TITLE: METHOD FOR ALLOWING IMMUNE CELLS INFILTRATION IN TUMORS

TECHNICAL FIELD

The present disclosure generally relates to a method for allowing intra-tumor immune infdtration and/or for treating a subject having cancer. The method of the present disclosure is based on the administration of an anti-clusterin antibody or antigen binding fragment thereof either as a single agent or in combination therapy with docetaxel. Combination therapy, medicament and kits for such use are also provided.

BACKGROUND

The molecular mechanisms responsible for the occurrence of metastatic carcinomas are beginning to be elucidated with the identification of key regulators. Increasing evidence points to tumor cell epithelial-to-mesenchymal (EMT) as an important contributing process to metastatic evolution. The occurrence of EMT during tumor progression permits epithelial tumor cells, that are non-invasive and non-metastatic, to move from the primary tumor, invade the surrounding tissue, enter the bloodstream and finally disseminate to, and proliferate at secondary sites. In addition, epithelial cancer cells that undergo EMT adopt a behavior that is very similar to cancer stem cells (CSCs) including an inherent resistance to chemotherapy and immune evasion (Shibue et al. ,2017; Terry et al. 2017).

Despite the short-term effectiveness of first- and second-line therapies such as chemotherapeutic agents and immune checkpoint inhibitors in cancer therapy, a high proportion of subjects become refractory to these therapies due to the resistance of tumor cells to anti-cancer agents and the survival of tumor-initiating cells, two events that ultimately result in an increase in metastasis and poor subject survival.

The mechanism underlying resistance to immune checkpoint inhibitors can vary. However, it is generally accepted that checkpoint inhibitors work best against so-called immunologically hot tumors that is tumors that have been invaded by T cells creating an inflamed tumor. In contrast, immunologically cold tumors are poorly responsive to immunotherapy because for unknown reasons these tumors haven’t been recognized or haven’t provoke a strong immune response and therefore T cells have not penetrated to tumor or its microenvironment. Patients who have received a prior first line immune checkpoint inhibitor as a single agent are offered platinum-based chemotherapy in second line. Single agent docetaxel can be administered as second- or third- line therapy following failure of immune checkpoint inhibition and platinum doublet chemotherapy administered simultaneously or consecutively. Since most patients eventually progress following immunochemotherapy and since docetaxel has very limited efficacy in this setting, novel therapies are urgently needed.

SUMMARY

The Applicant came to the unexpected discovery that treatment with anti-clusterin antibody or antigen binding fragment thereof such as AB-16B5 leads to increased intra-tumor immune infiltration.

The Applicant has developed treatment based on the administration of an anti- clusterin antibody or antigen binding fragment thereof as a single agent or in a combination therapy with docetaxel.

The present disclosure provides a method for allowing infiltration of immune cells in a tumor (e.g., a solid tumor) microenvironment, which comprises a step of administering to a subject in need thereof an anti-clusterin antibody or an antigen binding fragmen t thereof.

In accordance with the present disclosure anti-clusterin antibody or an antigen binding fragment thereof may be used in a subject in need for allowing infiltration of immune cells in a tumor (e.g., solid tumor) microenvironment or in the manufacture of a medicament for allowing infiltration of immune cells in a tumor (e.g., solid tumor) microenvironment.

The present disclosure provides a method for treating a subject having cancer (e.g., a solid tumor), which comprises a step of administering to a subject in need thereof an anti- clusterin antibody or an antigen binding fragment thereof.

In accordance with the present disclosure anti-clusterin antibody or an antigen binding fragment thereof may be used for treating a subject having cancer or in the manufacture of a medicament for treating a subject having cancer.

In an exemplary embodiment, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose and/or an administration interval and/or for a treatment period sufficient to result in infiltration of immune cells in the tumor (e.g., solid tumor) microenvironment. The method of the present disclosure may also comprise a step of administering docetaxel to the subject in need.

In an exemplary embodiment, docetaxel is administered at a dose and/or an administration interval and/or for a treatment period sufficient to allow chemotherapy- induced immunogenic modulation of tumor.

In an exemplary embodiment, both the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are each administered at a dose and/or an administration interval and/or for a treatment period sufficient to allow infiltration of immune cells in a tumor microenvironment and/or chemotherapy -induced immunogenic modulation of tumor.

In accordance with the present disclosure, the subject in need is a subject having a tumor or having cancer and a functional immune system.

In accordance with the present disclosure, the subject in need is a subject having a tumor or having cancer and an adequate organ and immune function.

The present disclosure therefore provides a method of treating a subject having cancer, that comprises a step of administering a combination therapy comprising an anti- clusterin antibody or antigen binding fragment thereof and docetaxel, wherein the subject has a functional immune system or an adequate organ and immune function.

In accordance with the present disclosure, the anti-clusterin antibody or an antigen binding fragment thereof and docetaxel combination therapy may be used for treating a subject having cancer or in the manufacture of a medicament for treating a subject having cancer, wherein the subject has a functional immune system or an adequate organ and immune function.

In accordance with the present disclosure, the method may result in an increase (in the presence or in the amount) of immune cells in the tumor microenvironment.

In accordance with the present disclosure, the method may result in an increase in the activity of immune cells in the tumor microenvironment.

In accordance with the present disclosure, the method may result in modulation of an immune response towards tumor cells.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof or combination therapy may result in a less immune-refractory tumor microenvironment. In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel combination therapy may contribute to the creation of a more favorable immune environment with an increased anti-tumor cytotoxic T cell activity.

In accordance with the present disclosure, the cell killing activity of specific CD8 ⁺ cytotoxic T cells may be enhanced after treatment with the combination therapy.

In accordance with the present disclosure, the method may result in the tumor being more susceptible to treatment by immunotherapy.

In accordance with 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.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO:9 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO:9 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO: 10 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 10.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO: 11 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain having an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO: 12 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 12.

In accordance with the present disclosure, the antibody or antigen binding fragment thereof is capable of competing with an antibody comprising a light chain variable region having an amino acid sequence set forth in SEQ ID NO:9 and a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 10 for the binding of 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:35.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof comprises the amino acid sequence of CDRs, light chain and heavy chain variable regions or light chain and heavy chain set forth in Table 9.

In accordance with the present disclosure, the method may result in infdtration of immune cells in a primary tumor microenvironment.

In accordance with the present disclosure, the method may result in infdtration of plasmocytes in a tumor microenvironment.

In accordance with the present disclosure, the method may result in infdtration of T cells in a tumor microenvironment. In some embodiments, the T cells comprise CD4 ⁺ T cells. In some embodiments, the T cells comprise CD8 ⁺ T cells. In other embodiments, T cells comprises both CD4 ⁺ T cells and CD8 ⁺ T cells.

In accordance with the present disclosure, the method may result in infdtration of B cells in a tumor microenvironment.

In accordance with the present disclosure, the method may result in infdtration of T cells and B cells in a tumor microenvironment.

In accordance with the present disclosure, the method may result in necrosis of a tumor.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered once weekly.

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

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

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

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

In some embodiments, docetaxel is administered once every week. In some embodiments, docetaxel is administered once every two weeks.

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

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

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of between approximately 3 mg/kg and approximately 20 mg/kg, such as for example, between approximately 4 mg/kg and approximately 20 mg/kg, between approximately 5 mg/kg and approximately 20 mg/kg, between approximately 6 mg/kg and approximately 20 mg/kg, between approximately 6 mg/kg and approximately 18 mg/kg, between approximately 6 mg/kg and approximately 17 mg/kg, between approximately 6 mg/kg and approximately 16 mg/kg, between approximately 6 mg/kg and approximately 15 mg/kg, between approximately 6 mg/kg and approximately 14 mg/kg, between approximately 6 mg/kg and approximately 13 mg/kg, between approximately

6 mg/kg and approximately 12 mg/kg, between approximately 7 mg/kg and approximately 18 mg/kg, between approximately 7 mg/kg and approximately 17 mg/kg, between approximately

7 mg/kg and approximately 16 mg/kg, between approximately 7 mg/kg and approximately 15 mg/kg, between approximately 7 mg/kg and approximately 14 mg/kg, between approximately

7 mg/kg and approximately 13 mg/kg, between approximately 7 mg/kg and approximately 12 mg/kg, between approximately 8 mg/kg and approximately 18 mg/kg, between approximately

8 mg/kg and approximately 17 mg/kg, between approximately 8 mg/kg and approximately 16 mg/kg, between approximately 8 mg/kg and approximately 15 mg/kg, between approximately

8 mg/kg and approximately 14 mg/kg, between approximately 8 mg/kg and approximately 13 mg/kg, between approximately 8 mg/kg and approximately 12 mg/kg, between approximately

9 mg/kg and approximately 18 mg/kg, between approximately 9 mg/kg and approximately 17 mg/kg, between approximately 9 mg/kg and approximately 16 mg/kg, between approximately 9 mg/kg and approximately 15 mg/kg, between approximately 9 mg/kg and approximately 14 mg/kg, between approximately 9 mg/kg and approximately 13 mg/kg, between approximately 9 mg/kg and approximately 12 mg/kg, between approximately 10 mg/kg and approximately 18 mg/kg, between approximately 10 mg/kg and approximately 17 mg/kg, between approximately 10 mg/kg and approximately 16 mg/kg, between approximately 10 mg/kg and approximately 15 mg/kg, between approximately 10 mg/kg and approximately 14 mg/kg, between approximately lOmg/kg and approximately 13 mg/kg, or between approximately 10 mg/kg and approximately 12 mg/kg. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6 mg/kg. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 9 mg/kg.

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

In accordance with the present disclosure docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² such as for example, between approximately 60 mg/m ² to approximately 95 mg/m ² , between approximately 60 mg/m ² to approximately 90 mg/m ² , between approximately 60 mg/m ² to approximately 85 mg/m ² , between approximately 60 mg/m ² to approximately 80 mg/m ² , between approximately 60 mg/m ² to approximately 75 mg/m ² , between approximately 75 mg/m ² to approximately 95 mg/m ² , between approximately 75 mg/m ² to approximately 90 mg/m ² , between approximately 75 mg/m ² to approximately 85 mg/m ² , between approximately 75 mg/m ² to approximately 80 mg/m ² , between approximately 70 mg/m ² to approximately 95 mg/m ² , between approximately 70 mg/m ² to approximately 90 mg/m ² , between approximately 70 mg/m ² to approximately 85 mg/m ² , between approximately 70 mg/m ² to approximately 80 mg/m ² , or between approximately 70 mg/m ² to approximately 75 mg/m ² .

