weekly, and docetaxel is administered at a dose of 60 mg / m once every three weeks. 2 and both are administered essentially over the course of the treatment period.

[0626] 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.

[0627] For example, if both the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered weekly, the treatment cycle is considered to be 7 days.

[0628] For example, if the anti-clusterin antibody or antigen-binding fragment thereof is administered weekly and docetaxel is administered every two weeks, the treatment cycle is considered to be 14 days.

[0629] For example, if the anti-clusterin antibody or antigen-binding fragment thereof is administered weekly and docetaxel is administered every three weeks, the treatment cycle is considered to be 21 days.

[0630] In some exemplary embodiments, one treatment cycle is approximately 21 days.

[0631] In some exemplary embodiments, essentially every treatment cycle is about 21 days.

[0632] In some exemplary embodiments, each treatment cycle is approximately 21 days.

[0633] According to the present disclosure, a subject may therefore undergo a new treatment cycle every 21 days.

[0634] According to the present disclosure, a subject may undergo at least one cycle of treatment.

[0635] According to the present disclosure, a subject may undergo at least two cycles of treatment.

[0636] According to the present disclosure, a subject may receive at least three cycles of treatment.

[0637] According to the present disclosure, a subject may receive at least four cycles of treatment.

[0638] According to the present disclosure, a subject may undergo four or more cycles of treatment.

[0639] According to the present disclosure, a subject may receive at least five treatment cycles.

[0640] According to the present disclosure, a subject may receive at least six treatment cycles.

[0641] According to the present disclosure, a subject may receive at least seven treatment cycles.

[0642] According to the present disclosure, a subject may receive at least eight treatment cycles.

[0643] According to the present disclosure, a subject may receive at least nine treatment cycles.

[0644] According to the present disclosure, a subject may receive at least 10 treatment cycles.

[0645] According to the present disclosure, a subject may receive at least 11 treatment cycles.

[0646] According to the present disclosure, a subject may receive at least 12 treatment cycles.

[0647] According to the present disclosure, a subject may receive at least 13 treatment cycles.

[0648] According to the present disclosure, a subject may receive at least 14 treatment cycles.

[0649] According to the present disclosure, a subject may receive at least 15 treatment cycles.

[0650] According to the present disclosure, a subject may receive at least 16 treatment cycles.

[0651] According to the present disclosure, a subject may receive at least 17 treatment cycles.

[0652] According to the present disclosure, a subject may receive at least 18 treatment cycles.

[0653] According to the present disclosure, a subject may receive at least 19 treatment cycles.

[0654] According to the present disclosure, a subject may receive at least 20 treatment cycles.

[0655] According to the present disclosure, a subject may undergo more than 20 cycles of treatment.

[0656] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered by injection, for example, intravenous infusion.

[0657] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof is administered by infusion over a time frame of approximately one hour.

[0658] In some embodiments, the docetaxel is administered by infusion over a time frame of approximately one hour.

[0659] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are administered on the same day.

[0660] The anti-clusterin antibody or antigen-binding fragment thereof and docetaxel may be administered separately.

[0661] The anti-clusterin antibody or antigen-binding fragment thereof and docetaxel may be administered sequentially.

[0662] 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.

[0663] 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.

[0664] According to the present disclosure, the combination therapy may be used in subjects with carcinoma.

[0665] According to the present disclosure, the combination therapy may be used in subjects with metastatic cancer.

[0666] In some embodiments, the combination therapy may be used in subjects with non-small cell lung cancer (NSCLC), such as metastatic NSCLC or stage III-IV NSCLC.

[0667] In exemplary embodiments, the combination therapy may be used in subjects with breast cancer, prostate cancer, gastric cancer, head and neck cancer, thyroid cancer, or ovarian cancer.

[0668] In exemplary embodiments, the combination therapy may be used in subjects with metastatic breast cancer, metastatic prostate cancer, metastatic gastric cancer, metastatic head and neck cancer, metastatic thyroid cancer, or metastatic ovarian cancer.

[0669] According to the present disclosure, both the pharmaceutical composition comprising the anti-clusterin antibody or antigen-binding fragment thereof and the pharmaceutical composition comprising docetaxel are administered essentially over the course of the treatment period.

[0670] Anti-clusterin antibody or antigen-binding fragment thereof The present disclosure relates to the use of anti-clusterin antibodies or antigen-binding fragments thereof alone (single agent) or in combination with chemotherapeutic agents that induce immunogenic modulation, such as docetaxel.

[0671] In some embodiments, the anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure may inhibit epithelial to mesenchymal transition.

[0672] In some embodiments, the anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure may bind to 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).

[0673] In some embodiments, the anti-clusterin antibodies or antigen-binding fragments thereof of the present disclosure may bind to an epitope contained 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).

[0674] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises the CDRs of an anti-clusterin antibody or antigen-binding fragment thereof of the present disclosure.

[0675] 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:41.

[0676] 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.

[0677] In certain embodiments, all CDRs are identified using the Kabat definition (Wu and Kabat, 1970), which is the most commonly used definition.

[0678] 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.

[0679] 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: 9, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 10.

[0680] 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.

[0681] 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.

[0682] 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:35, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:36, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:37.

[0683] 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.

[0684] 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:35, CDRH2 having the amino acid sequence set forth in SEQ ID NO:36, and CDRH3 having the amino acid sequence set forth in SEQ ID NO:37.

[0685] 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:7, 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:8.

[0686] 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:7, 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:8.

[0687] 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:7, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:8.

[0688] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO:7 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:8 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:41.

[0689] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:9, and a heavy chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:10.

[0690] 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:9, 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:10.

[0691] 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:9, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:10.

[0692] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 10 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: 41.

[0693] 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:11, and a heavy chain having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:12.

[0694] 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:11, and a heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:12.

[0695] 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:11, and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:12.

[0696] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO:11 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:12 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:41.

[0697] In other specific 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: 15, CDRL2 having the amino acid sequence set forth in SEQ ID NO: 16, and CDRL3 having the amino acid sequence set forth in SEQ ID NO: 17.

[0698] 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: 18, a CDRH2 having the amino acid sequence set forth in SEQ ID NO: 19, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO: 20.

[0699] 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:38, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:39, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:40.

[0700] 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: 15, CDRL2 having the amino acid sequence set forth in SEQ ID NO: 16, and CDRL3 having the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain variable region comprising CDRH1 having the amino acid sequence set forth in SEQ ID NO: 18, CDRH2 having the amino acid sequence set forth in SEQ ID NO: 19, and CDRH3 having the amino acid sequence set forth in SEQ ID NO: 20.

[0701] 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: 15, CDRL2 having the amino acid sequence set forth in SEQ ID NO: 16, and CDRL3 having the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain variable region comprising CDRH1 having the amino acid sequence set forth in SEQ ID NO: 38, CDRH2 having the amino acid sequence set forth in SEQ ID NO: 39, and CDRH3 having the amino acid sequence set forth in SEQ ID NO: 40.

[0702] 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:21, 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:22.

[0703] 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:21, 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:22.

[0704] 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:21, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:22.

[0705] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO:21 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:22 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:41.

[0706] 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:23, 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:24.

[0707] 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:23, 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:24.

[0708] 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:23, and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:24.

[0709] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 23 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 24 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: 41.

[0710] 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:25, and a heavy chain having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:26.

[0711] 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:25, and a heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:26.

[0712] 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:25, and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:26.

[0713] In some embodiments, the anti-clusterin antibody or antigen-binding fragment thereof can compete with an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO:25 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:26 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:41.

[0714] 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 9. The amino acid sequences of the antibodies identified as 16B5, 21B12, 20E11, 11E2, and 16C11 are disclosed in International Application No. PCT / CA2006 / 001505, filed Sep. 13, 2006, and published Mar. 22, 2007 under WO2007 / 030930, the entire contents of which are incorporated herein by reference. 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.

[0715] 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 9.

[0716] subject

[0717] The anti-cancer therapies disclosed herein are administered to a subject, such as a subject in need thereof, hi some embodiments, the subject in need thereof is a subject with cancer.

[0718] According to the present disclosure, the subject is a human.

[0719] In some embodiments, the subject is an adult, 18 years of age or older. The single and combination therapies disclosed herein are generally administered to human subjects.

[0720] In some aspects and embodiments of the present disclosure, the subject in need is a subject with cancer.

[0721] In some aspects and embodiments of the present disclosure, the subject in need is a subject who has, or has been selected as having, early stage cancer.

