WO2023147673A1 - Combination therapy for use in treatment of non-small cell lung cancer - Google Patents

Combination therapy for use in treatment of non-small cell lung cancer Download PDF

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Publication number
WO2023147673A1
WO2023147673A1 PCT/CA2023/050151 CA2023050151W WO2023147673A1 WO 2023147673 A1 WO2023147673 A1 WO 2023147673A1 CA 2023050151 W CA2023050151 W CA 2023050151W WO 2023147673 A1 WO2023147673 A1 WO 2023147673A1
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approximately
dose
treatment
antigen binding
weeks
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English (en)
French (fr)
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Mario Filion
Julie Laurin
Jacques Jolivet
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Alethia Biotherapeutics ULC
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Alethia Biotherapeutics ULC
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Priority to KR1020247029988A priority Critical patent/KR20240153627A/ko
Priority to US18/729,922 priority patent/US20250108110A1/en
Priority to EP23749327.5A priority patent/EP4475885A4/en
Priority to AU2023216333A priority patent/AU2023216333A1/en
Priority to JP2024546456A priority patent/JP2025505652A/ja
Priority to MX2024009671A priority patent/MX2024009671A/es
Priority to IL314600A priority patent/IL314600A/en
Priority to CA3243096A priority patent/CA3243096A1/en
Priority to CN202380028327.7A priority patent/CN118900700A/zh
Publication of WO2023147673A1 publication Critical patent/WO2023147673A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • the present disclosure generally relates to a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and a taxane and its use in the treatment of subjects having non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • EMT tumor cell epithelial-to-mesenchymal
  • first- and second-line therapies such as chemotherapeutic agents and immune checkpoint inhibitors in cancer therapy
  • 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.
  • checkpoint inhibitors work best against so-called immunologically hot tumors that is tumors that have been invaded by T cells creating an inflamed tumor.
  • 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.
  • 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.
  • the present disclosure relates to a combination therapy which comprises an anticlusterin antibody or an antigen binding fragment thereof and a taxane such as docetaxel.
  • the present disclosure also relates to a method of treating lung cancer in a subject in need thereof by administering a combination therapy which comprises an anti -clusterin antibody or an antigen binding fragment thereof and a taxane such as docetaxel.
  • the combination therapy of the present disclosure is used for the treatment of patients having lung cancer (e.g., lung carcinoma) and may more particularly provide a clinical benefit to patients that suffer from non-small cell lung cancer and that have failed prior treatment with an anti-programmed death 1 (anti-PD-1) or anti-programmed death ligand 1 (PD-L1) immune checkpoint antibody and a platinum-containing doublet treatment.
  • lung cancer e.g., lung carcinoma
  • the combination therapy of the present disclosure is used for treating lung cancer in a subject in need thereof.
  • the combination therapy is used to treat non-small cell lung cancer in a subject in need.
  • the combination therapy is used to treat metastatic non-small cell lung cancer in a subject in need.
  • a therapeutically effective combination therapy is administered to the subject in need.
  • the combination therapy of the present application represents an alternative to NSCLC patients that have failed prior treatment that comprises an immune checkpoint antibody.
  • evidence of partial response (as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria) has been observed in four patients having a tumor with a PD-L1 tumor proportion score (TPS) of ⁇ 15% including one patient having a KRAS mutation.
  • TPS PD-L1 tumor proportion score
  • Evidence of stable disease as defined by RECIST 1.1 has also been observed in NSCLC patients having a tumor carrying a KRAS mutation.
  • the combination therapy of the present disclosure may represent an alternative for NSCLC patients that is not eligible for or would unlikely benefit from treatment comprising an immune checkpoint antibody.
  • the combination therapy of the present disclosure may represent an alternative to immune checkpoint antibody monotherapy or combination treatment for NSCLC patients having a tumor with no evidence of PD-L1 expression or with low expression of PD-L1.