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

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

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

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

In some embodiments, the subject is treated with the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 9 mg/kg once weekly and docetaxel at a dose of approximately 75 mg/m ² once every three weeks. In some embodiments, the subject is treated with the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 9 mg/kg once weekly and docetaxel at a dose of approximately 60 mg/m ² once every three weeks.

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

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

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

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

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

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel may be administered by infusion over approximately a 1-hour time frame.

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

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

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered during the first one, the first two, the first three, the first four or the first five cycles of the treatment period and then are both essentially administered during the remaining cycles of the treatment period.

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

In some embodiments, the subject in need does not receive concurrent treatment other than the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel.

In some embodiments, the subject in need does not require concurrent treatment other than the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel.

In accordance with the present disclosure, the subject in need is a human in need.

In accordance with the present disclosure, the subject in need is a subject having a tumor characterized as metastatic.

In accordance with the present disclosure, the subject in need is a subject having a carcinoma.

In accordance with the present disclosure, the subject in need is a subject having a metastatic carcinoma.

In accordance with the present disclosure, the subject in need is a subject having or selected for having a tumor characterized as immunologically cold.

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

In other embodiments, the subject in need is a subject having or selected for having a carcinoma that progressed after a first line immune checkpoint therapy.

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

In additional embodiments, the subject in need is a subject having or selected for having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti-PDl or PD-L1 immune checkpoint antibody (e.g., simultaneously or sequentially). In accordance with the present disclosure, the subject in need has a tumor that expresses or secrete clusterin.

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

In accordance with the present disclosure, the subject in need is a subject having non small cell lung cancer (NSCLC).

In some embodiments, the subject in need is a subject having metastatic NSCLC.

In some embodiments, the subject in need is a subject having stage III to IV NSCLC.

In accordance with the present disclosure, the subject in need is a subject having breast cancer.

In some embodiments, the subject in need is a subject having metastatic breast cancer.

In accordance with the present disclosure, the subject in need is a subject having prostate cancer.

In some embodiments, the subject in need is a subject having metastatic prostate cancer.

In accordance with the present disclosure, the subject in need is a subject having gastric cancer.

In some embodiments, the subject in need is a subject having metastatic gastric cancer.

In accordance with the present disclosure, the subject in need is a subject having head and neck cancer.

In some embodiments, the subject in need is a subject having metastatic head and neck cancer.

In accordance with the present disclosure, the subject in need is a subject having thyroid cancer.

In some embodiments, the subject in need is a subject having metastatic thyroid cancer. In accordance with the present disclosure, the subject in need is a subject having ovarian cancer.

In some embodiments, the subject in need is a subject having metastatic ovarian cancer.

In accordance with the present disclosure, the subject in need is a subject having endometrial cancer.

In some embodiments, the subject in need is a subject having metastatic endometrial cancer.

In accordance with the present disclosure, the subject in need is a subject having liver cancer.

In some embodiments, the subject in need is a subject having metastatic liver cancer.

In accordance with the present disclosure, the subject in need is a subject having colorectal cancer.

In some embodiments, the subject in need is a subject having metastatic colorectal cancer.

In accordance with the present disclosure, the subject in need is a subject having pancreatic cancer.

In some embodiments, the subject in need is a subject having metastatic pancreatic cancer.

In accordance with the present disclosure, the subject in need is a subject having cholangiocarcinoma.

In some embodiments, the subject in need is a subject having metastatic cholangiocarcinoma.

In accordance with the present disclosure, the subject in need is a subject having mesothelioma.

In some embodiments, the subject in need is a subject having metastatic mesothelioma.

In accordance with the present disclosure, the subject in need is a subject having melanoma. In some embodiments, the subject in need is a subject having metastatic melanoma.

In accordance with the present disclosure, the subject in need is a subject that is not immunosuppressed or has not received an immunosuppressive medication within 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 days or 1 day prior to treatment.

In accordance with the present disclosure, the subject in need is a subject that has not received prior treatment with docetaxel.

In accordance with the present disclosure the subject is treated for one or more cycles of treatment. In some embodiments, one cycle of treatment is approximately 21 days.

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

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

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

In yet an additional exemplary embodiment, the subject is treated for at least four cycles of treatment.

In other exemplary embodiments, the subject is treated or receives four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more treatment cycles.

In some embodiments, the treatment cycles are consecutive.

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

In accordance with the present disclosure, the infiltration of immune cells in the tumor microenvironment is confirmed by biopsy.

In accordance with the present disclosure, the infiltration of immune cells in the tumor microenvironment is confirmed by imaging (e.g., magnetic resonance imaging). In accordance with the present disclosure, the method comprises a step of administering immunotherapy (immune checkpoint inhibitors, cellular immunotherapy) after one or more cycles of anti-clusterin antibody or antigen binding fragment thereof as a single agent or in combination therapy with docetaxel.

In some embodiments, the immunotherapy comprises cellular immunotherapy (CAR- T, TILs, etc ).

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

In some embodiments, the method comprises a step of administering ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab after one or more cycles of anti-clusterin antibody or antigen binding fragment thereof as a single agent or in combination therapy with docetaxel. In some embodiments, the subjects is treated with one or more cycles of anti-clusterin antibody or antigen binding fragment thereof as a single agent or in combination therapy with docetaxel and is subsequently treated with an immune checkpoint inhibitor that he has not previously received.

The present disclosure also provides a medicament comprising an anti-clusterin antibody or antigen binding fragment thereof for allowing infdtration of immune cells in a tumor (e.g., a solid tumor) microenvironment in a subject having cancer.

In some embodiments, the medicament is for use in combination with docetaxel.

The present disclosure also provides a medicament comprising an anti-clusterin antibody or antigen binding fragment thereof for use in combination with docetaxel for the treatment of a subject having cancer wherein the subject has a functional immune system or an adequate organ and immune function.

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.

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

In some embodiments, docetaxel is formulated is formulated as an injectable solution at a concentration of between approximately 10 mg/mL to approximately 40 mg/mL. In some embodiments, docetaxel is formulated as an intravenous infusion for delivery of a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² .

The present disclosure also provides a combination therapy comprising a pharmaceutical composition comprising an anti-clusterin antibody or antigen binding fragment thereof formulated for administration at a dose of between approximately 3 mg/kg and approximately 20 mg/kg and a pharmaceutical composition comprising docetaxel formulated for administration at a dose of between approximately 60 mg/m ² to 100 mg/m ² .

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof comprises CDRs, variable regions or light chain and heavy chains as described herein.

In accordance with the present disclosure, the combination therapy or medicament is used or is for use in treating a subject in need.

In accordance with the present disclosure, the combination therapy or medicament is used or is for use in treating a subject having cancer as described herein.

In some exemplary embodiments, the combination therapy or medicament is used or is for used in treating a subject having a carcinoma.

In some exemplary embodiments, the combination therapy or medicament is used or is for use in treating a subject having a metastatic carcinoma.

In accordance with the present disclosure, the combination therapy or medicament is used or is for used in treating a subject having or selected for having a carcinoma that progressed after a first line immune checkpoint therapy.

In accordance with the present disclosure, the combination therapy or medicament is used or is for use in treating a subject having or selected for having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and immune checkpoint therapy (e.g., simultaneously or sequentially).

In accordance with the present disclosure, the combination therapy or medicament is used or is for use in treating a subject having or selected for having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti-PDl or PD- L1 immune checkpoint antibody (e.g., simultaneously or sequentially). In some exemplary embodiments, the combination therapy or medicament is used or is for use in treating a subject having non-small cell lung cancer. In some embodiments, the subject has metastatic NSCLC or stage III to IV NSCLC.

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

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

In some exemplary embodiments, the combination therapy or medicament is used or is for use in a subject that is not immunosuppressed or that has not received an immunosuppressive medication within 7 days prior to treatment.

In some exemplary embodiments, the combination therapy or medicament is used or is for use in a subject that has not received prior treatment with docetaxel.

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

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dosage disclosed herein.

In accordance with the present disclosure, docetaxel is used or is for use at a dosage disclosed herein.

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

In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 12 mg/kg once weekly and docetaxel is used at a dose of 60 mg/m ² once every three weeks.

In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 9 mg/kg once weekly and docetaxel is used at a dose of 75 mg/m ² once every three weeks. In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 9 mg/kg once weekly and docetaxel is used at a dose of 60 mg/m ² once every three weeks.

In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 6 mg/kg once weekly and docetaxel is used at a dose of 75 mg/m ² once every three weeks.

In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 6 mg/kg once weekly and docetaxel is used at a dose of 60 mg/m ² once every three weeks.

In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 3 mg/kg once weekly and docetaxel is used at a dose of 75 mg/m ² once every three weeks.

In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is used or is for use at a dose of 3 mg/kg once weekly and docetaxel is used at a dose of 60 mg/m ² once every three weeks.

The present disclosure also provides a kit comprising one or more containers comprising at least one dose of an anti-clusterin antibody or antigen binding fragment thereof, one or more containers comprising at least one dose of docetaxel for use in combination therapy and a package insert comprising instructions for treating a subject in need.

The kit of the present disclosure comprises the anti-clusterin antibody or antigen binding fragment thereof disclosed herein.

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

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that is metastatic.

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

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that progressed after a first line immune checkpoint therapy. In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and immune checkpoint therapy (e.g., simultaneously or sequentially).

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti-PDl or PD-L1 immune checkpoint antibody (e.g., simultaneously or sequentially).

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

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having breast cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic breast cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having prostate cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic prostate cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having gastric cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic gastric cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having head and neck cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic head and neck cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having thyroid cancer. In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic thyroid cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having ovarian cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic ovarian cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having endometrial cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic endometrial cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having liver cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic liver cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having colorectal cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic colorectal cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having pancreatic cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic pancreatic cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having cholangiocarcinoma.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic cholangiocarcinoma.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having mesothelioma. In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic mesothelioma.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having melanoma.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic melanoma.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject that is not immunosuppressed has not received an immunosuppressive medication within 7 days prior to treatment.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject that has not received prior treatment with docetaxel.

In some embodiments, the package insert states that the combination therapy is for administration essentially over the entire course of the treatment period (e.g., throughout the treatment period).

The present disclosure also relates to a kit comprising one or more containers comprising at least one dose of the medicament disclosed herein and a package insert as disclosed herein comprising instructions for treating a subject in need, wherein the anti- clusterin antibody or antigen binding fragment thereof and docetaxel are provided in separate containers.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: 4T1 Lung Metastases Are Immunologically “Cold” Which Prevents Immune Lymphocyte Infdtration. CD3+ and CD8+ T cells are present in the margins of 4T1 lung metastases resulting from the creation of a restrictive tumor microenvironment as a consequence of the epithelial to mesenchymal transitions that prevents lymphocytic infdtration.