[0722] In some aspects and embodiments of the present disclosure, a subject in need is a subject who has, or has been selected as having, late stage cancer.

[0723] In some aspects and embodiments of the present disclosure, a subject in need is a subject who has, or is selected as having, a resectable tumor.

[0724] In other aspects and embodiments of the present disclosure, the subject in need is a subject who has cancer and has a functional immune system.

[0725] Thus, the subject has, or is selected as having, a functional immune system.

[0726] In yet other aspects and embodiments of the present disclosure, the subject in need is a subject with cancer and adequate organ and immune function.

[0727] Thus, subjects have, or are selected to have, suitable organ and immune function.

[0728] In some exemplary embodiments, the subject does not receive a concurrent anti-cancer therapy in combination with the single agent anti-clusterin antibody, or antigen-binding fragment thereof.

[0729] In some exemplary embodiments, the subject does not receive a concurrent anti-cancer treatment in conjunction with the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel combination therapy.

[0730] In some exemplary embodiments, the subject does not require a concomitant anti-cancer treatment in combination with the anti-clusterin antibody, or antigen-binding fragment thereof, as a single agent.

[0731] In some exemplary embodiments, the subject does not require a concomitant anti-cancer treatment in conjunction with the anti-clusterin antibody, or antigen-binding fragment thereof, and docetaxel combination therapy.

[0732] In some embodiments, the subject in need has, or is selected because, has carcinoma.

[0733] In some embodiments, the subject in need has, or is selected as having, early stage carcinoma.

[0734] In some embodiments, the subject in need has, or is selected as having, late stage carcinoma.

[0735] In some embodiments, the subject in need has, or is selected because, has metastatic cancer.

[0736] In some embodiments, the subject in need has, or is selected because, has non-small cell lung cancer (NSCLC).

[0737] In some embodiments, the subject in need has, or is selected because, has metastatic NSCLC.

[0738] In some embodiments, the subject in need has, or is selected as having, stage III-IV NSCLC.

[0739] In some embodiments, the subject in need has, or is selected because, has stage III NSCLC.

[0740] In some embodiments, the subject in need has, or is selected because, has stage IV NSCLC.

[0741] In some embodiments, the subject has or is selected as having lung adenocarcinoma.

[0742] In some embodiments, the subject has, or is selected as having, squamous cell lung cancer.

[0743] In some embodiments, the subject has or is selected for having large cell lung cancer.

[0744] In some embodiments, the subject has or is selected as having adenosquamous lung carcinoma.

[0745] In some embodiments, the subject has, or is selected as having, non-small cell lung cancer characterized by having a KRAS mutation.

[0746] In some embodiments, the subject in need has, or is selected because, has breast cancer.

[0747] In some embodiments, the subject in need has, or is selected because, has metastatic breast cancer.

[0748] In some embodiments, the subject in need has, or is selected because he or she has, prostate cancer.

[0749] In some embodiments, the subject in need has, or is selected because, has metastatic prostate cancer.

[0750] In some embodiments, the subject in need has, or is selected because he or she has, bladder cancer.

[0751] In some embodiments, the subject in need has, or is selected because, has metastatic bladder cancer.

[0752] In some embodiments, the subject in need has, or is selected because, has cervical cancer.

[0753] In some embodiments, the subject in need has, or is selected because, has metastatic cervical cancer.

[0754] In some embodiments, the subject in need has, or is selected because, has gastric cancer.

[0755] In some embodiments, the subject in need has, or is selected as having, metastatic gastric cancer.

[0756] In some embodiments, the subject in need has, or is selected because, has head and neck cancer.

[0757] In some embodiments, the subject in need has, or is selected because, has metastatic head and neck cancer.

[0758] In some embodiments, the subject in need has, or is selected because he or she has, thyroid cancer.

[0759] In some embodiments, the subject in need has, or is selected because, has metastatic thyroid cancer.

[0760] In some embodiments, the subject in need has, or is selected because he or she has, ovarian cancer.

[0761] In some embodiments, the subject in need has, or is selected because, has metastatic ovarian cancer.

[0762] In some embodiments, the subject in need has, or is selected because, has endometrial cancer.

[0763] In some embodiments, the subject in need has, or is selected because, has metastatic endometrial cancer.

[0764] In some embodiments, the subject in need has, or is selected because hepatic cancer.

[0765] In some embodiments, the subject in need has, or is selected as having, metastatic liver cancer.

[0766] In some embodiments, the subject in need has, or is selected because, has colorectal cancer.

[0767] In some embodiments, the subject in need has, or is selected because, has metastatic colorectal cancer.

[0768] In some embodiments, the subject in need has, or is selected because, has pancreatic cancer.

[0769] In some embodiments, the subject in need has, or is selected as having, metastatic pancreatic cancer.

[0770] In some embodiments, the subject in need has, or is selected as having, cholangiocarcinoma.

[0771] In some embodiments, the subject in need has, or is selected as having, metastatic cholangiocarcinoma.

[0772] In some embodiments, the subject in need has or is selected because he or she has mesothelioma.

[0773] In some embodiments, the subject in need has, or is selected as having, metastatic mesothelioma.

[0774] In some embodiments, the subject in need has, or is selected because, has melanoma.

[0775] In some embodiments, the subject in need has, or is selected because, has metastatic melanoma.

[0776] In some embodiments, the subject in need has, or is selected because, a tumor that is characterized as immunologically cold.

[0777] In some embodiments, the subject in need has, or is selected because, has one or more immunological cold pathologies.

[0778] In some embodiments, the subject has or is selected as having one or more lesions with poor infiltration of immune cells.In some cases, the level of immune cell infiltration can be determined by a trained pathologist.In other cases, the level of immune cell infiltration can be determined by computer-based quantification, for example, for tumor imaging.Other techniques may also be used.

[0779] In some embodiments, the subject in need has, or is selected as having, a tumor that is characterized as immunologically warm or hot, that is non-responsive to immunotherapy.

[0780] In some embodiments, the subject has or is selected as having one or more lesions that have or show signs of EMT signature.EMT signature can be determined by a trained pathologist.EMT signature can be determined, for example, by computer-based quantification of tumor imaging.

[0781] 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)).

[0782] 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).

[0783] In some exemplary embodiments, the subject has not received prior therapy comprising a PD-1 or PD-L1 immune checkpoint inhibitor.

[0784] In some exemplary embodiments, the subject has not received prior therapy involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0785] In some exemplary embodiments, the subject has undergone prior therapy comprising a PD-1 or PD-L1 immune checkpoint inhibitor.

[0786] In another exemplary embodiment, the subject is one who has undergone, or is selected because they have undergone, a prior treatment involving an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0787] In a further embodiment, the subject has undergone, or is selected because they have undergone, a prior treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and chemotherapy.

[0788] In yet a further embodiment, the subject has undergone, or is selected because they have undergone, a prior treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody and a chemotherapy doublet treatment.

[0789] In some embodiments, the subject in need has, or is selected as having, a carcinoma that has progressed after first-line immune checkpoint therapy.

[0790] In other embodiments, the subject has, or is selected as having, a carcinoma that has progressed following treatment comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0791] In other embodiments, the subject has, or is selected as having, a carcinoma that has progressed following chemotherapy treatment.

[0792] In additional embodiments, the subject has, or is selected as having, a carcinoma that has progressed following anti-PD-1 or anti-PD-L1 immune checkpoint antibody and chemotherapy doublet treatment.

[0793] In some embodiments, the subject in need has, or is selected as having, a carcinoma that has failed prior treatment with an immune checkpoint inhibitor and a platinum-containing doublet therapy.

[0794] In some embodiments, the subject in need has, or is selected as having, a carcinoma that has failed prior treatment with an immune checkpoint inhibitor and a platinum-containing doublet therapy administered simultaneously or sequentially.

[0795] In some embodiments, the subject in need has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0796] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed a prior treatment comprising an anti-PD-1 immune checkpoint antibody.

[0797] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed a prior treatment comprising a PD-L1 immune checkpoint antibody.

[0798] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0799] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0800] In some embodiments, the subject has, or is selected as having, metastatic cancer that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0801] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior therapy comprising an anti-PD-1 or anti-PD-L1 immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab, alone or in combination with platinum-based chemotherapy.

[0802] In some embodiments, the subject in need has, or is selected as having, a carcinoma that has failed prior treatment with ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab, and a platinum-containing doublet therapy.