  • taxane includes docetaxel, paclitaxel and derivatives or analogues including for example and without limitations, Abraxane®, Cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel and others described in Ojima et al., Expert Opin Ther Pat. 2016: 26(1): 1-20, the entire content of which is incorporated herein by reference.
  • the anti-clusterin antibody or antigen binding fragment thereof is selected amongst those that inhibit epithelial to mesenchymal transition in carcinoma cells.
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise, for example, an anti-clusterin antibody or antigen binding fragment thereof capable of binding to a C-terminal portion of a B-subunit of human clusterin.
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise, for example, an anti-clusterin antibody or antigen binding fragment thereof capable of binding to amino acids 421 and 443 or to an epitope comprised within amino acids 421 and 443 of a C-terminal portion of a B-subunit of human clusterin.
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise, for example, a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise, for example, a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2) and SEQ ID NO:6 (CDRH3).
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise, for example, a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2) and SEQ ID NO:9 (CDRH3).
  • the anti -clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13.
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may comprise a light chain having the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15.
  • anti-clusterin antibodies or antigen binding fragments thereof of the present disclosure include those that may compete with an antibody or antigen binding fragment thereof that comprises the light chain variable region set forth in SEQ ID NO: 12 and the heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • the combination therapy of the present disclosure may be used for treating a subject having lung cancer (e.g., lung carcinoma).
  • lung cancer e.g., lung carcinoma
  • the combination therapy of the present disclosure may be used for treating a subject having non-small cell lung cancer.
  • the non-small cell lung cancer is metastatic non-small cell lung cancer.
  • the metastatic non-small cell lung cancer is stage III non-small cell lung cancer.
  • the metastatic non-small cell lung cancer is stage IV non-small cell lung cancer.
  • the non-small cell lung cancer is adenocarcinoma.
  • the non-small cell lung cancer is squamous cell lung cancer.
  • the non-small cell lung cancer is large cell carcinoma.
  • the non-small cell lung cancer is adenosquamous carcinoma
  • the non-small cell lung cancer (e.g., metastatic non-small cell lung cancer) is characterized has having a KRAS mutation.
  • the combination therapy comprises an anticlusterin antibody or antigen binding fragment thereof and a taxane for use in the treatment of a subject having non-small cell lung cancer such as for example, metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen binding fragment thereof is as set forth herein.
  • the combination therapy of the present disclosure may be used to procure a clinical benefit to a subject having non-small cell lung cancer.
  • the combination therapy of the present disclosure may be used to procure a clinical benefit to a subject having metastatic non-small cell lung cancer.
  • the combination therapy comprises an anti-clusterin antibody or antigen binding fragment thereof and a taxane for use in procuring a clinical benefit to a subject having non-small cell lung cancer such as for example, metastatic non-small cell lung cancer, wherein the anti-clusterin antibody or antigen binding fragment thereof is as set forth herein.
  • the combination therapy is administered in a therapeutically effective dosage.
  • the combination therapy is administered in a safe dosage. In certain embodiments, the combination therapy is administered at a tolerable dosage.
  • the combination therapy is administered in accordance with a therapeutically effective schedule of administration.
  • the combination therapy is administered at a tolerable schedule of administration.
  • the combination therapy is administered in accordance with a schedule of administration that is safe.
  • the combination therapy is administered in accordance with a therapeutically effective treatment regimen.
  • the combination therapy is administered in accordance with a treatment regimen that is safe.
  • the combination therapy is administered at a tolerable treatment regimen.
  • the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of between approximately 3 mg/kg to approximately 20 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof is formulated as an intravenous infusion.
  • the anti-clusterin antibody or antigen binding fragment thereof is formulated as an injectable solution at a concentration of approximately 10 mg/mL.