Figure 2A: Inhibition of EMT with the 16B5 Anti-sCLU mAb Results in B (B220) and T (CD3, CD4, CD8) Lymphocytes Infdtration in 4T1 Lung Metastases.

Figure 2B: Picture of human tumor biopsies of patients treated with AB-16B5 as single agent. Figure 3: Graph of the number of lung nodules in 4T1 -implanted animals treated with AB-16B5 in monotherapy or in combination with docetaxel.

Figure 4A and Figure 4B: 4T1 lung metastases from animals treated with AB-16B5 in monotherapy or in combination with docetaxel are infdtrated by B and T lymphocytes.

4T1 lung metastases were dissected at Day 36 post-implantation and processed with collagenase and hyaluronidase for immunophenotyping by flow cytometry.

Further scope, applicability and advantages of the present disclosure will become apparent from the non-restrictive detailed description given hereinafter. It should be understood, however, that this detailed description, while indicating exemplary embodiments of the disclosure, is given by way of example only, with reference to the accompanying drawings.

DETAILED DESCRIPTION

Definitions

Unless indicated otherwise, the amino acid numbering indicated for the dimerization domain are in accordance with the EU numbering system.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing embodiments (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Unless specifically stated or obvious from context, as used herein the term “or” is understood to be inclusive and covers both “or” and “and”.

The term “and/or” where used herein is to be taken as specific disclosure of each of the specified features or components with or without the other.

The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. The term “consisting of’ is to be construed as close-ended.

The term "treatment" for purposes of this disclosure 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 have the disorder or those in whom the disorder is to be prevented. The term “about” or “approximately” with respect to a given value means that variation in the value is contemplated. In some embodiments, the term “about” or “approximately” shall generally mean a range within +/- 20 percent, within +/- 10 percent, within +/- 5 percent, within +1- 4 percent, within +/- 3 percent, within +1- 2 percent or within +1- 1 percent of a given value or range.

The expression “over the entire course of the treatment period” means that both the anti-clusterin antibody or antigen binding fragments and docetaxel are administered at each treatment cycle.

The term “essentially” is used to characterize an action that is carried out most of the time or a state that occurs most of the time. For example, the expression “essentially over the entire course of the treatment period” means that both the anti-clusterin antibody or antigen binding fragments and docetaxel are administered at each treatment cycle and during the entire treatment period but occasionally a dose of either of the anti-clusterin antibody or antigen binding fragments or docetaxel or a dose of each may be intentionally or non- intentionally missed.

The term “functional immune system” with respect to a subject means that the immune system of the subject is essentially not affected by cancer or by medication or that the subject is not immunosuppressed.

The expression “adequate organ and immune function” refers to one or more of the parameters provided in Table 7.

Methods and Uses

The present disclosure provides a method for allowing infdtration of immune cells in the tumor microenvironment.

In some aspects and embodiments, the method comprises a step of administering an anti-clusterin antibody or an antigen binding fragment thereof to a subject in need thereof.

The anti-clusterin antibody or an antigen binding fragment thereof may be used as a single agent or in combination therapy as described herein.

For example, the anti-clusterin antibody or an antigen binding fragment thereof may be used in combination with docetaxel such as to generate chemotherapy -induced immunogenic modulation. In some embodiments, the method of the present disclosure more particularly comprises administering an anti-clusterin antibody or an antigen binding fragment thereof in combination with docetaxel to a subject in need thereof.

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

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

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

In yet 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 having cancer (e.g., a solid tumor).

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

In yet 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 the treatment of a subject having cancer (e.g., a solid tumor).

In some embodiments, the subject in need is a subject having cancer and a functional immune system.

In some embodiments, the subject in need is a subject having cancer and an adequate organ and immune function.

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

In some embodiments, the method or use of the present disclosure may result in infdtration of immune cells in a primary tumor microenvironment. In some embodiments, the tumor microenvironment may be infiltrated with immune cells such as plasmocytes.

In some embodiments, method or use of the present disclosure may result in infiltration of T cells in the tumor microenvironment.

In some embodiments, method or use of the present disclosure may result in infiltration of CD4 ⁺ T cells in the tumor microenvironment.

In some embodiments, method or use of the present disclosure may result in infiltration of CD8 ⁺ T cells in the tumor microenvironment.

In some embodiments, method or use of the present disclosure may result in infiltration of B cells in the tumor microenvironment.

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

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

A tumor may be characterized as “immunologically cold” when the tumor microenvironment is not sufficiently infiltrated by immune cells (especially by lymphocytes) or when the tumor microenvironment is not inflamed. In contrast, a tumor may be characterized as “immunologically warm” or “immunologically hot” when infiltration of immune cells (especially by lymphocytes) in the tumor microenvironment is observed or when the tumor shows sign of inflammation.

Generally, a pathologist, a technologist, a trained scientist or trained technician equipped with proper reagents and/or apparatus may be able to determine the absence or presence of immune cells in the tumor microenvironment and may thus be able to evaluate whether a tumor is “immunologically cold”, “immunologically warm” or “immunologically hot”.

Single agent or combination therapy may thus be administered subsequent to confirmation that the subject has a “immunologically cold tumor”.

In addition, detection of immune cells in the tumor microenvironment may reveal that treatment with anti-clustering antibody or antigen binding fragment thereof as a single agent or in combination therapy with docetaxel effectively allows infiltration of immune cells in a the tumor microenvironment.

The method or use of the present disclosure may result in the tumor being more susceptible to treatment by immunotherapy. The present disclosure therefore includes a step of administering immunotherapy after one or more cycle of the anti-clusterin antibody or antigen binding fragment thereof as single agent or in combination therapy with docetaxel.

The immunotherapy includes for example, immune checkpoint inhibitors (anti -PD 1 or anti-PDL-1 antibodies, anti-CTL-A4 antibodies) and cellular immunotherapy (e.g., CAR-T cells, TILs).

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

In some embodiments, the method or use of the present disclosure may result in modulation of an immune response towards tumor cells.

The method or use of the present disclosure may result in an increased immune response towards tumor cells.

In some embodiments, the method or use of the present disclosure may result in necrosis of a tumor.

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

In yet other aspects and embodiments, the present disclosure relates to a method of treating a subject having 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 an adequate organ and immune function.

In some embodiments, the method or use of the present disclosure does not require concurrent anti-cancer treatment during the treatment period.

In some embodiments, the method or use of the present disclosure does not involve concurrent anti-cancer treatment during the treatment period. In accordance with the present disclosure the method or use comprises administering an anti-clusterin antibody or antigen binding fragment thereof at a dose of between approximately 3 mg/kg to approximately 20 mg/kg.

Also, in accordance with the present disclosure the method or use comprises administering an anti-clusterin antibody or antigen binding fragment thereof at a dose of between approximately 3 mg/kg to approximately 20 mg/kg and docetaxel at a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² .

The anti-clusterin antibody or antigen binding fragment thereof and docetaxel are generally administered on same day. However, it is possible that they be administered on a different day.

The anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered over the entire course of the treatment period. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered at each cycle.

The anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both essentially administered over the entire course of the treatment period. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered at all cycles.

The anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both generally administered at each treatment cycle. However, it is possible that one or more doses of the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel is missed without negatively impacting the treatment. It is also possible that one or more additional doses of the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel is administered without negatively impacting the treatment.

The method or use may also involve interrupting treatment (single agent or combination therapy) for a period of time (e.g., for one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, at least ten weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, at least six months, at least ten months, at least one year, once cycle, two cycles, three cycles, four cycles, five cycles, six cycles, seven cycles, eight cycles, nine cycles, ten cycles, at least ten cycles). Treatment may be reinitiated afterward. In some embodiments, at least one treatment cycle is interrupted.

In other embodiments, more than one treatment cycles are interrupted.

In some embodiments the interruption lasts from one day to one week. In some embodiments the interruption lasts from one day to two weeks. In some embodiments the interruption lasts from one day to three weeks. In some embodiments the interruption lasts from one day to one month. In some embodiments the interruption lasts from one day to two months. In some embodiments the interruption lasts from one day to three months. In some embodiments the interruption lasts from one day to four months. In some embodiments the interruption lasts from one day to five months. In some embodiments the interruption lasts from one day to six months. In some embodiments the interruption lasts from one day to more than six months.

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

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

In accordance with the present disclosure, the method or use is for the treatment of a carcinoma in a subject in need thereof.

In accordance with the present disclosure, the method or use is for the treatment of a metastatic carcinoma in a subject in need thereof.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In an exemplary embodiment, the cancer is metastatic NSCLC such as stage III to IV NSCLC.

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

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

In some embodiments, the cancer is gastric cancer. In an exemplary embodiment, the cancer is metastatic gastric cancer. In some embodiments, the cancer is head and neck cancer. In an exemplary embodiment, the cancer is metastatic head and neck cancer.

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

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

Dosages treatment regimens and schedules

Anti-clusterin antibody

In accordance with 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 in the tumor microenvironment.

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

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered at an administration interval sufficient to result in infiltration of immune cells in the tumor microenvironment.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered for a treatment period sufficient to result in infiltration of immune cells in the tumor microenvironment.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose, administration interval and/or treatment period sufficient to result in infiltration of immune cells in the tumor microenvironment.

In accordance with an exemplary embodiment of the disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered once weekly.

In accordance with another exemplary embodiment of the disclosure, the anti- clusterin antibody or antigen binding fragment thereof is administered twice weekly.

In accordance with yet another exemplary embodiment of the disclosure, the anti- clusterin antibody or antigen binding fragment thereof is administered thrice weekly.

In accordance with a further exemplary embodiment of the disclosure, the anti- clusterin antibody or antigen binding fragment thereof is administered once every two weeks. In accordance with yet a further exemplary embodiment of the disclosure, the anti- clusterin antibody or antigen binding fragment thereof is administered once every three weeks.

In accordance with an additional exemplary embodiment of the disclosure, the anti- clusterin antibody or antigen binding fragment thereof is administered once every four weeks.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of between approximately 3 mg/kg and approximately 20 mg/kg.

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

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

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

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

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

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

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

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

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

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 13.0 mg/kg. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 14.0 mg/kg.

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

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

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

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

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

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

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is humanized 16B5 and is administered at a dose of between approximately 3 mg/kg and approximately 20 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 4 mg/kg and approximately 20 mg/kg.