[0803] In some embodiments, the subject in need has, or is selected as having, a carcinoma that has failed prior treatment with an anti-PD1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet therapy administered simultaneously or sequentially.

[0804] In some embodiments, the subject has, or is selected as having, a carcinoma that has failed prior treatment with pembrolizumab alone or in combination with platinum-based chemotherapy.

[0805] In some embodiments, the subject has, or is selected as having, low expression of PD-L1.

[0806] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of ≧50%.

[0807] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of <50%.

[0808] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 Tumor Proportion Score (TPS) of 1-49%.

[0809] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦15%.

[0810] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of ≦1%.

[0811] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of <1%.

[0812] In some embodiments, the subject has, or is selected as having, one or more lesions with a PD-L1 tumor proportion score of 0%.

[0813] In some embodiments, the subject is selected as having no or no evidence of PD-L1 expression.

[0814] 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%.

[0815] 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%.

[0816] 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%.

[0817] 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%.

[0818] According to the present disclosure, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 combined positive score (CPS) of such lesion is, for example, <10%.

[0819] More particularly, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 CPS of such lesion is, for example, <5%.

[0820] More specifically, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 CPS of such lesion is, for example, ≦1%.

[0821] Even more specifically, a lesion may be characterized as having low expression of PD-L1 if the PD-L1 CPS of such lesion is, for example, <1%.

[0822] 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 or CPS of 0%, or if PD-L1 expression is undetectable.

[0823] In some embodiments, the tumor proportion score is determined at baseline.

[0824] In some embodiments, the tumor proportion score is determined prior to administration of an anti-cancer therapy of the present disclosure.

[0825] In some embodiments, the tumor proportion score is determined after primary therapy.

[0826] In some embodiments, the tumor proportion score is determined at the initiation of anti-cancer therapy.

[0827] In some embodiments, the PD-L1 tumor proportion score is determined by a scientist or pathologist.

[0828] In some embodiments, the PD-L1 tumor proportion score is determined in accordance with drug regulatory agency guidance (e.g., FDA, EMA, etc.).

[0829] In some embodiments, the subject has, or is selected as having, a carcinoma with one or more lesions that have low expression of PD-L1.

[0830] In some embodiments, the subject has, or is selected as having, a carcinoma that has no evidence of PD-L1 expression.

[0831] In some embodiments, the subject has, or is selected as having, a carcinoma that is not eligible for, or would not likely benefit from, treatment with an anti-PD-1 or anti-PD-L1 immune checkpoint inhibitor.

[0832] In some embodiments, the subject has, or is selected as having, a carcinoma that would not be eligible for, or would likely not benefit from, treatment with an anti-PD-1 or anti-PD-L1 immune checkpoint antibody.

[0833] 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.

[0834] 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.

[0835] According to the present disclosure, the subject has, or is selected as having, metastatic cancer with one or more lesions that have low expression of PD-L1, have no evidence of PD-L1 expression, or are ineligible for treatment including anti-PD-1 or anti-PD-L1 immune checkpoint antibodies.

[0836] In some embodiments, the subject in need is selected as not being immunosuppressed or not immunosuppressed.

[0837] In some embodiments, the subject is immunocompetent or selected to be immunocompetent.

[0838] According to the present disclosure, subjects are selected because they are not immunosuppressed or have not received immunosuppressive drugs within 1-14 days prior to treatment.

[0839] In some embodiments, the subject in need has not received an immunosuppressant drug within 14, 7, 6, 5, 4, 3, 2, or 1 days prior to treatment. In some embodiments, the subject in need may have received a corticosteroid prior to treatment.

[0840] In some embodiments, the subject is selected as having not received or will not have received immunosuppressive drugs within at least 7 days prior to treatment.

[0841] In some embodiments, a subject in need has not had prior treatment with docetaxel.

[0842] In some embodiments, a subject in need thereof is treated for at least two cycles of treatment.

[0843] PD-L1 expression and immune cell infiltration PD-L1 expression can be determined using methods known to those of skill in the art.

[0844] In an exemplary embodiment, PD-L1 Tumor Proportion Score (TPS) is assessed using the 22C3 antibody (Agilent Technologies, Carpinteria, Calif., code SK006).

[0845] 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).

[0846] In yet another exemplary embodiment, PD-L1 TPS is assessed using the SP263 antibody, Roche Diagnostic, Ref. 740-4907.

[0847] In a further exemplary embodiment, PD-L1 TPS is assessed using the SP142 antibody (Abcam, Toronto, Canada, Catalog No. Ab228462).

[0848] 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).

[0849] PD-L1 expression can be assessed using an anti-PD-L1 antibody appropriate for the type of carcinoma the subject has.

[0850] 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.

[0851] In some cases, PD-L1 expression is assessed by immunohistochemistry.

[0852] In other cases, PD-L1 expression is assessed by a fluorescent assay, such as, for example, by quantitative fluorescence or fluorescent in situ hybridization.

[0853] In some embodiments, the assay is an assay approved by at least one regulatory agency.

[0854] According to the present disclosure, the assay is a diagnostic test (Dx) approved by the US Food and Drug Administration (FDA).

[0855] According to this disclosure, the assay is an FDA approved test (Rx) for research purposes.

[0856] In an exemplary embodiment, the assay is based on PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, Calif., code SK006).

[0857] In another exemplary embodiment, the assay is based on PD-L1 IHC 28-8 pharmDx (Agilent Technologies, Carpinteria, Calif., code SK005).

[0858] In yet another exemplary embodiment, the assay is based on Ventana PD-L1 (SP263) (Roche Diagnostics, Ref. 740-4907).

[0859] In some aspects and embodiments, immunohistochemistry assays are performed according to the manufacturer's instructions.

[0860] In some embodiments, the assay uses the Autostainer Link 48 immunohistochemistry platform (Dako).

[0861] In some embodiments, the assay uses the Omnis immunohistochemistry platform (Dako).

[0862] In some embodiments, the assay is performed using the Bond-III immunohistochemistry platform (Leica).

[0863] In some embodiments, the assay uses the BenchMark ULTRA immunohistochemistry platform (Ventana).

[0864] Assay results are interpreted using the manufacturer's interpretation manual.

[0865] 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.

[0866] In some embodiments, the absence or presence of immune cells in the tumor microenvironment may be confirmed by tumor biopsy.

[0867] 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).

[0868] A tumor may be characterized as "immunologically cold" if the tumor microenvironment is not sufficiently infiltrated by immune cells (particularly by lymphocytes) or if the tumor microenvironment is not inflamed. In contrast, a tumor may be characterized as "immunologically warm" or "immunologically hot" if infiltration of immune cells (particularly by lymphocytes) into the tumor microenvironment is observed or if the tumor shows signs of inflammation. Failure to respond to immunotherapy may be an indication that a tumor or lesion is "immunologically cold." Thus, the present disclosure relates to methods of treating a subject with one or more lesions that are unresponsive to immunotherapy.

[0869] 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."

[0870] kit The present disclosure, in some aspects and embodiments, provides kits comprising anti-cancer therapies for use in the methods described herein and for treating the subjects described herein.

[0871] In some embodiments, the kit comprises 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 chemotherapeutic agent for use in combination therapy, and a package insert containing instructions for use for treating a subject in need thereof.

[0872] In some embodiments, the kit comprises one or more containers containing at least one dose of a pharmaceutical agent disclosed herein, and a package insert containing instructions for treating a subject in need thereof.

[0873] In an embodiment, the kit comprises 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 treating a subject in need thereof.

[0874] According to the present disclosure, the anti-clusterin antibody or antigen-binding fragment thereof and docetaxel are provided in separate containers.

[0875] According to the present disclosure, the antibody or antigen-binding fragment thereof is as described herein.

[0876] In some embodiments, the package insert states that the combination therapy is intended for the treatment of a subject with carcinoma.

[0877] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic cancer.

[0878] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma that has progressed after first-line immune checkpoint therapy.

[0879] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinomas who have failed prior treatment with immune checkpoint therapy and platinum-containing doublet therapy.

[0880] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma who have failed prior treatment with immune checkpoint therapy and platinum-containing doublet therapy administered simultaneously or sequentially.

[0881] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma who have failed prior treatment with an anti-PD1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet therapy.

[0882] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with carcinoma who have failed prior treatment with an anti-PD1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet therapy administered simultaneously or sequentially.