  • the taxane is formulated for administration at a dose of between approximately 50 mg/m 2 to approximately 100 mg/m 2 , such as for example and without limitations, between approximately 60 mg/m 2 to 100 mg/m 2 , between approximately 50 mg/m 2 to 80 mg/m 2 , between approximately 50 mg/m 2 to 75 mg/m 2 , between approximately 60 mg/m 2 to 75 mg/m 2 .
  • the taxane is docetaxel and is formulated for administration at a dose of between approximately 50 mg/m 2 to approximately 100 mg/m 2 ’ such as for example and without limitations, between approximately 60 mg/m 2 to 100 mg/m 2 , between approximately 50 mg/m 2 to 80 mg/m 2 , between approximately 50 mg/m 2 to 75 mg/m 2 , between approximately 60 mg/m 2 to 75 mg/m 2 .
  • docetaxel is formulated as an intravenous infusion.
  • docetaxel is formulated is formulated as an injectable solution at a concentration of between approximately 10 mg/mL to approximately 40 mg/mL.
  • the combination therapy comprises an anti -clusterin antibody or antigen binding fragment thereof and docetaxel for use in treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer, where the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 .
  • CDRs complementarity determining regions
  • the combination therapy comprises an anticlusterin antibody or antigen binding fragment thereof and docetaxel for use in treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer, where the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • CDRs complementarity determining regions
  • the combination therapy comprises an anticlusterin antibody or antigen binding fragment thereof and docetaxel for use in treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer, where the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 12 mg/kg and comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • the combination therapy comprises an anticlusterin antibody or antigen binding fragment thereof and docetaxel for use in procuring a clinical benefit to a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer, where the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 .
  • CDRs complementarity determining regions
  • the combination therapy comprises an anticlusterin antibody or antigen binding fragment thereof and docetaxel for use in procuring a clinical benefit to a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer, where the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • CDRs complementarity determining regions
  • the combination therapy comprises an anticlusterin antibody or antigen binding fragment thereof and docetaxel for use in procuring a clinical benefit to a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer, where the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 12 mg/kg and comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • the combination therapy is for use in procuring a clinical benefit to a subject having non-small cell lung cancer, wherein the combination therapy is used for at least two cycles of treatment each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week, once every two weeks, once every three weeks, once every four weeks and administration of a taxane at a dose of approximately 50 mg/m 2 to 100 mg/m 2 once every two to three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the combination therapy is for use in procuring a clinical benefit to a subject having non-small cell lung cancer, wherein the combination therapy is used for at least two cycles of treatment each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 12 mg/kg once per week, once every two weeks, once every three weeks, once every four weeks and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the combination therapy is for use in procuring a clinical benefit to a subject having non-small cell lung cancer, wherein the combination therapy is used for at least two cycles of treatment each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 12 mg/kg once per week, once every two weeks, once every three weeks, once every four weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the clinical benefit is defined as per RECIST 1.1 guidelines.
  • the combination therapy is used to procure a clinical benefit for at least 6 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 6 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 12 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 12 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 18 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 18 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 24 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 24 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 30 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 30 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 36 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 36 weeks after first determination of response to treatment. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 42 weeks after first determination of response to treatment. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 42 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 48 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 48 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 54 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 54 weeks after first determination of response to treatment.
  • the combination therapy is used to procure a clinical benefit for at least 60 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 60 weeks after first determination of response to treatment. In some embodiments, the combination therapy is used to procure a clinical benefit for at least 66 weeks. In certain embodiments, the combination therapy is used to procure a clinical benefit for at least 66 weeks after first determination of response to treatment.
  • the subject in need is a subject as described herein.
  • the present disclosure therefore involves methods involving administration of the combination therapy to a subject in need.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once per week.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once every four weeks.
  • docetaxel is administered once per week.
  • docetaxel is administered once every two weeks.
  • docetaxel is administered once every three weeks.
  • docetaxel is administered once every four weeks.
  • the frequency of treatment i.e., once per week, every two weeks, every three weeks, every four weeks and the like
  • a physician may decide to administer a dose ahead of the schedule or delay the dose by a few days or longer.