In accordance with the present disclosure, the humanized 16B5 is administered at a dose of between approximately 5 mg/kg and approximately 20 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 20 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 18 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 17 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 16 mg/kg. In accordance with the present disclosure, humanized 16B5 administered at a dose of between approximately 6 mg/kg and approximately 15 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 14 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 13 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 6 mg/kg and approximately 12 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 7 mg/kg and approximately 12 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 8 mg/kg and approximately 12 mg/kg.

In accordance with the present disclosure, humanized 16B5 is administered at a dose of between approximately 9 mg/kg and approximately 12 mg/kg.

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.

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.

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.

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.

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.

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.

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. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Docetaxel

In accordance with the present disclosure, docetaxel is administered at a dose sufficient to allow chemotherapy -induced immunogenic modulation of tumor.

In some embodiments, the dose of the docetaxel is a therapeutically effective and safe dose. In accordance with the present disclosure, docetaxel is administered at an administration interval sufficient to allow chemotherapy-induced immunogenic modulation of tumor.

In accordance with the present disclosure, docetaxel is administered for a treatment period sufficient to allow chemotherapy-induced immunogenic modulation of tumor.

In some embodiments, docetaxel is administered at a dose and/or an administration interval and/or for a treatment period sufficient to allow chemotherapy -induced immunogenic modulation of tumor.

In accordance with an exemplary embodiment of the disclosure, docetaxel is administered once every week.

In accordance with another exemplary embodiment of the disclosure, docetaxel is administered once every two weeks.

In accordance with yet another exemplary embodiment of the disclosure, docetaxel is administered once every three weeks.

In accordance with a further exemplary embodiment of the disclosure, docetaxel is administered once every four weeks.

In accordance with a further exemplary embodiment of the disclosure, docetaxel is administered once every five weeks.

In accordance with a further exemplary embodiment of the disclosure, docetaxel is administered once every six weeks.

In accordance with the present disclosure, docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² .

In accordance with the present disclosure docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 95 mg/m ² .

In accordance with the present disclosure docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 90 mg/m ² .

In accordance with the present disclosure docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 85 mg/m ² .

In accordance with the present disclosure docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 80 mg/m ² . In accordance with the present disclosure docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 75 mg/m ² .

In accordance with the present disclosure docetaxel is administered at a dose of between approximately 70 mg/m ² to approximately 75 mg/m ² .

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

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

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

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

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

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

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

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

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

Combinations and medicaments

The present disclosure provides in some aspects and embodiments, a medicament comprising an anti-clusterin antibody or antigen binding fragment thereof for allowing infdtration of immune cells in a tumor (e.g., solid tumor) microenvironment in a subject having cancer.

In some embodiments, the medicament is for use in combination with docetaxel. In yet other aspects and embodiments, the present disclosure provides a medicament comprising an anti-clusterin antibody or antigen binding fragment thereof for use in combination with docetaxel for the treatment of a subject having cancer.

The present disclosure provides in other aspects and embodiments, a combination therapy which comprises a pharmaceutical composition comprising an anti-clusterin antibody or antigen binding fragment thereof formulated for administration at a dose of between approximately 3 mg/kg and approximately 20 mg/kg and a pharmaceutical composition comprising docetaxel formulated for administration at a dose of approximately 60 mg/m ² to 100 mg/m ² .

In some embodiments, the combination therapy or medicament is for use in allowing infdtration of immune cells in a tumor (e.g., solid tumor) microenvironment.

In other embodiments, the combination therapy or medicament is for use in treating a subject having cancer.

In yet other embodiments, the combination therapy or medicament is for use in treating a subject having cancer and a functional immune system.

In yet other embodiments, the combination therapy or medicament is for use in treating a subject having cancer and an adequate organ and immune function.

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

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are each administered at administration interval sufficient to allow infiltration of immune cells in a tumor microenvironment and/or chemotherapy -induced immunogenic modulation of tumor.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are each administered for a treatment period sufficient to allow infiltration of immune cells in a tumor microenvironment and/or chemotherapy -induced immunogenic modulation of tumor.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are each administered at a dose, administration interval and/or for a treatment period sufficient to allow infiltration of immune cells in a tumor microenvironment and/or chemotherapy -induced immunogenic modulation of tumor.

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 docetaxel is administered at a dose of approximately 75 mg/m ² once every three weeks.

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 docetaxel is administered at a dose of approximately 60 mg/m ² once every three weeks.

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 docetaxel is administered at a dose of approximately 75 mg/m ² once every three weeks.

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 docetaxel is administered at a dose of approximately 60 mg/m ² once every three weeks.

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 docetaxel is administered at a dose of approximately 75 mg/m ² once every three weeks.

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 docetaxel is administered at a dose of approximately 60 mg/m ² once every three weeks.

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

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

The anti-clusterin antibody or antigen binding fragment thereof used in the combination therapy or in the medicament is as described herein.

For example, the anti-clusterin antibody or antigen binding fragment thereof that is used in the combination therapy or in the medicament 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.

In an exemplary embodiment, the anti-clusterin antibody or antigen binding fragment thereof that is used in the combination therapy or in the medicament may have a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:l, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3 and 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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6.

In another exemplary embodiment, the anti-clusterin antibody or antigen binding fragment thereof that is used in the combination therapy or in the medicament may have a light chain variable region comprising a CDRLl having the amino acid sequence set forth in SEQ ID NO:l, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3 and 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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:37.

In yet another exemplary embodiment, the anti-clusterin antibody or antigen binding fragment thereof that is used in the combination therapy or in the medicament may have a light chain variable region having an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with 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%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO: 8.

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.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO:9 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO: 10.

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.

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence identical 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.

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 ² once every three weeks.

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 ² once every three weeks.

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 ² once every three weeks.

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 ² once every three weeks. 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 ² once every three weeks.

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 ² once every three weeks.

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 ² once every three weeks.

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 ² once every three weeks.

In some embodiments, 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 once weekly, and docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 6 mg/kg to approximately 15 mg/kg once weekly, and docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² once every three weeks and both are essentially administered over the entire course of the treatment period. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is humanized 16B5 and is administered at a dose of approximately 6 mg/kg to approximately 12 mg/kg once weekly, and docetaxel is administered at a dose of between approximately 60 mg/m ² to approximately 100 mg/m ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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 ² once every three weeks and both are essentially administered over the entire course of the treatment period.

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

For example, when both the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered every week, a treatment cycle is considered to be of 7 days.

For example, when the anti-clusterin antibody or antigen binding fragment thereof is administered every week and docetaxel is administered every two weeks, a treatment cycle is considered to of 14 days.

For example, when the anti-clusterin antibody or antigen binding fragment thereof is administered every week and docetaxel is administered every three weeks, a treatment cycle is considered to of 21 days.

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

In some exemplary embodiments, essentially all treatment cycles are approximately 21 days.

In some exemplary embodiments, each treatment cycles are approximately 21 days.

In accordance with the present disclosure, the subject may thus receive a new treatment cycle every 21 days.

In accordance with the present disclosure, a subject may receive at least one treatment cycle.

In accordance with the present disclosure, a subject may receive at least two treatment cycles s.

In accordance with the present disclosure, a subject may receive at least three treatment cycles.

In accordance with the present disclosure, a subject may receive at least four treatment cycles.

In accordance with the present disclosure, a subject may receive four or more treatment cycles. In accordance with the present disclosure, a subject may receive at least five treatment cycles.

In accordance with the present disclosure, a subject may receive at least six treatment cycles.

In accordance with the present disclosure, a subject may receive at least seven treatment cycles.

In accordance with the present disclosure, a subject may receive at least eight treatment cycles.

In accordance with the present disclosure, a subject may receive at least nine treatment cycles.

In accordance with the present disclosure, a subject may receive at least ten treatment cycles.

In accordance with the present disclosure, a subject may receive at least eleven treatment cycles.

In accordance with the present disclosure, a subject may receive at least twelve treatment cycles.

In accordance with the present disclosure, a subject may receive at least thirteen treatment cycles.

In accordance with the present disclosure, a subject may receive at least fourteen treatment cycles.

In accordance with the present disclosure, a subject may receive at least fifteen treatment cycles.

In accordance with the present disclosure, a subject may receive at least sixteen treatment cycles.

In accordance with the present disclosure, a subject may receive at least seventeen treatment cycles.

In accordance with the present disclosure, a subject may receive at least eighteen treatment cycles. In accordance with the present disclosure, a subject may receive at least nineteen treatment cycles.

In accordance with the present disclosure, a subject may receive at least twenty treatment cycles.

In accordance with the present disclosure, a subject may receive more than twenty treatment cycles.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered by infusion over approximately a 1-hour time frame.

In some embodiments, docetaxel is administered by infusion over approximately a 1- hour time frame.

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered on same day.

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

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered by infusion over approximately a 1-hour time frame and docetaxel is subsequently administered by infusion on same day over approximately a 1-hour time frame.

In some embodiments, docetaxel is administered by infusion over approximately a 1- hour time frame and the anti-clusterin antibody or antigen binding fragment thereof is subsequently administered by infusion on same day over approximately a 1-hour time frame.

In accordance with the present disclosure, the combination therapy or medicament may be used for subjects having carcinoma.

In accordance with the present disclosure, the combination therapy or medicament may be used for subjects having metastatic carcinoma.

In some embodiment, the combination therapy or medicament may be used for subjects having non-small cell lung cancer (NSCLC) such as metastatic NSCLC or stage III to IV NSCLC. In exemplary embodiments, the combination therapy or medicament may be used for subjects having breast cancer, prostate cancer, gastric cancer, head and neck cancer, thyroid cancer or ovarian cancer.

In exemplary embodiments, the combination therapy or medicament may be used for subjects having metastatic breast cancer, metastatic prostate cancer, metastatic gastric cancer, metastatic head and neck cancer, metastatic thyroid cancer or metastatic ovarian cancer.

In accordance with the present disclosure, the pharmaceutical composition comprising the anti-clusterin antibody or antigen binding fragment thereof and the pharmaceutical composition comprising docetaxel are both administered essentially over the entire course of the treatment period.

Anti-clusterin antibodies or antigen binding fragments thereof

The present disclosure relates to the use of an anti-clusterin antibody or antigen binding fragment thereof either alone (single agent) or in combination with a chemotherapeutic that induces immunogenic modulation such as docetaxel.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of inhibiting epithelial to mesenchymal transition.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of binding to amino acids 421 and 443 of a C-terminal portion of a B-subunit of human clusterin (SEQ ID NO: 35 see PCT/CA2006/001505 published under No. W02007/030930 and international application No. PCT/CA2010/0001882 published under No. WO2011/063523 the entire content of which is incorporated herein by reference).