[0883] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects whose carcinomas have failed prior treatment with ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab, and platinum-containing doublet therapy, administered simultaneously or sequentially.

[0884] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with non-small cell lung cancer (NSCLC).

[0885] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with advanced NSCLC.

[0886] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with stage III NSCLC.

[0887] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with stage IV NSCLC.

[0888] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with breast cancer.

[0889] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic breast cancer.

[0890] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with prostate cancer.

[0891] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic prostate cancer.

[0892] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with gastric cancer.

[0893] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic gastric cancer.

[0894] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with head and neck cancer.

[0895] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic head and neck cancer.

[0896] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with thyroid cancer.

[0897] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic thyroid cancer.

[0898] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with ovarian cancer.

[0899] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects with metastatic ovarian cancer.

[0900] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects who are not immunosuppressed or who have not received an immunosuppressant within 14, 7, 6, 5, 4, 3, 2, or 1 day prior to treatment.

[0901] In some embodiments, the package insert states that the combination therapy is intended for the treatment of subjects who have not received prior treatment with docetaxel.

[0902] In some embodiments, the package insert describes the combination therapy as being for administration essentially over the course of or throughout the treatment period. EXAMPLES

[0903] Example 1 Nonclinical Pharmacokinetics The pharmacokinetics of AB-16B5 (humanized 16B5) was investigated in single and repeated dosing studies in Sprague-Dawley rats and rhesus monkeys. In general, peak serum AB-16B5 concentrations were reached shortly after the start of the infusion. In rats, AB-16B5 systemic exposure over 24 hours increased with increasing dose levels in a dose-proportional manner. There was an approximately 70% increase in systemic exposure after repeated dosing from day 1 to day 26, which is consistent with the elimination half-life and dosing interval of AB-16B5. In monkeys, AB-16B5 systemic exposure generally increased with increasing dose levels in a greater than dose-proportional manner. With repeated dosing, there was no significant difference in systemic exposure to AB-16B5, regardless of whether it was administered once or twice weekly. max There was no evidence of drug accumulation in terms of AUC 0-72 A lower degree of accumulation was observed for AB-16B5. Interestingly, after single-dose administration of AB-16B5 in rhesus monkeys, sCLU serum concentrations were significantly decreased after dosing. sCLU concentrations generally returned to their baseline levels after 3-5 days. The parallel decrease in sCLU concentrations immediately after dosing with AB-16B5 is consistent with an antigen-sink phenomenon.

[0904] Example 2 Non-clinical toxicity In Sprague-Dawley rats, weekly administration of AB-16B5 (humanized 16B5) did not result in any treatment-related clinical signs or any treatment-related changes in body weight, food consumption, ophthalmology, clinical pathology, or organ masses. Similarly, there were no treatment-related macroscopic changes. A very low incidence of minimal lymphoid hyperplasia was noted in the mesenteric lymph nodes (2 / 20) and submandibular lymph nodes (1 / 20) of animals from the high-dose group. This microscopic finding was not seen in any of the recovered animals after the 28-day recovery period, indicating complete reversibility. This finding most likely reflects a slight antigenic stimulation by AB-16B5 in these two regional lymph nodes. Therefore, the No Observable Adverse Effect Level (NOAEL) was determined to be 100 mg / kg / dose.

[0905] In rhesus monkeys, weekly administration of AB-16B5 did not result in any signs of overt toxicity. Few emetic episodes were observed during infusion of AB-16B5 in animals at all dose levels. There were no treatment-related effects observed on body weight, ophthalmology, electrocardiography, and organ masses. A slight decrease in mean white blood cell count was seen at 60 mg / kg (males only) and 100 mg / kg (males and females). Slight changes in mean albumin, globulin, A / G, and phosphorus levels were also seen at 20, 60, and / or 100 mg / kg. Although potentially related to AB-16B5, these changes were minor, reversible, lacked a dose-response relationship, and were not associated with any histopathological correlates. As a result, they were not considered toxicologically significant. Hepatocellular vacuolation was noted in the liver of two animals (one primary and one recovery animal) dosed at 100 mg / kg. The relationship of this finding to treatment with AB-16B5 remains unclear due to the low incidence and because this finding is known to occur spontaneously. In the absence of clinical pathology (liver enzymes) and organ mass (liver mass) correlates, this finding was considered an adaptive change and not adverse. Therefore, the NOAEL was determined to be 100 mg / kg / dose.

[0906] In addition, a tissue cross-reactivity study was performed to determine the potential cross-reactivity of AB-16B5 with frozen tissues from human, rhesus monkey, and Sprague-Dawley rat tissues. AB-16B5 staining at 2 and 10 μg / mL was observed in several tissue elements in human, rhesus monkey, and Sprague-Dawley rat tissue panels. However, no membrane staining was observed in any of the tissues examined in this study, supporting the lack of potential toxicological concerns due to off-target binding.

[0907] Example 3 Phase I Clinical Investigation A first-in-human Phase I study assessing the safety and tolerability of AB16B5 (humanized 16B5) was conducted in subjects with histologically or cytologically confirmed advanced solid malignancies that had become refractory to prior therapy and were unlikely to benefit from known therapies (Clinical Trial Registration Number: NCT2412462) (Ferrario et al., 2017). AB-16B5 was administered in 15 subjects enrolled in a Phase 1, single-center, open-label, dose-escalation study (AB-16B5-101).

[0908] The dose levels of AB-16B5 assessed during the study were 1.5, 3.0, 6.0, 9.0, and 12.0 mg / kg. Dose escalation was performed using two dose escalation schemes; accelerated dose escalation scheme and standard dose escalation scheme. Only one subject was enrolled in each of the first two cohorts per protocol (accelerated dose escalation scheme). The final cohort (12 mg / kg) was expanded to at least six subjects per protocol.

[0909] Subjects received AB-16B5 by 60-minute IV infusion once weekly on days 1, 8, and 15 of each cycle of treatment. One cycle of treatment consisted of 21 days.

[0910] Target Features The majority of subjects treated with AB-16B5 were female (10 of 15 subjects, 67%), and the mean subject age was 61 years (range: 32-79 years). The most common cancer diagnoses found in the subject population were breast, colorectal, prostate, and thyroid (2 subjects each, 13%). Other tumor types were found in only 1 subject each (7%) and included endometrial, gastric, lung, ovarian, pancreatic, soft tissue sarcoma, and vulvar melanoma.

[0911] Number of surveys Fourteen subjects (93%) received at least two cycles of treatment (range: 2-17 cycles). One subject (subject 004) completed 17 cycles of treatment. This subject received 6 mg / kg AB-16B5 from cycle 1 to cycle 7, with the dose subsequently escalated to 9 mg / kg. Thirteen subjects (87%) discontinued the study due to disease progression; two subjects discontinued due to adverse events (subject 004 had grade 3 bronchial obstruction; subject 011 had grade 3 biliary obstruction, associated with disease progression). Subject 011 in the 12 mg / kg cohort was discontinued by the investigator after one dose of AB-16B5 and replaced by a new subject; however, subject 011 was not included in the RECIST-evaluable population. The average number of cycles received in the RECIST-evaluable population was 4.4 cycles.

[0912] Safety Profile Administration of AB-16B5 given as a 60-minute IV weekly infusion was safe and well tolerated at doses up to 12 mg / kg. No dose-limiting toxicities were observed.

[0913] A total of 167 Ae were reported. Of those Ae, 68 of the 167 Ae were possibly, probably, or definitely related to AB-16B5, and 12 (12) were grade 3 to 5.

[0914] The most frequently reported Ae (all causalities) were nausea, abdominal pain, back pain, vomiting, chills, dyspnea, constipation, and pruritus.

[0915] There were no dose-related trends in the incidence of these Aes. The most frequently reported Aes associated with AB-16B5 were nausea, pruritus, headache, and rash. There were no dose-related trends in the incidence of drug-related Aes. Drug-related Aes were primarily grade 1 or 2.

[0916] There were 12 Ae of grades 3 to 5 reported by 8 subjects. Only 2 of them were related to AB-16B5 (grade 3 infusion-related reaction and grade 3 rash). Two deaths were reported in the study (subjects 004 and 014). In both cases, the deaths were associated with disease progression.

[0917] A total of 5 of 15 (33%) subjects reported 6 SAEs. All SAEs were considered unrelated to AB-16B5. Two subjects (13%) discontinued the study due to adverse events; subject 004 (grade 3 bronchial obstruction; associated with disease progression) and subject 011 (grade 3 biliary obstruction).