  • one or more doses be skipped without affecting treatment.
  • the anti -clusterin antibody or antigen binding fragment thereof is administered at a dose of between approximately 3 mg/kg to approximately 20 mg/kg.
  • the taxane is administered at a dose of between approximately 50 mg/m 2 to approximately 100 mg/m 2 , such as for example and without limitations, between approximately 60 mg/m 2 to approximately 100 mg/m 2 , between approximately 50 mg/m 2 to approximately 80 mg/m 2 , between approximately 50 mg/m 2 to approximately 75 mg/m 2 , between approximately 60 mg/m 2 to approximately 75 mg/m 2 .
  • the taxane is docetaxel and is administered at a dose of between approximately 50 mg/m 2 to approximately 100 mg/m 2 , such as for example and without limitations, between approximately 60 mg/m 2 to approximately 100 mg/m 2 , between approximately 50 mg/m 2 to approximately 80 mg/m 2 , between approximately 50 mg/m 2 to approximately 75 mg/m 2 , between approximately 60 mg/m 2 to approximately 75 mg/m 2 .
  • the taxane is docetaxel and is administered at a dose of between 50 mg/m 2 to 100 mg/m 2 , such as for example and without limitations, between 60 mg/m 2 to 100 mg/m 2 , between 50 mg/m 2 to 80 mg/m 2 , between 50 mg/m 2 to 75 mg/m 2 , between 60 mg/m 2 to 75 mg/m 2 .
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 12 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 75 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 12 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 60 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 9 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 75 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 9 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 60 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 6 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 75 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 6 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 60 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 3 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 75 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 3 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 60 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 12 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 9 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 6 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 3 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 12 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 9 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 6 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 3 mg/kg once weekly (once per week), once every two weeks, or once every three weeks and docetaxel is administered at a dose of 50 mg/m 2 once every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel may be administered on same day.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel may be administered on same day and separately.
  • the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel may be administered by infusion.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered over the entire course of the treatment period.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered at each cycle of treatment.
  • the present disclosure therefore relates to a method of treating a subject having nonsmall cell lung cancer with the combination therapy disclosed herein.
  • the present disclosure also relates to a method of treating a subject having metastatic non-small cell lung cancer with the combination therapy disclosed herein. Accordingly, in certain aspects, the present disclosure provides a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and docetaxel, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2
  • CDRs complementarity determining regions
  • the method is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs)
  • the method is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID
  • the present disclosure relates to a method of treating non- small cell lung cancer (NSCLC) in a subject in need thereof, comprising administering a combination therapy for at least one cycle of treatment comprising administration of the anticlusterin antibody at a dose of approximately 12 mg/kg once per week, once every two weeks, once every three weeks or once every four weeks and administration of docetaxel at a dose of between approximately 50 mg/m 2 to approximately 75 mg/m 2 once every two to three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the present disclosure also relates to a method of treating a subject having non-small cell lung cancer with the combination therapy disclosed herein so as to obtain and/or maintain a clinical benefit.
  • the present disclosure further relates to a method of treating a subject having metastatic non-small cell lung cancer with the combination therapy disclosed herein so as to obtain and/or maintain a clinical benefit.
  • the present disclosure provides a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 .
  • a combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and docetaxel
  • the method is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain
  • the method is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2
  • the present disclosure also relates to a method of procuring a clinical benefit to a subject having non-small cell lung cancer with the combination therapy disclosed herein.
  • the present disclosure further relates to a method of procuring a clinical benefit to a subject having metastatic non-small cell lung cancer with the combination therapy disclosed herein.
  • Exemplary embodiments of clinical benefit include, without limitation reduction in the size of a lesion, stabilization in the size of a lesion, regression of a lesion, complete response (CR) as per RECIST 1.1 guidelines, partial response (PR) as per RECIST 1.1 guidelines, stable disease (SD) as per RECIST 1.1 guidelines, improvement in a symptom associated with the cancer, and/or reduction in or an elimination of metabolic activity in a lesion etc.