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of binding to an epitope comprised within amino acids 421 and 443 of a C-terminal portion of a B-subunit of human clusterin (SEQ ID NO: 35 see PCT/CA2006/001505 published under No. W02007/030930 and international application No. PCT/CA2010/0001882 published under No. WO2011/063523 the entire content of which is incorporated herein by reference).

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. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is an antibody or antigen binding fragment thereof that is capable of competing with an anti- clusterin antibody or antigen binding fragment thereof of the present disclosure for the binding of 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:35.

In some embodiments, the CDRs are identified using methods known to a person skilled in the art and which are reviewed in Antibody Engineering Vol. 2, Chapter 3 by Andrew C.R. Martin, the entire content of which is incorporated herein by reference.

In particular embodiments, all CDRs are identified using the Rabat definition which is the most commonly used definition (Wu and Rabat, 1970).

In particular embodiments, all CDRs are identified using the contact definition (MacCallum et al., 1996) which is likely to be the most useful for people wishing to perform mutagenesis to modify the affinity of an antibody since these are residues which take part in interactions with antigen.

In particular 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.

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

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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6.

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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:37.

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

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:l, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:2, a CDRL3 having the amino acid sequence set forth in SEQ ID NO:3 and 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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:37.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 80% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO: 8.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO: 8.

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.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing 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 the binding of 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:35.

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

In some embodiments, the anti -clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO: 10.

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.

In some embodiments, the anti -clusterin antibody or antigen binding fragment thereof is capable of competing 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 the binding of 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:35.

In some embodiments, the anti -clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 12.

In some embodiments, the anti -clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO: 12.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence identical 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.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing 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 the binding of 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:35.

In other particular embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 15, a CDRL2 having the amino acid sequence set forth in SEQ ID NO: 16, a CDRL3 having the amino acid sequence set forth in SEQ ID NO:17.

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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:20.

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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:40.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 15, a CDRL2 having the amino acid sequence set forth in SEQ ID NO: 16, a CDRL3 having the amino acid sequence set forth in SEQ ID NO: 17 and 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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:20.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 15, a CDRL2 having the amino acid sequence set forth in SEQ ID NO: 16, a CDRL3 having the amino acid sequence set forth in SEQ ID NO: 17 and 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, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:40.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 80% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO:22.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO:22.

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.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing 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 the binding of 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:35.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 80% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO:24.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with 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% identity with the amino acid sequence set forth in SEQ ID NO:24.

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.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing 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 the binding of 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:35.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO:25 and a heavy chain having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO:26.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:25 and a heavy chain having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:26.

In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence identical 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. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing 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 the binding of 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:35.

In yet other particular embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises the CDRs, variable regions or full chains amino acid sequence of the antibody or antigen binding fragment thereof listed in Table 9. The amino acid sequence of antibodies identified as 16B5, 21B12, 20E11, 11E2 and 16C11 is disclosed in international application No. PCT/CA2006/001505 filed on September 13, 2006 and published on March 22, 2007 under no. W02007/030930 the entire content of which is incorporated herein by reference. The amino acid sequence of murine 16B5, humanized 16B5, murine 21B12 and humanized 21B12 is disclosed in international application No. PCT/CA2010/001882 filed on November 24, 2010 and published on June 3, 2011 under No. WO2011/063523, the entire content of which is incorporated herein by reference.

In yet further particular embodiments, the anti-clusterin antibody or antigen binding fragment thereof may be able to compete with one or more of the antibody or antigen binding fragment thereof listed in Table 9.

Subject

The single and combination therapy disclosed herein is generally administered to a human subject.

In some aspects and embodiments of the present disclosure, the subject in need is a subject having cancer.

In other aspects and embodiments of the present disclosure, the subject in need is a subject having cancer and having a functional immune system.

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

In some exemplary embodiments, the subject does not receive concurrent anti-cancer treatment with the anti-clusterin antibody or antigen binding fragment thereof single agent. In some exemplary embodiments, the subject does not receive concurrent anti-cancer treatment with the anti-clusterin antibody or antigen binding fragment thereof and docetaxel combination therapy.

In some exemplary embodiments, the subject does not require concurrent anti-cancer treatment with the anti-clusterin antibody or antigen binding fragment thereof single agent.

In some exemplary embodiments, the subject does not require concurrent anti-cancer treatment with the anti-clusterin antibody or antigen binding fragment thereof and docetaxel combination therapy.

In some embodiments, the subject in need has a carcinoma.

In some embodiments, the subject in need has a metastatic carcinoma.

In some embodiments, the subject in need has non-small cell lung cancer (NSCLC).

In some embodiments, the subject in need has metastatic NSCLC.

In some embodiments, the subject in need has stage III to IV NSCLC.

In some embodiments, the subject in need has breast cancer.

In some embodiments, the subject in need has metastatic breast cancer.

In some embodiments, the subject in need has prostate cancer.

In some embodiments, the subject in need has metastatic prostate cancer.

In some embodiments, the subject in need has gastric cancer.

In some embodiments, the subject in need has metastatic gastric cancer.

In some embodiments, the subject in need has head and neck cancer.

In some embodiments, the subject in need has metastatic head and neck cancer.

In some embodiments, the subject in need has thyroid cancer.

In some embodiments, the subject in need has metastatic thyroid cancer.

In some embodiments, the subject in need has ovarian cancer.

In some embodiments, the subject in need has metastatic ovarian cancer.

In some embodiments, the subject in need has endometrial cancer.

In some embodiments, the subject in need has metastatic endometrial cancer. In some embodiments, the subject in need has liver cancer.

In some embodiments, the subject in need has metastatic liver cancer.

In some embodiments, the subject in need has colorectal cancer.

In some embodiments, the subject in need has metastatic colorectal cancer.

In some embodiments, the subject in need has pancreatic cancer.

In some embodiments, the subject in need has metastatic pancreatic cancer.

In some embodiments, the subject in need has cholangiocarcinoma.

In some embodiments, the subject in need has metastatic cholangiocarcinoma.

In some embodiments, the subject in need has mesothelioma.

In some embodiments, the subject in need has metastatic mesothelioma.

In some embodiments, the subject in need has melanoma.

In some embodiments, the subject in need has metastatic melanoma.

In some embodiments, the subject in need has or is selected for having a tumor characterized as immunologically cold.

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

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

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

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

In some embodiments, the subject in need has or is selected for having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti -PD 1 or PDL-1 immune checkpoint antibody. In some embodiments, the subject in need has or is selected for having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab.

In some embodiments, the subject in need has or is selected for having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti -PD 1 or PDL-1 immune checkpoint antibody simultaneously or sequentially.

In some embodiments, the subject in need is not immunosuppressed.

In some embodiments, the subject in need has not received an immunosuppressive medication within 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day prior to treatment. In some embodiments, the subject in need may have received corticosteroids prior to treatment.

In some embodiments, the subject in need has not received prior treatment with docetaxel.

In some embodiments, the subject in need is treated for at least two cycles of treatment.

Kits

The present disclosure provides in some aspects and embodiments, a kit comprising one or more containers comprising at least one dose of the medicament disclosed herein and a package insert comprising instructions for treating a subject in need.

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

In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are provided in separate containers.

In accordance with the present disclosure, the antibody or antigen binding fragment thereof is as described herein.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma. In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic carcinoma.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that progressed after a first line immune checkpoint therapy.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and immune checkpoint therapy.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and immune checkpoint therapy administered either simultaneously or sequentially.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti-PDl or PDL-1 immune checkpoint antibody.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and an anti-PDl or PDL-1 immune checkpoint antibody administered either simultaneously or sequentially.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having a carcinoma that has failed prior treatment with a platinum-containing doublet treatment and ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab administered either simultaneously or sequentially.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having non-small cell lung cancer (NSCLC).

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having advanced NSCLC.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having stage III NSCLC. In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having stage IV NSCLC.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having breast cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic breast cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having prostate cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic prostate cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having gastric cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic gastric cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having head and neck cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic head and neck cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having thyroid cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic thyroid cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having ovarian cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject having metastatic ovarian cancer.

In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject that is not immunosuppressed has not received an immunosuppressive medication within 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day prior to treatment. In some embodiments, the package insert states that the combination therapy is intended for treatment of a subject that has not received prior treatment with docetaxel.

In some embodiments, the package insert states that the combination therapy is for administration essentially over the entire course of the treatment period or throughout the treatment period.

EXAMPLES

Example 1- NON-CLINICAL PHARMACOKINETICS

The pharmacokinetics of AB-16B5 (humanized 16B5) was investigated in single and repeat-dose studies in Sprague-Dawley rats and Rhesus monkeys. In general, peak serum AB- 16B5 concentrations were reached shortly after the start of infusion. In rats, AB-16B5 systemic exposure over 24 hours increased with increasing dose levels in a dose proportional manner. There was an approximate 70% increase in systemic exposure following repeated dosing from Day 1 to Day 26 which is consistent with the elimination half-life of AB-16B5 and the dosing intervals. In monkeys, AB-16B5 systemic exposure increased with increasing dose levels in a generally greater than dose proportional manner. For repeated dosing, there were no notable differences in systemic exposure to AB-16B5 whether it was administered once weekly or twice weekly. There was no evidence of drug accumulation in terms of Cmax while a lower extent of accumulation was observed for AUCo- ₇₂ . Interestingly, after single dose administration of AB-16B5 in Rhesus monkeys, sCLU serum concentrations decreased significantly following dosing. The sCLU concentrations were generally back to their baseline levels after 3 to 5 days. The concurrent decrease in sCLU concentrations immediately following dosing with AB-16B5 is consistent with an antigen-sink phenomenon.

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, organ weights. Similarly, there were no treatment-related macroscopic changes. A very low incidence of minimal lymphoid hypercellularity was noted in the mesenteric lymph node (2/20) and mandibular lymph node (1/20) of animals from the high dose group. This microscopic finding was not seen in any recovery animals following the 28-day recovery period indicating complete reversibility. This finding most likely reflects a slight antigenic stimulation by AB-16B5 in these 2 regional lymph nodes. The No Observable Adverse Effect Level (NOAEL) was therefore determined to be 100 mg/kg/dose.