[0918] Antitumor Activity and Best Overall Response Best overall response (BOR) in the RECIST-evaluable population is presented in Table 1 below:

[0919] [Table 1]

[0920] The best overall response in this population was stable disease (SD) for eight subjects (57%) and progressive disease (PD) for six subjects (43%). AB-16B5 treatment lasting four or more cycles could suggest clinical benefit.

[0921] It was noted that the majority of subjects who progressed during treatment did so due to the appearance of new lesions. Indeed, the tumor response at the last assessment for subjects 003, 007, 008, 009, 013, 014, and 015 was consistent with stable target lesions, but progression in non-target lesions due to the appearance of new lesions. This finding is consistent with the mechanism of action of AB-16B5. Indeed, new lesions contain mostly epithelial phenotype tumor cells as a result of mesenchymal to epithelial transition. Therefore, these new lesions contain low amounts of TA-sCLU because they have not been exposed to chemotherapy or EMT-promoting conditions such as hypoxia that limit their exposure to AB-16B5.

[0922] AB-16B5-101: Pharmacodynamics Tumor biopsies were collected during standard dose escalation to examine the presence of AB-16B5 within the tumor. A total of four pre-treatment and five post-treatment tumor biopsies were eligible for analysis. These post-treatment tumor biopsies were collected after cycle 2 day 15 dosing (cycle 2 day 15 - cycle 2 day 18). Biopsy sites included liver (n=2), lymph node (n=2), bladder, skin, and vulva.

[0923] [Table 2]

[0924] All pre-treatment tumor biopsies were negative for the presence of AB-16B5, whereas the presence of AB-16B5 was confirmed in all post-treatment tumor biopsies analyzed, confirming that AB-16B5 preferentially binds to TA-sCLU and that tumors may potentially be an important reservoir.

[0925] Immunohistochemistry studies were performed on paired tumor biopsies to determine whether treatment with AB-16B5 was associated with reacquisition of an epithelial phenotype. Among the four evaluable paired tumor biopsies, two cases showed increased E-cadherin expression (subjects 006 and 007), one of which was combined with loss of vimentin expression (subject 007). One case (subject 013) showed strong epithelial features in the pretreatment biopsy that did not change with AB-16B5 treatment.

[0926] [Table 3]

[0927] AB-16B5-101: Pharmacokinetics Plasma PK parameters for AB-16B5 were derived from concentration-time profiles following the first dose of cycle 1 and the first dose of cycle 2 using noncompartmental analysis (NCA) with Phoenix WinNonlin.

[0928] In cycle 1, AB-16B5 T max The medians were similar across dose levels. max and AUC 0-t increased with dose. This increase appeared to be dose proportional over the dose range of 3.0 to 12.0 mg / kg. The AB-16B5 terminal phase was well characterized with an overall residual value of <20.00%. Characterization of the terminal phase was improved at 12.0 mg / kg when compared to that observed at other doses. Mean T 半分 were similar at the 1.5, 3.0, and 6.0 mg / kg dose levels, but slightly higher at the 9.0 and 12.0 mg / kg dose levels.

[0929] In cycle 2, AB-16B5 T max Median values ​​were similar across dose levels, with values ​​ranging from 1.00 to 1.08 h. max and AUC 0-tincreased with dose. This increase appeared to be dose proportional across the dose range of 3.0 to 12.0 mg / kg. The AB-16B5 terminal phase in cycle 2 was well characterized with an overall residual value of <15.00%. Characterization of the terminal phase was improved at 9.0 mg / kg and 12.0 mg / kg when compared to that observed at the lower doses (<1.00%). Mean t 1 / 2 was similar across the dose range of 1.5 mg / kg to 6.0 mg / kg, while the mean T 半分 was slightly higher at the 9.0 and 12.0 mg / kg dose levels.

[0930] No significant accumulation of AB-16B5 was observed between cycles 1 and 2.

[0931] A summary of the pharmacokinetic parameters is presented in Table 4.

[0932] [Table 4]

[0933] Tumor Biomarkers Several well-established circulating biomarkers were assessed to monitor response to therapy, including CA 15-3, CA-125, CA 19-9, CEA, LDH, and PSA.

[0934] In general, tumor biomarker levels increased over time, which correlated with disease progression. Interestingly, CEA levels remained stable or decreased in a minority of patients.

[0935] conclusion Patients received 1 to 53 weekly doses (median: 9 doses). The most frequently reported treatment-emergent adverse events (TEAEs, all causal) were nausea, abdominal pain, back pain, vomiting, chills, constipation, and pruritus. Most of the Aes were grade 1 or 2. Among the ≥ grade 3 Aes, only two (grade 3 infusion-related reaction and rash) were judged to be related to AB-16B5. No dose-limiting toxicities were identified during the first cycle of treatment for any patient, and five serious Aes were reported (sepsis, fever, dyspnea, intraperitoneal hemorrhage, and main bronchial obstruction), none of which were judged to be related to study treatment. PK analysis across all dose levels supported that systemic exposure to AB-16B5 increased in a dose-proportional manner. The presence of AB-16B5 at the tumor site was confirmed in all 5 patients (pts) in whom post-treatment tumor lysates could be generated. Biomarker analysis in paired tumor biopsies provided evidence of EMT inhibition, as seen by increased E-cadherin expression after treatment with AB-16B5 in two patients. In one of these two patients with advanced gastric cancer, this was also accompanied by loss of vimentin expression. This patient had stable disease (SD) with clinical benefit and continued treatment for 24 weeks. The other patient with follicular thyroid cancer had SD for nearly a year.

[0936] Weekly infusions of AB-16B5 are well tolerated up to 12 mg / kg. Initial correlative studies on tumor tissue provide evidence of molecular modulation of the tumor environment in humans.

[0937] Example 4 Effect of AB-16B5 on immune cell infiltration into the tumor microenvironment Balb / c mice were treated with 5 × 10 54T1 cells were orthotopically implanted. Animals received IP saline treatments three times a week. Primary tumors were surgically removed 16 days after implantation. Animals were sacrificed on day 36 and lungs were excised. Tissues were fixed in paraformaldehyde and processed for paraffin embedding. Tissue sections were probed with anti-mouse CD3, anti-mouse CD8, and anti-mouse B220 antibodies. Signals were revealed with specific secondary antibodies conjugated with horseradish peroxidase and counterstained with hematoxylin and eosin. The results presented in Figure 1 show that 4T1 lung metastases generate an immunologically cold microenvironment that blocks infiltration of B and T lymphocytes into the tumor. The outlined area shows that CD3 and CD8 T lymphocytes are restricted to the tumor periphery as a result of EMT.

[0938] Animals bearing 4T1 tumors were treated with AB-16B5 antibody (mouse 16B5) IP at 10 mg / kg three times a week. Primary tumors were surgically removed 16 days after implantation. Animals were sacrificed on day 36 and lungs were excised. Tissues were fixed in paraformaldehyde and processed for paraffin embedding. Tissue sections were probed with anti-mouse CD3, anti-mouse CD8, and anti-mouse B220 antibodies. Signals were revealed using specific secondary antibodies conjugated with horseradish peroxidase and counterstained with hematoxylin and eosin. The results presented in Figure 2A show that there were fewer and much smaller lung metastases densely infiltrated with CD3 and CD8 T cells. There was also evidence of plasma cell infiltration in 16B5-treated tumors.

[0939] Thus, AB-16B5 allows infiltration of immune cells into the tumor microenvironment in immune-competent mice, which may represent a new therapeutic avenue to generate a warmer tumor environment and stimulate a robust immune response against tumors.

[0940] In parallel, human tumor biopsies from patients treated with AB-16B5 as a single agent were analyzed (Figures 2B-E). Needle biopsies obtained from a patient with metastatic thyroid cancer and from a patient with inoperable metastatic gastric cancer were sectioned and stained with hematoxylin and eosin. An on-treatment biopsy from a patient with metastatic thyroid cancer to the lung was obtained after a second cycle of treatment with AB-16B5. As shown in Figure 2B, essentially all tumor fragments were necrotic. Along the edges of the presented fragments, lymphoplasmocytic infiltrates were observed. Hemosiderin-laden macrophages were observed inside the necrotic areas, somewhat reflecting erythrocyte extravasation associated with necrosis (not shown). Figure 2C shows a perivascular infiltrate composed of plasma cells along the edges of a tumor fragment from the same patient found presented. Analysis of a pretreatment biopsy from a metastatic gastric cancer case showed several fragments of gastric mucosa infiltrated by diffuse poorly differentiated gastric cancer (signet ring cells). The fragments presented showed foci of necrosis with a predominantly acute neutrophilic infiltrate. Figure 2E shows an on-treatment biopsy obtained after the second cycle of treatment with AB-16B5, consisting of three tumor fragments. The larger fragments were composed of normal superficial gastric mucosa, and the smaller fragments were infiltrated by a mixed neutrophilic and mononuclear immune cell infiltrate.