  • the reduction or stabilization in size or the regression may be observed in a target lesion.
  • the reduction or stabilization in size or the regression may be observed in a non-target lesion.
  • the present disclosure provides a method of procuring a clinical benefit to a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2
  • CDRs complementarity determining regions
  • the method is a method of procuring a clinical benefit to a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and docetaxel, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • a combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and docetaxel
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity
  • the method is a method of procuring a clinical benefit to a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and docetaxel, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • the combination therapy is administered in dosages sufficient to result in a clinical benefit.
  • the combination therapy is administered for a period of time sufficient to result in a clinical benefit.
  • the combination therapy is administered according to a schedule of treatment sufficient to result in a clinical benefit.
  • the combination therapy is administered according to treatment regimen sufficient to result in a clinical benefit.
  • the combination therapy is administered in one or more cycles of treatment including administration of the anti-clusterin antibody or antigen binding fragment thereof once per week, once every two weeks, or once every three weeks and administration of docetaxel once every three weeks. It is to be understood that the interval of treatment may be changed without significantly changing the effect of the combined therapy.
  • the combination therapy is administered for at least two cycles of treatment.
  • the combination therapy is administered for more than two cycles of treatment.
  • the present disclosure also provides a method of procuring a clinical benefit to a subject having non-small cell lung cancer, in a method of treatment which comprises administering a combination therapy for at least two cycles of treatment, each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week, once every two weeks, or once every three weeks and administration of a taxane at a dose of approximately 50 mg/m 2 to 100 mg/m 2 once every two to three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the present disclosure provides a method of procuring a clinical benefit to a subject having non-small cell lung cancer, in a method of treatment which comprises administering a combination therapy for at least two cycles of treatment each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 12 mg/kg once per week, once every two weeks, or once every three weeks and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the present disclosure provides a method of procuring a clinical benefit to a subject having non-small cell lung cancer, in a method of treatment which comprises administering a combination therapy for at least two cycles of treatment each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 12 mg/kg once per week, once every two weeks, or once every three weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks, wherein the anti-clusterin antibody comprises a tight chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the clinical benefit is regression of a target lesion.
  • the clinical benefit is a decrease in the size of a target lesion.
  • the clinical benefit is a stabilization in the size of a target lesion.
  • the clinical benefit is a reduction in the number of tumor cells in a target lesion.
  • the clinical benefit is regression of a non-target lesion.
  • the clinical benefit is a decrease in the size of a non-target lesion.
  • the clinical benefit is a stabilization in the size of a non-target lesion.
  • the clinical benefit is a reduction in the number of tumor cells in a non-target lesion.
  • the clinical benefit is defined as per RECIST 1.1 guidelines.
  • the clinical benefit may be qualitative, such as for example, an improvement in the quality of life (e.g., health-related quality of life).
  • the clinical benefit may last for a certain period of time. Duration of clinical benefit may vary from subjects to subjects.
  • the combination therapy may reduce tumor burden.
  • tumor burden may be assessed by measuring the size of one or more tumor lesions.
  • tumor burden may be determined by assessing tumor markers in solid biopsies, liquid biopsies, blood sample, serum sample, urine sample and the like.
  • tumor burden is assessed by detecting circulating tumor cells (CTCs).
  • tumor burden is assessed by detecting circulating tumor DNA.
  • the method procures a clinical benefit for at least 6 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 12 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 18 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 24 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 30 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 36 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 42 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 48 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 54 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 60 weeks after first determination of response to treatment.
  • the method procures a clinical benefit for at least 66 weeks after first determination of response to treatment.
  • the subject s health and condition is monitored.