In Rhesus monkeys, weekly administration of AB-16B5 did not result in any signs of overt toxicity. Few episodes of emesis were observed during the infusion of AB-16B5 in animals of all dose levels. There were no treatment-related effects observed on body weight, ophthalmology, electrocardiography and organ weight. Slight decreases in mean white blood cell counts were seen at 60 mg/kg (males only) and 100 mg/kg (males and females). Slight changes in mean albumin, globulin, AJG 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 histopathology correlates. Consequently, they were not considered to be toxicologically significant. Hepatocellular vacuolation was noted in the liver of 2 animals dosed at 100 mg/kg (1 main and 1 recovery animal). The relationship of this finding to treatment with AB-16B5 remains uncertain because of the low incidence and because this finding is known to occur spontaneously. In absence of clinical pathology (liver enzymes) and organ weight (liver weight) correlates, this finding was considered to be an adaptive change and non- adverse. The NOAEL was therefore determined to be 100 mg/kg/dose.

In addition, a tissue cross-reactivity study was conducted 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 pg/mL was observed in a number of 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 concern due to off-target binding.

Example 3- PHASE I CLINICAL STUDY

A first-in-human phase I trial to assess safety and tolerability of AB16B5 (humanized 16B5) was carried out (clinical trial registry number: NCT2412462) (Ferrario el ah, 2017) in subjects with a histologically or cytologically confirmed advanced solid malignancy that has been refractory to prior therapy and is unlikely to benefit from known therapies. AB-16B5 has been administered in 15 subjects enrolled in a phase 1, single-center, open-label, dose- escalation study (AB-16B5-101).

The dose levels of AB-16B5 that were assessed during the study were 1.5, 3.0, 6.0, 9.0, and 12.0 mg/kg. The dose escalation was performed using 2 dose escalation schemes; the accelerated dose escalation scheme and the standard dose escalation scheme. Only 1 subject was enrolled in each of the first 2 cohorts as per protocol (accelerated dose escalation scheme). The last cohort (12 mg/kg) was expanded to at least 6 subjects as per protocol.

Subjects received AB-16B5 by a 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.

Subject Characteristics

Majority of AB-16B 5 -treated subjects were female (10 of the 15 subjects, 67%) and the mean subject age was 61 years old (range: 32 - 79 years old). 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 no more than 1 subject each (7%) and included endometrium, gastric, lung, ovarian, pancreatic, soft-tissue sarcoma and vulvar melanoma.

Time on Study

Fourteen subjects (93%) received at least 2 cycles of treatment (range: 2 to 17 cycles). One subject (Subject 004) completed 17 cycles of treatment. This subject received AB-16B5 at 6 mg/kg from Cycle 1 to cycle 7 and the dose was escalated to 9 mg/kg thereafter. Thirteen subjects (87%) discontinued the study due to disease progression; 2 subjects discontinued due an adverse event (Subject 004 with Grade 3 bronchial obstruction; associated with disease progression and Subject 011 with Grade 3 biliary obstruction). Subject 011 in cohort 12 mg/kg was discontinued after one dose of AB-16B5 by the Investigator and was replaced by a new subject; however, Subject 011 was not included in the RECIST evaluable population. The mean number of cycles received in the RECIST-evaluable population was 4.4 cycles.

Safety Profile

The 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 toxicity was observed.

A total of 167 AEs were reported. Among those AEs, 68 out of 167 AEs were related (possibly, probably or definitely) to AB-16B5 and twelve (12) were of Grade 3 to 5.

The most frequently reported AEs (all causalities) were nausea, abdominal pain, back pain, vomiting, chills, dyspnea, constipation and pruritus.

There was no dose-related trend in the incidence of these AEs. The most frequently reported AEs related to AB-16B5 were nausea, pruritus, headache and rash. There was no dose-related trend in the incidence of drug-related AEs. The drug-related AEs were mainly of Grade 1 or 2.

There were 12 AEs of Grade 3 to 5 that were 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, death was associated with the progression of the disease.

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 an adverse event; Subject 004 (Grade 3 bronchial obstruction; associated with disease progression) and Subject 011 (Grade 3 biliary obstruction).

Antitumor Activity and Best Overall Response

The best overall response (BOR) in the RECIST-evaluable population is presented in Table 1 below:

Table 1: Tumor Response at Last Assessment and Best Overall Response

The best overall response in this population was stable disease (SD) for 8 subjects (57%) and progressive disease (PD) for 6 subjects (43%). AB-16B5 treatment lasting 4 or more cycles might suggest a clinical benefit.

It was noted that the majority of subjects who had progressed during treatment progressed due to the appearance of a new lesion. Indeed, the tumor response at the last assessment for Subjects 003, 007, 008, 009, 013, 014 and 015 was consistent with stable disease at the target lesions but progressive disease at the non-target lesions because of the appearance of a new lesion. This finding is consistent with the mechanism of action of AB- 16B5. Indeed, new lesions contain tumor cells mostly of epithelial phenotype as a consequence of mesenchymal to epithelial transition. Hence, these new lesions contain low amounts of TA-sCLU since they have not been exposed to EMT-promoting conditions such as chemotherapy or hypoxia which limits exposure to AB-16B5.

AB-16B5-101: Pharmacodynamics

Tumor biopsies were collected during the standard dose escalation to investigate the presence of AB-16B5 within the tumor. A total of 4 pre-treatment and 5 post-treatment tumor biopsies were suitable for analysis. These post-treatment tumor biopsies were collected following dosing on Cycle 2 Day 15 (between Cycle 2 Day 15 and Cycle 2 Day 18). The biopsy sites were liver (n=2), lymph node (n=2), bladder, skin and vulva.

Table 2: Detection of AB-16B5 in Tumor Biopsies

NA: Not available

All pre-treatment tumor biopsies were negative for the presence of AB-16B5 while the presence of AB-16B5 was confirmed in all post-treatment tumor biopsies analyzed. This confirms that AB-16B5 preferentially binds to TA-sCLU and that the tumor potentially may represent an important reservoir.

Immunohistochemistry studies were conducted on paired tumor biopsies to determine if the treatment with AB-16B5 was associated with a reacquisition of an epithelial phenotype. Among the 4 evaluable paired tumor biopsies, two cases showed an increase in E-cadherin expression (Subjects 006 and 007) one of which was combined with a loss of vimentin expression (Subject 007). One case (Subject 013) showed strong epithelial characteristics in the pre-treatment biopsy that did not change with AB-16B5 treatment.

Table 3: Expression of E-cadherin and Immune Response of AB-16B5

Based on these limited results, AB-16B5 treatment may increase epithelial characteristics and induce necrosis.

AB-16B5-101: Pharmacokinetics

Plasma PK parameters for AB-16B5 were derived from the concentration-time profiles following the first dose of Cycle 1 and the first dose of Cycle 2 using a non- compartmental analysis (NCA) with Phoenix WinNonlin.

On Cycle 1, median AB-16B5 T _m ax were similar across the dose levels. Mean Cmax and AUCo-t increased with the dose. This increase seemed to be dose proportional over the dose range of 3.0 to 12.0 mg/kg. AB-16B5 terminal phase was well characterized with overall residual values < 20.00%. The characterization of the terminal phase was improved at 12.0 mg/kg when compared to that observed at the other doses. Mean T _haif was similar at the 1.5, 3.0 and 6.0 mg/kg dose levels, but were slightly higher at the 9.0 and 12.0 mg/kg dose levels.

On Cycle 2, median AB-16B5 T _m ax were similar across the dose levels, with values ranging from 1.00 to 1.08 h. Mean C _max and AUCo- _t increased with the doses. This increase seemed to be dose proportional over the dose range of 3.0 to 12.0 mg/kg. AB-16B5 terminal phase on Cycle 2 was well characterized with overall residual values < 15.00%. The characterization of the terminal phase was improved at 9.0 mg/kg and 12.0 mg/kg (< 1.00%) when compared to that observed at lower doses. Mean ti/2 was similar across the dose range of 1.5 mg/kg to 6.0 mg/kg while mean Thaif were slightly higher at the 9.0 and 12.0 mg/kg dose levels.

No significant accumulation of AB-16B5 was observed between Cycle 1 and Cycle 2.

A summary of the pharmacokinetic parameters is presented in Table 4.

Table 4: Summary of Mean (CV%) Pharmacokinetic Parameters of AB-16B5 a ^: Values are mean (CV%) except for T _max where the median (range) is presented; NC: Not calculated

Tumor biomarkers Several well-established circulating biomarkers were evaluated to monitor the response to therapy. They included CA 15-3, CA-125, CA 19-9, CEA, LDH and PSA.

In general, tumor biomarker levels increased over time which correlated with disease progression. Interestingly, the level of CEA remained stable or decreased in few patients.

Conclusion

Patients received between 1 and 53 weekly doses (median: 9 doses). The most frequently reported treatment-emergent adverse events (TEAEs, all causalities) were nausea, abdominal pain, back pain, vomiting, chills, constipation and pruritus. Most of the AEs were of Grade 1 or 2. Among the AEs > Grade 3, only 2 (Grade 3 infusion-related reaction and rash) were judged related to AB-16B5. No dose-limiting toxicities were identified during the first cycle of treatment for any patient 5 serious AEs were reported (sepsis, pyrexia, dyspnea, intra-abdominal hemorrhage and main stem bronchus obstruction), none of which were judged related to the study treatment. PK analysis across all dose levels confirmed 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 pts where a post-treatment tumor lysate could be generated. Biomarker analysis in paired tumor biopsies provided some evidence for EMT inhibition as seen by increased E-cadherin expression after treatment with AB-16B5 in 2 pts. In one of these 2 pts with advanced gastric cancer, this was also accompanied by a loss of vimentin expression. This patient had stable disease (SD) with clinical benefit and remained on treatment for 24 weeks. Another patient with follicular thyroid cancer had SD for almost 1 year.

Weekly infusions of AB-16B5 are well tolerated up to 12 mg/kg. Early correlative studies on tumor tissue provide evidence of molecular modulation of the tumor environment in humans.

Example 4- Effect of AB-16B5 on infiltration of immune cells in the tumor microenvironment

Balb/c mice were orthotopically implanted with 5 X 10 ⁵ 4T1 cells in the 4 ^th mammary fat pad. Animals received IP saline treatment thrice weekly. The primary tumor was surgically removed at Day 16 post-implantation. The animals were sacrificed at Day 36 and the 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 counter stained with hematoxylin and eosin. Results presented in Figure 1 indicate that the 4T1 lung metastases create an immune cold microenvironment which prevents the infiltration of B and T lymphocytes in tumors. Delineated regions indicate that CD3 and CD8 T lymphocytes are restricted in the tumor margin as a consequence of EMT.