[0941] Example 5 Effect of AB-16B5 and docetaxel combination therapy on immune cell infiltration into the tumor microenvironment An immunocompetent mouse cancer model was selected to test the extent of immune responses using murine 16B5 upon treatment with AB-16B5 monotherapy or the combination of AB-16B5 and docetaxel.

[0942] Five groups, each consisting of 10 female Balb / c mice, were assigned to the study (see Table 5 below). All animals received subcutaneous implantation of 4T1 mouse breast cancer cells in the fourth inguinal mammary gland. Treatment began on the day of implantation (defined as day 1). Animals from group 1 (Gr. 1) received IP treatment of saline vehicle control twice weekly for the duration of the study. Animals from group 2 (Gr. 2) received docetaxel at 10 mg / kg once weekly for 5 weeks by IP administration. Animals from group 3 (Gr. 3) received docetaxel at 10 mg / kg once weekly for 2 weeks and AB-16B5 at 10 mg / kg twice weekly for 5 weeks. Animals from group 4 (Gr. 4) received 10 mg / kg docetaxel once a week and 5 mg / kg 16B5 twice a week over the course of treatment for 5 weeks, respectively. Animals from group 5 (Gr. 5) received AB-16B5 twice a week for 5 weeks. Primary tumors were excised on day 36, animals were sacrificed on day 37, and the number of macroscopic metastatic nodules on the lung surface was counted.

[0943] [Table 5]

[0944] The results presented in FIG. 3 show that the lungs of animals from groups 4 and 5 contained fewer metastatic lung nodules than saline control-treated mice. However, mice treated in monotherapy with docetaxel had as many metastatic lung nodules as the saline control group. Treatment with docetaxel for 2 weeks in combination with 16B5 led to fewer metastatic lung nodules than in groups 1 and 2, but the response to treatment was not as extensive as in groups 4 and 5. There were more animals in group 4 with no detectable nodules than in any other group. These results suggest that AB-16B5 monotherapy or combination therapy with docetaxel effectively inhibits metastatic invasion in immunocompetent mice. These results also suggest that it may be preferable to administer AB-16B5 and docetaxel throughout the course of treatment.

[0945] Primary tumors excised 16 days after implantation were treated with collagenase and hyaluronidase, and immune cells were purified by positive selection using magnetic latex beads coated with anti-CD45 antibodies. The purified cells were transferred to small petri dishes containing culture medium supplemented with IL2 and IL7 for phenotypic analysis. It was found that there were very few CD45+ in the primary tumors removed from animals in groups 1 and 2. In contrast, there were more immune cells in the tumors removed from animals in groups 3, 4, and 5.

[0946] Treatment of mice implanted with 4T1 tumor cells with docetaxel (DTX 5W) was relatively ineffective. 4T1 tumors have a high EMT signature that causes resistance to many chemotherapeutic agents, including docetaxel. Treatment of mice with docetaxel for 2 weeks and with 16B5 for 5 weeks was not as effective as treatment with 16B5 in monotherapy, possibly because transient exposure of tumors to docetaxel led to increased resistance of the tumors. The combination of docetaxel for 5 weeks with 16B5 proved to be the most effective treatment regimen. The combination of increased shed antigens caused by docetaxel and inhibition of EMT led to an increased immune response leading to fewer lung metastases in this group compared to 16B5 in monotherapy.

[0947] AB-16B5 in monotherapy and in combination with docetaxel thus allow infiltration of immune cells into the tumor microenvironment in immunocompetent mice. These results also suggest that primary tumors can be affected by AB-16B5 monotherapy or combination therapy.

[0948] Example 6 Characterization of tumor-infiltrating lymphocytes Balb / c mice were treated with 5 × 10 54T1 cells were orthotopically implanted. Animals received either IP AB-16B5 (mouse 16B5) 10 mg / kg twice weekly (group 15: animals 1501, 1502, and 1503) or IP AB-16B5 10 mg / kg twice weekly (group 25: animals) in combination with intraperitoneal (IP) docetaxel 10 mg / kg once weekly. Primary tumors were surgically removed 16 days after implantation. Animals were sacrificed on day 36, lungs resected, and each visible lung metastasis was carefully dissected. Each visible metastatic nodule, if any, was excised and processed for rapid expansion of tumor infiltrating lymphocytes protocol. Metastatic nodules were sectioned into small pieces with 2-3 mm edges, which were grown individually in 24-well plates containing culture medium supplemented with FBS, IL2, IL7, ITS (1,000 U / mL IL2, 2.0 ng / mL IL7, and 1x insulin-transferrin-selenium cocktail (Gibco 41400-045)).

[0949] After 3 weeks in culture, 100,000 cells were removed from each of the lymphocyte cultures (6 cultures representing 3 animals from group 15 and 3 animals from group 25) and placed in culture with 100,000 4T1 tumor cells. After overnight co-culture, supernatants were collected for INFγ quantification by ELISA.

[0950] The results of INFγ secretion from lymphocyte cultures in the presence of 4T1 cells show that lymphocytes isolated from lung metastatic nodules secreted high levels of INFγ, with the highest levels observed in the docetaxel-16B5 group (see Table 6). These results support that inhibition of EMT using anti-sCLU 16B5 mAb contributes to the generation of a "warm" tumor microenvironment that allows infiltration of T lymphocytes into tumors.

[0951] [Table 6]

[0952] Lymphocytes were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. Lymphocytes from each donor animal were pooled and processed for flow cytometry analysis with antibodies against CD45 (lymphocyte common antigen), CD3, CD4, CD8, and CD19 (B cell biomarker) (Figures 4A and 4B). The resulting single cell preparations were first selected for their size to select those representing immune cells. They were further gated on an FSC / SSC plot to exclude dead cells and debris. Flow cytometry was then performed with antibodies against CD45, CD3, CD19, CD3, CD4, and CD8. Immune cells positive for CD45 were gated for CD3 and CD19 (P3). CD3+ cells were further gated for CD4 and CD8 (Q1-LR).

[0953] The results showed 80-90% cell viability of CD45+ cells for both groups. CD45+ cells from group 15 (Figure 4A) contained 40.2%-55.0% CD19 cells and 14.0%-21.1% CD3+ cells. CD3+ cells contained 63.7%-66.5% CD4+ T cells and 20.6%-27.0% CD8+ T cells. CD45+ cells from group 25 (Figure 4B) contained 14.0%-35.0% CD19 cells and 21.3%-42.0% CD3+ cells. CD3+ cells contained 47.5%-67.8% CD4+ T cells and 25.9%-41.1% CD8+ T cells.

[0954] Again, these results suggest that primary tumors can be affected by AB-16B5 monotherapy or combination therapy, and that tumor cell invasion occurs in both AB-16B5 monotherapy and combination therapy in immunocompetent mice.

[0955] Therefore, enhancing tumor T cell infiltration with AB-16B5 may render tumors more susceptible to immunotherapy with checkpoint inhibitors or with cellular immunotherapy.

[0956] Example 7 Phase II Clinical Investigation Applicants evaluate the use of an anti-clusterin antibody in combination with docetaxel in previously treated subjects with metastatic non-small cell lung cancer.

[0957] 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-PD1 or PDL-1 immune checkpoint antibody administered simultaneously or sequentially. All recruited patients 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 75 mg / m2 once every 3 weeks.

[0958] the purpose The primary objective of this study is to determine the objective response rate (ORR) by RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

[0959] Another primary objective of this study is to determine the objective response rate (ORR) by RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

[0960] Another primary objective of this study is to determine the safety and tolerability of the combination of AB-16B5 and docetaxel.

[0961] 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.

[0962] 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.

[0963] 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.

[0964] 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.

[0965] Another secondary objective of this study is to determine overall survival (OS) in subjects receiving the combination of AB-16B5 and docetaxel.

[0966] A further secondary objective of this study is to determine the pharmacokinetics of AB-16B5 in this subject population.