Animals bearing 4T1 tumors were treated with the AB-16B5 antibody (murine 16B5) thrice a week IP at 10 mg/kg. The primary tumor was surgically removed at Day 16 post implantation. The animals were sacrificed at Day 36 and the 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 counter stained with hematoxylin and eosin. Results presented in Figure 2A indicate that there were fewer and much smaller lung metastases that were densely infiltrated with CD3 and CD8 T cells. There was also evidence of plasmocytes penetration in 16B5-treated tumors.

AB-16B5 thus allows infiltration of immune cells in the tumor microenvironment in immunocompetent mice. AB-16B5 might represent a new therapeutic avenue to create a warmer tumor environment to stimulate a strong immune response against tumors.

In parallel human tumor biopsies of patients treated with AB-16B5 as single agent were analyzed (Figures 2B - 2E). Needle biopsies obtained from a patient with metastatic thyroid cancer and form a patient with inoperable metastatic gastric cancer were sectioned and stained with hematoxylin and eosin. An on-treatment biopsy from a patient with thyroid cancer metastasic to the lungs was obtained after the second cycle treatment with AB-16B5. As shown in Figure 2B, essentially all tumor fragments were necrotic. A lymphoplasmacytic infiltrate was observed along the edge of the fragment on display. Hemosiderin-laden macrophages were observed inside necrotic areas some reflecting red blood cell extravasation associated with necrosis (not shown). Figure 2C shows a perivascular infiltrate composed of plasma cells along the edge of tumor fragment from the same patient on display one finds. The analysis of the pre-treatment biopsy from the metastatic gastric cancer case showed several fragments of gastric mucosa infiltrated by a diffuse poorly differentiated gastric cancer (signet-ring cells) The fragment on display showed foci of necrosis with a predominantly acute neutrophilic infiltrate. Figure 2E shows the on-treatment biopsy obtained after the second cycle of treatment with AB-16B5 comprised of three tumor fragments. The larger fragment consisted of normal superficial gastric mucosa and that the small fragments were infiltrated by a mix neutrophilic and mononucleated immune cells infiltrate.

Example 5- Effect of the combination therapy of AB-16B5 and docetaxel on infiltration of immune cells in the tumor microenvironment

An immunocompetent mouse cancer model was selected for testing the extent of the immune response upon treatment with AB-16B5 monotherapy or combination of AB-16B5 and docetaxel using the murine 16B5.

Five groups, each consisting of 10 female Balb/c mice were assigned to this study (see Table 5 below). All animals received subcutaneous implantation of 4T1 mouse mammary carcinoma cells in the 4 ^th inguinal mammary gland. Treatment was initiated on the day of implantation (defined as Day 1). Animals from Group 1 (Gr. 1) received IP treatment of saline vehicle control twice a week for the duration of the study. Animals from Group 2 (Gr. 2) received 10 mg/kg of docetaxel weekly for five weeks by IP administration. Animals from Group 3 (Gr. 3) received 10 mg/kg of docetaxel weekly for two weeks and 10 mg/kg of AB- 16B5, twice weekly for five weeks. Animals from Group 4 (Gr. 4) received 10 mg/kg of docetaxel weekly and 5 mg/kg of 16B5 twice weekly each over the course of a five weeks treatment. Animals from Group 5 (Gr. 5) received AB-16B5 twice weekly for five weeks. On Day 36, the primary tumors were excised and on Day 37, the animals were sacrificed and the number of grossly visible metastatic nodules on the surface of the lungs was counted.

Table 5: Dosing schedule:

* 2 animals from Group 4 received docetaxel on the same day as AB16B5 (day 4) on week 3

Results presented in Figure 3, show that lungs of the animals from Group 4 and Group 5 comprised less metastatic lung nodules than the saline- control-treated mice. As well, mice that were treated in monotherapy with docetaxel had as many metastatic lung nodules as the saline control group. Treatment with docetaxel for two weeks in combination with 16B5 led to fewer metastatic lung nodules that in Group 1 and Group 2 but the response to treatment was not as extensive as in Group 4 and Group 5. There were more animals in Group 4 for which no nodules could be detected than in any other groups. These results suggest that AB-16B5 monotherapy or combination therapy with docetaxel effectively inhibit metastatic invasion in immunocompetent mice. These results also suggest that it may be preferable to administer AB-16B5 and docetaxel over the entire course of treatment.

The primary tumors excised at Day 16 post implantation, were processed with collagenase and hyaluronidase and immune cells were purified by positive selection using magnetic latex beads coated with an anti-CD45 antibody. The purified cells were transferred into small petri dishes containing culture medium supplemented with IL2 and IL7 to perform phenotypic analyses. It was found that very few CD45+ were present in the primary tumors retrieved from Group 1 and Group 2 animals. In contrast, there were more immune cells in tumors retrieved from Group 3, Group 4 and Group 5 animals.

Treatment of mice implanted with 4T1 tumor cells with docetaxel (DTX 5W) was relatively ineffective. The 4T1 tumors bear an EMT-high 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 resulted in increased resistance of tumors. The combination of docetaxel with 16B5 for 5 weeks proved to be the most effective therapeutic regimen. The combined increase of shed antigens caused by docetaxel and inhibition of EMT resulted in an increased immune response that translated in fewer lung metastases in this group compared to 16B5 in monotherapy. AB-16B5 in monotherapy and the combination of AB-16B5 with docetaxel thus allow infdtration of immune cells in the tumor microenvironment in immunocompetent mice. These results also suggest that the primary tumors may be affected by the AB-16B5 monotherapy or combination therapy.

Example 6- Characterization of tumor infiltrating lymphocytes

Balb/c mice were orthotopically implanted with 5 X 10 ⁵ 4T1 cells in the 4 ^th mammary fat pad. Animals received intraperitoneal (IP) AB-16B5 (murine 16B5) 10 mg/kg twice weekly in combination with IP docetaxel 10 mg/kg weekly (Group 15: animals 1501, 1502 and 1503) or IP AB-16B5 10 mg/kg twice weekly (Group 25: animal). The primary tumor was surgically removed at Day 16 post-implantation. The animals were sacrificed at Day 36 and the lungs were excised and each visible lung metastasis was carefully dissected. Each visible metastatic nodule, if any, was excised and processed for a rapid expansion of tumor infiltrating lymphocyte protocol. The metastatic nodules were sectioned into small pieces of 2-3 mm edge that were individually grown in 24 well plates containing culture medium supplemented with FBS, IL2, IL7, ITS (1,000 U/mL IL2, 2.0 ng/mL IL7 and IX insulin - transferrin - selenium cocktail (Gibco 41400-045)).

After three weeks in culture, 100,000 cells were taken from each of the lymphocyte cultures (six cultures corresponding to three animals from Group 15 and three animals from Group 25) and placed in culture with 100,0004T1 tumor cells. After overnight co-culture, the supernatant was recovered for INFy quantification by ELISA.

The results of INFy secretion from lymphocyte cultures in the presence of 4T1 cells indicate that lymphocytes isolated from lung metastatic nodules secrete INFy at high levels with highest levels observed in the docetaxel- 16B5 group (see Table 6). These results confirm that inhibition of EMT with the anti-sCLU 16B5 mAh contributes to the generation of a “warm” tumor microenvironment that allows the infiltration of T lymphocytes in tumors.

Table 6 The 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 CD 19 (B-cell biomarker) (Figure 4A and Figure 4B). The resulting single cell preparations were initially selected on their size to select those corresponding to immune cells. They were further gated on an FSC/SSC plot to exclude dead cells and debris. Flow cytometric were then performed with antibodies against CD45, CD3, CD19, CD3, CD4 and CD8. Immune cells positive for CD45 were gated on CD3 and CD 19 (P3). The CD3+ cells were further gated on CD4 and CD8 (Ql-LR).

Results indicated 80-90% cell viability of CD45+ cells for both groups. The CD45+ cells from group 15 (Figure 4A) comprised 40.2% to 55.0% of CD19 cells and 14.0% to 21.1% of CD3+ cells. The CD3+ cells comprised 63.7% to 66.5% of CD4+ T cells and 20.6% to 27.0% CD8+ T cells. The CD45+ cells from group 25 (Figure 4B) comprised 14.0% to 35.0% of CD19 cells and 21.3% to 42.0% of CD3+ cells. The CD3+ cells comprised 47.5% to 67.8% of CD4+ T cells and 25.9% to 41.1 % CD8+ T cells.

Again, these results suggest that the primary tumors may be affected by the AB-16B5 monotherapy or combination therapy and that infdtration of tumor cells occur in both AB- 16B5 monotherapy or combination therapy in immunocompetent mice.

Enhancing tumor T-cell infdtration with AB-16B5 may thus render tumors more susceptible to immunotherapy with checkpoint inhibitors or with cellular immunotherapy.

Example 7- PHASE II CLINICAL STUDY

The Applicant will evaluate the use of anti-clusterin antibodies combined with docetaxel in previously treated subjects with metastatic non-small cell lung cancer.

This Phase II study recruits 40 metastatic non-small cell lung cancer patients who failed treatment with a platinum-containing doublet treatment and an anti -PD 1 or PDL-1 immune checkpoint antibody, administered simultaneously or sequentially. All recruited patients receive AB-16B5 (herein referred to as humanized 16B5) at a dose of 12 mg/kg once weekly combined with docetaxel at a dose of 75 mg/m2 once every 3 weeks.

Objectives A primary objective of this study is to determine the objective response rate (ORR) per RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

Another primary objective of this study is to determine the objective response rate (ORR) per RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

Yet another primary objective of this study is to determine the safety and tolerability of the combination of AB-16B5 and docetaxel.

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

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

Yet another secondary objective of this study is to determine the duration of stable disease per RECIST 1.1 in subjects receiving the combination of AB-16B5 and docetaxel.

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

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

Yet another secondary objective of this study is to determine the pharmacokinetics of AB-16B5 in this subject population.

An exploratory objective of this study is to perform exploratory pharmacodynamic 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.

An exploratory objective of this study is to evaluate disease response using iRECIST in subjects pursuing treatment beyond progression.

Study design

The study is an open-label, single-arm, multi-center Phase II trial 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 treatment and an anti-PDl or PDL-1 immune checkpoint antibody, administered simultaneously or sequentially. Approximately 40 subjects are enrolled in this trial and receive AB-16B5 at a dose of 12 mg/kg once weekly on Days 1, 8 and 15 combined with docetaxel at a dose of 75 mg/m ² once every 3 weeks on Day 1. One cycle of treatment consists of 21 days (3 weeks). The safety profde of the AB-16B5 and docetaxel combination is examined during a safety lead-in period with the first 8 subjects completing one cycle of treatment.

Subjects are evaluated every 6 weeks with radiographic imaging to assess response to treatment using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for determination of the objective response rate (ORR) and progression free survival (PFS). A futility analysis is conducted to minimize subject exposure to an ineffective treatment. Paired tumor biopsies (pre-treatment and on-treatment) are collected in all subjects. Adverse events are monitored throughout the study and graded for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE). Study treatment continues 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. Treatment beyond progression is allowed if the Investigator considers the subject to be clinically stable. Subjects who must discontinue docetaxel due to toxicity continue treatment with AB-16B5.

Safety Lead-In Period

The safety profile of AB-16B5 at a dose of 12 mg/kg administered once weekly on Days 1, 8 and 15 combined with docetaxel at a dose of 75 mg/m ² once every 3 weeks on Day 1 is examined during a safety lead-in period with the first 8 subjects completing one cycle of treatment. Decision to de-escalate the dose of AB-16B5 can be made using the modified toxicity probability interval method (mTPI) ^{Error! Bookmark not defined} .

The study treatment is considered acceptable if no more than 3 dose limiting toxicity (DLTs) are observed during the first cycle in the first 8 subjects treated.

For these purposes, a DLT is defined as a Grade > 3 non-hematologic toxicity occurring during Cycle 1 of therapy. In addition, the following hematologic toxicities are considered as a DLT:

• Grade > 4 neutropenia or thrombocytopenia > 7 days • Grade > 3 thrombocytopenia with bleeding

• Grade > 3 febrile neutropenia

Toxicities that are clearly and incontrovertibly due to disease progression or to extraneous causes are not to be considered DLTs. In addition, the following non-hematologic toxicities are not to be considered DLTs:

• Grade 3 arthralgia or myalgia which returns to Grade < 1 within < 7 days with appropriate supportive care

• Grade 3 nausea, vomiting or diarrhea which returns to Grade < 1 within < 72 hours with appropriate supportive care

• Grade 3 fatigue lasting < 7 days

• Grade 3 electrolyte abnormalities that last less than 72 hours and are not associated with clinical symptoms

• Grade 3 amylase or lipase elevation which is not associated with symptoms or clinical manifestations of pancreatitis

De-escalation of AB-16B5 is performed if more than 3 DLTs are observed in the first 8 subjects treated.

In such a case, the next three subjects are treated with AB-16B5 at 9 mg/kg AB-16B5 administered once weekly on Days 1, 8 and 15 combined with docetaxel at a dose of 75 mg/m ² once every 3 weeks on Day 1. If 0 or 1 DLT is observed during the first cycle in these 3 subjects, AB-16B5 at the 9 mg/kg dose is considered acceptable.

If more than 1 DLTs are observed, a final de-escalation of AB-16B5 to 6 mg/kg is performed and the safety profile is evaluated using the same process as described above.

Inclusion Criteria

Subjects enrolled in the study meet the following inclusion criteria:

• Subjects (male or non-pregnant female) having > 18 years of age on the day of signing the informed consent.

• Subjects having a histologically or cytologically confirmed diagnosis of (Stage III-IV) non-small cell lung cancer (NSCLC) and with at least one measurable lesion defined by RECIST 1.1. • Subjects having experienced a disease progression following treatment with a an anti- PD1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet treatment, administered simultaneously or sequentially.

• Subjects having targetable driver mutation in EGFR or ALK gene are allowed on trial after failing available targeted therapies and having experienced a disease progression following treatment with an anti -PD 1 or PDL-1 immune checkpoint antibody and a platinum-containing doublet treatment, administered simultaneously or sequentially.

• Subjects having adequate organ and immune function as indicated in Table 7 below:

• Subjects having a tumor lesion amenable for biopsies with no contraindication for biopsy.

• Subjects having an Eastern Cooperative Oncology Group (ECOG) performance status of < 2.

• Subjects having a life expectancy of at least 3 months.

• Subjects having recovered from the toxic effects resulting from the most recent cancer treatment to Grade 1 or less. If the subjects underwent major surgery or received radiation therapy, they have recovered from the complications and/or toxicity. • Female subjects of childbearing potential having a negative urine 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 the subject to be eligible.

• Subjects (both male and female) of reproductive potential are willing to practice highly effective methods of contraception throughout the study and for up to 90 days after the last dose of study medication. Abstinence is acceptable if this is the subject’s usual lifestyle.

• Female subjects are not considered of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following: o > 45 years of age and has not had menses for more than 2 years. o Amenorrhoeic for < 2 years without hysterectomy and oophorectomy and a follicle stimulating hormone (FSH) value in the postmenopausal range at screening. o Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.

It is to be understood herein that the inclusion criteria are for the purpose of the clinical trial only and are not to be considered limitations of the approved drug for treatment.

Exclusion Criteria

Subjects enrolled in the study meet the following exclusion criteria:

• Subjects having received prior therapy with AB-16B5.

• Subjects having received prior therapy with docetaxel for the treatment of NSCLC.

• Subjects who are currently participating or has participated in a study of an investigational agent or using an investigational device within 21 days prior to the first dose of study treatment. The 21 -day window should be calculated using the last dose of an antineoplastic investigational agent or last use of an investigational device with antineoplastic intent. • Subjects who have received any anti-cancer treatment within 3 weeks or radiation therapy within 2 weeks prior to receiving the first dose of study treatment or who have not recovered from adverse events 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 antineoplastic therapy while on the trial. This includes maintenance therapy with another agent or radiation therapy.

• Subjects who are receiving a dose > 10 mg/day of prednisone (or equivalent) within 7 days prior to the first dose of study treatment or any other form of immunosuppressive medication (corticosteroid pre-treatment and/or post-treatment of docetaxel is allowed).

• Subjects who require treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfmavir, ritonavir, saquinavir, telithromycin and voriconazole). Subjects may be included if there is an alternate treatment with a weak CYP3A4 inhibitor and they are willing to change prior to randomization. If the subject agrees to change from a strong inhibitor to a weak CYP3A4 inhibitor, the strong inhibitor must be stopped at least 7 days prior to the first dose of study treatment.

• Subjects who have another malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer.

• Subjects who have known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate if they have been 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 are not receiving a dose > 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 (HIV). • Subjects with an active Hepatitis B or C infection.

• Subjects with an active infection requiring antibiotic therapy.

• Subjects with a known history of alcohol or other substance abuse within the last year.

• Subjects with known hypersensitivity to docetaxel or drugs formulated with polysorbate 80.

• Subjects who have a history or current evidence of any condition, therapy or laboratory abnormalities that may confound the results of the trial, interfere with the subject’s participation for the full duration of the trial or if it is not in the best interest of the subject to participate in the trial.

• Subjects with medical, social or psychosocial factors that, in the opinion of the treating Investigator, could impact the safety or compliance with study procedures.

• Subjects who are pregnant or lactating or who are expecting to conceive or father children within the projected duration of the trial through 90 days after the last dose of AB-16B5 or the last dose of docetaxel.

It is to be understood herein that the exclusion criteria are for the purpose of the clinical trial only and are not to be considered limitations of the approved drug for treatment.

Study Treatment

Study Drug, Dose and Mode of Administration

AB-16B5

AB-16B5 is a humanized IgG2 monoclonal antibody targeting sCLU for the inhibition of cancer-associated EMT (humanized 16B5). AB-16B5 is provided in 10 mL vials at a protein concentration of 10.0 mg/mL. AB-16B5 is formulated in a citrate buffer solution at pH 6.0.

AB-16B5 vials are stored upright at 2-8°C.

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

Subjects who experience infusion-related reactions will be treated with corticosteroids such as dexamethasone. Antihistamines and acetaminophen can also be used, as deemed appropriate. Premedication to prevent infusion reaction related to AB-16B5 will not be employed initially. Subjects who have experienced infusion-related reactions will be premedicated as follows:

• Grade 1 (mild): No premedication at subsequent dosing

• Grade 2 (moderate): Dexamethasone 8 mg PO BID the day prior to AB-16B5 infusion and acetaminophen 650 mg PO and diphenhydramine 25-50 mg PO 30- 60 minutes prior to AB-16B5 infusion

• Grade 3 (severe) and Grade 4 (life-threatening): Subject will be discontinued from further treatment with AB-16B5

At any point during the study, if clinically significant infusion related reactions are observed in multiple subjects, the Investigator could decide in agreement with the Sponsor to implement a premedication for all new subjects.

Docetaxel

Docetaxel will be administered at the dosage of 75 mg/m ² by a 60-minute IV infusion once every 3 weeks on Day 1. Docetaxel will be prepared and administered as per the approved product label/monograph.

All subjects should be premedicated with corticosteroids as per hospital standard practices. Vein extravasation and accidental spillages should be dealt with according to the hospital standard practices.

Treatment duration

One cycle of treatment will consist of 21 days (3 weeks).

Study treatment will continue until there is evidence of disease progression, unacceptable toxicity, 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.

Treatment beyond progression will be allowed if the Investigator considers the subject to be clinically stable. The clinical judgment decision by the site should be based on the clinical stability of the subjects as defined below:

Clinical stability is defined as the following: • Absence of symptoms and signs indicating clinically significant progression of disease, including worsening of laboratory values

• No decline in ECOG performance status

• Absence of rapid progression of disease

• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention

Any subject deemed clinically unstable should be discontinued from trial treatment at first radiologic evidence of PD.

Study Treatment Dose Reduction after Safety Lead-In

AB-16B5 Dose Reduction

Subjects who experience any Grade > 3 adverse event that is judged to be possibly, probably or likely related to AB-16B5 and not requiring treatment discontinuation should have a reduction in AB-16B5 dose by one dose level (Table 8 below).

Treatment will be re-initiated at the lower dose only after recovery of the adverse event to Grade < 1.

Subjects whose original AB-16B5 dose has been reduced for toxicity will not be re escalated.

Docetaxel Dose Reduction

Subjects who experience either febrile neutropenia, neutrophils < 500 cells/mm ³ for more than one week, severe or cumulative cutaneous reactions, or other Grade > 3 non- hematological toxicities that is judged to be related to docetaxel should have treatment withheld until resolution of the toxicity and then resumed at 60 mg/m ² . Based upon subject’s condition, treatment with AB-16B5 may continue during this period. Subjects who develop Grade > 3 peripheral neuropathy should have docetaxel discontinued.

The embodiments and examples described herein are illustrative and are not meant 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 claims. Citations listed in the present application are incorporated herein by reference.

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