[0967] 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.

[0968] The exploratory objective of this study is to assess disease response using iRECIST in subjects pursuing treatment beyond progression.

[0969] 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 following treatment with a platinum-containing doublet therapy and an anti-PD1 or PDL-1 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.

[0970] 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). Futility analyses 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. If the investigator considers the subject to be clinically stable, treatment beyond progression will be permitted. Subjects who must discontinue docetaxel due to toxicity will continue treatment with AB-16B5.

[0971] Safety introduction period 75 mg / m once every 3 weeks on day 12 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).

[0972] 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.

[0973] 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

[0974] 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

[0975] If more than three DLTs are observed in the first eight subjects treated, a reduction in AB-16B5 will be performed.

[0976] 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.

[0977] 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.

[0978] 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-PD1 or PDL-1 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-PD1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet therapy, administered simultaneously or sequentially. Subjects with appropriate organ and immune function as shown in Table 7 below:

[0979] [Table 7]

[0980] -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 study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 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.

[0981] 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.

[0982] 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 an anti-neoplastic investigational agent or last use of an investigational device with an anti-neoplastic 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 >10 mg / day of 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 prior to 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 be enrolled 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 taken >10 mg / day of 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 study 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 medical 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.

[0983] 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.

[0984] Investigational Treatment Investigational drugs, doses, and modes of administration AB-16B5 AB-16B5 is a humanized IgG targeting sCLU for inhibition of cancer-associated EMT 2 It is a monoclonal antibody (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.

[0985] 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 the safety run-in period.

[0986] Subjects who experience infusion-related reactions will be treated with corticosteroids such as dexamethasone. Antihistamines and acetaminophen may also be used where deemed appropriate.

[0987] 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): Subjects will be discontinued from further treatment with AB-16B5

[0988] 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.

[0989] Docetaxel Docetaxel was administered at 75 mg / m2 by 60-minute IV infusion on day 1 once every 3 weeks. 2 Docetaxel will be prepared and administered in accordance with the approved product label / monograph.

[0990] 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.

[0991] Treatment duration One cycle of treatment will consist of 21 days (3 weeks).

[0992] 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.

[0993] If the investigator considers the subject to be clinically stable, treatment beyond progression will be permitted. Clinical decision-making by the site should be based on the subject's clinical stability, as specified below:

[0994] 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

[0995] Any subject considered clinically unstable should be discontinued from study treatment upon the first radiological evidence of PD.

[0996] 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 8 below).

[0997] Treatment will be resumed at a lower dose only after resolution of adverse events to grade ≦1.

[0998] [Table 8]

[0999] Subjects whose original AB-16B5 dose was reduced due to toxicity will not be re-escalated.

[1000] 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.

[1001] Subjects who develop grade ≧3 peripheral neuropathy should discontinue docetaxel.

[1002] Example 8 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.

[1003] FIG. 5 is a chart showing patient duration on treatment as best response by RECIST 1.1 for 5 patients with partial response (PR), 11 patients with stable disease (SD), and 4 patients with progressive disease (PD) in 20 evaluable patients.

[1004] As can be seen in Figure 5, four of five NSCLC patients (patients 1, 2, 4, and 12) who showed evidence of a partial response had low expression of PD-L1 (TPS of ≦15%).

[1005] Moreover, as can be seen from FIG. 5, 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.

[1006] Additionally, screening for KRAS mutations was performed in eight patients who showed evidence of partial response or stable disease (patients 3, 4, 6, 7, 8, 9, 12, and 13). Four were found to be negative for KRAS mutations (patients 3, 4, 6, and 8) and four were positive (7, 9, 12, and 13) (data not shown).

[1007] 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™.

[1008] Histological analysis of pre- and on-treatment biopsies from two patients under study is illustrated in Figures 6a-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.

[1009] 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 demonstrates evidence of a partial response.

[1010] 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 plasma cell 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.

[1011] Analysis of the Ki-67 proliferation biomarker showed high intensity staining in the pre-treatment disease 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.

[1012] 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.

[1013] 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.

[1014] 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.

[1015] 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.

[1016] 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.

[1017] Analysis of tumor biopsies revealed that pretreatment samples were more basophilic, reflecting the presence of numerous tumor cell aggregates. In contrast, samples from on-treatment (end of cycle 2) showed large eosinophilic areas, reflecting extensive stromal fibrosis. Higher magnification fields of the pretreatment pathology 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 on-treatment pathology, key findings were reported: cytopathic effects, fibrosis, and chronic lymphoplasmocytic and histiocytic inflammation. There were areas of densely sclerotic tissue with chronic inflammatory cells, and few residual tumor cells with cytopathic changes consistent with chemotherapy agents acting on the cellular spindles. Large aneuploidies and giant cells are reminiscent of changes induced by docetaxel.

[1018] Analysis of the Ki-67 proliferation biomarker showed high intensity staining in the pre-treatment condition 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.

[1019] 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.

[1020] 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.

[1021] 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.

[1022] 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.

[1023] 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 tumor lesion. Therefore, the patient shows evidence of stable disease.

[1024] 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 the size of the tumor lesions after two and four cycles of treatment, respectively. This patient therefore shows evidence of a partial response.

[1025] In summary, tumor biopsies obtained prior to anti-clusterin antibody and docetaxel combination treatment revealed that tumors were poorly infiltrated by T lymphocytes. In contrast, biopsies during treatment showed evidence of lymphoplasmocytic and / or histiocytic inflammation. The presence of tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures (TLSs), macrophages, and NK cells was notably observed.

[1026] Records also show that some of the subjects enrolled in this clinical trial had tumors with low or no evidence of PD-L1 expression prior to immune checkpoint antibody treatment. Nine of 15 patients have a TPS of ≦15%. Of these nine patients, seven can be characterized as having a TPS of ≦1%, and five can be further characterized as having a TPS of <1%.

[1027] The relatively poor immune cell infiltration observed in tumor biopsies combined with low expression of PD-L1 may partly explain the failure of treatments involving anti-PD-1 or anti-PD-L1 immune checkpoint antibodies.

[1028] Preliminary results of NCT04364620 show that the best response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was partial response (PR) for 5 patients, stable disease (SD) for 11 patients, and progressive disease (PD) for 4 patients for a total of 20 evaluable patients (for RECIST 1.1 criteria, see Eisenhauer, Eur J Cancer, 45 (2009) 228-247). These preliminary data suggest signs of efficacy. Furthermore, the current data suggest increased progression-free survival compared to single-agent docetaxel in the same patient population.

[1029] It also appears that NSCLC patients with low PD-L1 tumor proportion score (TPS) may benefit from the treatment of the present disclosure.

[1030] For example, evidence of partial responses (as defined by RECIST 1.1) was found for four NSCLC patients with tumors with a PD-L1 tumor proportion score (TPS) of ≦15%. Three of these patients had a PD-L1 TPS of <1%, including one patient with a KRAS mutation.

[1031] Evidence of stable disease as defined by RECIST 1.1 has also been observed in three NSCLC patients with tumors with a PD-L1 Tumor Proportion Score (TPS) of ≦1%, including one patient with a tumor with a KRAS mutation and a PD-L1 TPS of <1%.

[1032] The anti-cancer therapies of the present disclosure may be an alternative to anti-PD-1 or anti-PD-L1 immune checkpoint monotherapy or combination with chemotherapy, particularly in patients with lesions that have low or no evidence of PD-L1 expression. The anti-cancer therapies of the present disclosure may also be an alternative for cancer patients who are not eligible for or would likely not benefit from treatments that include PD-1 or PD-L1 immune checkpoint inhibitors.

[1033] The data presented herein demonstrate that the anti-cancer treatments of the present disclosure are safe and show signs of efficacy.

[1034] The data presented herein also show that the anti-cancer treatments of the present disclosure promote the infiltration of immune cells. The treatments, in turn, can lead to the regression of lesions or stabilization of their growth. Thus, the anti-cancer therapies of the present disclosure can be used to modulate anti-tumor immune responses.

[1035] 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.

[1036] 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 VJ and VDJ sequence analysis. Nucl Acids Res 36:W503-W508, 2008. Andrew CR 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 -24 . 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. 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.

[1037]

Table 9-1

[1038]

Table 9-2

[1039]

Table 9-3

[1040]

Table 9-4

[1041]

Table 9-5

[1042]

Table 9-6

[1043]

Table 9-7

[1044]

Table 9-8

Claims

1. A pharmaceutical composition comprising an anti-clusterin antibody or an antigen-binding fragment thereof for enabling infiltration of immune cells into a tumor microenvironment in a subject in need thereof, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the β subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

2. A pharmaceutical composition comprising an anti-clusterin antibody or an antigen-binding fragment thereof for use in treating a subject having cancer by promoting infiltration of immune cells into the subject's tumor microenvironment, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the beta subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

3. A pharmaceutical composition comprising an anti-clusterin antibody or an antigen-binding fragment thereof for use in neoadjuvant and / or adjuvant treatment of a subject with cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the beta subunit of human clusterin which comprises the amino acid sequence set forth in SEQ ID NO:

41.

4. A pharmaceutical composition comprising an anti-clusterin antibody or antigen-binding fragment thereof for use before and / or after tumor resection or surgery in a subject having a resectable tumor, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the β subunit of human clusterin which contains the amino acid sequence set forth in SEQ ID NO:

41.

5. A pharmaceutical composition comprising an anti-clusterin antibody or an antigen-binding fragment thereof for use as a first-line therapy in the treatment of a subject having cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the beta subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

6. A pharmaceutical composition described in any one of claims 1 to 5, used in combination with radiation therapy or chemotherapy.

7. The chemotherapy includes a chemotherapeutic agent associated with resistance mediated by MDR1 / P-glycoprotein or is selected from an alkylating agent, an antimetabolite, an alkaloid, an antitumor antibiotic, or a combination thereof, the alkylating agent is optionally selected from altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, or trabectedin, and the antimetabolite is 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, or a combination thereof.

7. The pharmaceutical composition of claim 6, wherein the alkaloid is optionally selected from vincristine, vinblastine, vinorelbine, a taxane, etoposide, teniposide, irinotecan, or topotecan, the antitumor antibiotic is optionally selected from daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, or valrubicin, and the taxane is optionally paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, mirataxel, ortataxel, or tesetaxel.

8. The pharmaceutical composition of claim 6, wherein the chemotherapy comprises docetaxel.

9. A combination pharmaceutical comprising a pharmaceutical composition comprising an anti-clusterin antibody or its antigen-binding fragment formulated for administration at a dose of approximately 3 mg / kg to approximately 20 mg / kg, and a pharmaceutical composition comprising docetaxel formulated for administration at a dose of approximately 60 mg / m2 to 100 mg / m2, wherein the anti-clusterin antibody or its antigen-binding fragment binds to the C-terminal portion of the β subunit of human clusterin comprising the amino acid sequence shown in SEQ ID NO:

41.

10. The pharmaceutical combination of claim 9, for a) enabling infiltration of immune cells into the tumor microenvironment in a subject in need thereof, b) for use in the treatment of a subject with cancer, c) for use in neoadjuvant and / or adjuvant treatment of a subject with cancer, d) for use prior to and / or after tumor resection or surgery in a subject with a resectable tumor, or e) for use as a first line therapy in the treatment of a subject with cancer.

11. The anti-clusterin antibody or antigen-binding fragment thereof, a) a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 9, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 10; b) a light chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:9, and a heavy chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:10; or c) a light chain having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:11, and a heavy chain having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:12; 11. The pharmaceutical composition according to any one of claims 1 to 5 or the pharmaceutical combination according to claim 9 or 10, comprising:

12. A pharmaceutical composition or combination pharmaceutical described in any one of claims 1 to 5, 9 and 10, wherein the antibody or antigen-binding fragment thereof is capable of competing for binding to clusterin with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 9 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:

10.

13. 11. The pharmaceutical composition or combination pharmaceutical of any one of claims 1 to 5, 9 and 10, wherein the immune cells comprise plasma cells, T cells, B cells, NK cells and / or macrophages, and the T cells optionally comprise CD4+ T cells or CD8+ T cells.

14. The pharmaceutical composition or combination pharmaceutical of any one of claims 1 to 5, 9 and 10, wherein the anti-clusterin antibody or antigen-binding fragment thereof is used at a dose of approximately 3 mg / kg to approximately 20 mg / kg.

15. 11. The pharmaceutical composition or combination pharmaceutical of any one of claims 1 to 5, 9 and 10, wherein the anti-clusterin antibody or antigen-binding fragment thereof is used at a dose of approximately 12 mg / kg and / or docetaxel is used at a dose of approximately 75 mg / m2.

16. Docetaxel is approximately 60 mg / m 2 ~ approx. 100 mg / m 2 The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is used in a dose of

17. 11. The pharmaceutical composition or combination of any one of claims 1 to 5, 9 and 10, wherein the subject has early stage cancer, late stage cancer and / or metastatic cancer.

18. 11. The pharmaceutical composition or combination of claims 1 to 5, 9 and 10, wherein the subject has a resectable tumor.

19. The subject matter comprises: A tumor or one or more lesions characterized as immunologically cold; b. A tumor or lesion or lesions characterized as immunologically warm or hot that are non-responsive to immunotherapy; c. Carcinoma that has failed prior anticancer therapy; d. Carcinoma that has progressed after first-line immune checkpoint therapy; e. Cancer that has failed prior treatment with immune checkpoint therapy and platinum-containing doublet therapy; or f. Cancer that has failed prior treatment with anti-PD1 or PDL-1 immune checkpoint antibodies and platinum-containing doublet therapy; 11. The pharmaceutical composition or pharmaceutical combination according to any one of claims 1 to 5, 9 and 10, which has or is selected because it has:

20. The pharmaceutical composition or combination pharmaceutical of any one of claims 1 to 5, 9 and 10, wherein the subject has endometrial cancer, breast cancer, liver cancer, prostate cancer, kidney cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, pancreatic cancer, lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, melanoma, metastatic endometrial cancer, metastatic breast cancer, metastatic liver cancer, metastatic prostate cancer, metastatic kidney cancer, metastatic bladder cancer, metastatic cervical cancer, metastatic ovarian cancer, metastatic colorectal cancer, metastatic pancreatic cancer, metastatic lung cancer, metastatic gastric cancer, metastatic head and neck cancer, metastatic thyroid cancer, metastatic cholangiocarcinoma, metastatic mesothelioma, or metastatic melanoma.

21. The pharmaceutical composition or combination of any one of claims 1 to 5, 9 and 10, wherein the subject has non-small cell lung cancer (NSCLC).

22. The pharmaceutical composition or combination according to claim 21, wherein the NSCLC is metastatic NSCLC or stage III to IV NSCLC.

23. The pharmaceutical composition or combination of any one of claims 1 to 5, 9 and 10, wherein the subject has a functional immune system, is not immunosuppressed, or has not received immunosuppressive drugs within 1 to 14 days prior to treatment.

24. A pharmaceutical composition or combination pharmaceutical described in any one of claims 1 to 5, 9 and 10, wherein the use results in tumors being more sensitive to treatment with immunotherapy, and the immunotherapy is used after one or more cycles of an anti-clusterin antibody or its antigen-binding fragment as a single agent or in combination with chemotherapy.

25. 25. The pharmaceutical composition or combination pharmaceutical of claim 24, wherein the immunotherapy comprises a cellular immunotherapy or an immune checkpoint inhibitor.

26. The pharmaceutical composition or combination pharmaceutical according to any one of claims 1 to 5, 9 and 10, wherein the subject is a human subject.

27. ​​Use of an anti-clusterin antibody or antigen-binding fragment thereof in the manufacture of a medicament for enabling infiltration of immune cells into a tumor microenvironment in a subject in need thereof, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the β subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

28. Use of an anti-clusterin antibody or an antigen-binding fragment thereof in the manufacture of a medicament for neoadjuvant and / or adjuvant treatment of a subject in need thereof, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the β subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

29. Use of an anti-clusterin antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of a subject having a resectable tumor prior to and / or after tumor resection or surgery, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the β subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

30. Use of an anti-clusterin antibody or antigen-binding fragment thereof in the manufacture of a medicament for use as a primary therapy for the treatment of a subject having cancer, wherein the anti-clusterin antibody or antigen-binding fragment thereof binds to the C-terminal portion of the beta subunit of human clusterin comprising the amino acid sequence set forth in SEQ ID NO:

41.

31. The anti-clusterin antibody or antigen-binding fragment thereof, a) a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 9, and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 10; b) a light chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:9, and a heavy chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:10; or c) a light chain having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:11, and a heavy chain having an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:12; 31. The use according to any one of claims 27 to 30, comprising:

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