  • the monitoring can include a physical examination, an interview with the subject concerning its quality of life, obtaining biological samples and/or performing a scan to monitor progression of the lung cancer and/or the presence of metastasis. Treatment is continued so long as the subject experiences a clinical benefit (qualitative or quantitative). Treatment may be discontinued once tumor progression is observed.
  • the anti-clusterin antibody or antigen binding fragment thereof is used as an IV infusion.
  • docetaxel is used as an IV infusion.
  • the combination therapy may promote infdtration of immune cells in the tumor microenvironment of one or more lesions (target and/or non-target lesions).
  • the combination therapy may promote infdtration of lymphocytes in the tumor microenvironment of one or more lesions (target and/or non-target lesions).
  • the combination therapy may promote infdtration of T-cells in the tumor microenvironment of one or more lesions (target and/or non-target lesions).
  • the method may result in the tumor or lesions being more susceptible to treatment by immunotherapy.
  • the method of the present disclosure may therefore also include a step of administering immunotherapy subsequently to the combination therapy disclosed herein.
  • the immunotherapy comprises cellular immunotherapy (CAR- T, TILs, etc ).
  • the immunotherapy comprises an immune checkpoint inhibitor.
  • the present disclosure relates to a method of treating NSCLC such as metastatic NSCLC by promoting infdtration of immune cells in one or more lesions.
  • the present disclosure encompasses a method of treating NSCLC such as metastatic NSCLC by promoting infdtration of immune cells in one or more lesions that have low expression of PD-L1 or no evidence of PD-L1 expression.
  • a lesion may be characterized as having low expression of PD-L1 when the PD-L1 tumor proportion score (TPS) of such lesion is, for example, ⁇ 15%.
  • TPS tumor proportion score
  • a lesion may be characterized as having low expression of PD-L1 when the PD-L1 TPS of such lesion is, for example, ⁇ 5%.
  • a lesion may be characterized as having low expression of PD-L1 when the PD-L1 TPS of such lesion is, for example, ⁇ 1%.
  • a lesion may be characterized as having low expression of PD-L1 when the PD-L1 TPS of such lesion is, for example, ⁇ 1%.
  • a lesion is characterized as having no evidence of PD-L1 expression when the PD-L1 TPS of such lesion of is 0% or when PD-L1 expression undetectable.
  • the combination therapy may promote reduction in the number of tumor cells in one or more lesions.
  • the combination therapy may result in a decrease in the size of a lesion.
  • a lesion is considered to decrease in size when measurements indicates that it is smaller than previous measurements or than baseline measurement.
  • administration of the combination therapy may result in a decrease of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% in the size of a lesion.
  • the combination therapy may result in a stabilization in the size of a lesion.
  • the combination therapy may result in an increase of less than 20% in the size of a lesion. It is also to be understood herein that an increase of less than approximately 20% in the size of a lesion, in comparison with previous measurements or baseline measurements is considered as a stabilization in the growth of a lesion.
  • the combination therapy may result in regression of a lesion.
  • the regression may be complete. In other instances, the regression may be partial.
  • the combination therapy may result in a stabilization in the size of a lesion.
  • the size of a lesion may increase or may remain stable while the number of tumor cells within the lesion decreases.
  • tumor cells might be replaced by fibrotic tissue and inflammatory cells and as such no decrease in the size of a lesion is detected.
  • the number of live tumor cells may decrease, and the number of immune cells may increase thereby resulting in pseudogrogression.
  • the combination therapy may result in a reduction in the number of tumor cells in a lesion.
  • the size of a lesion may be assessed by several methods including for example and without limitations, by CT scan.
  • the combination therapy may result in a reduction in or an elimination of metabolic activity in a lesion.
  • the metabolic activity of a lesion may be assessed by several methods including for example and without limitation, by positron emission tomography (PET) scan.
  • PET positron emission tomography
  • an increase in the size of a lesion conjugated with a decrease in the number of tumor cells within that lesion is also considered as a stabilization in the growth of a lesion.
  • the combination therapy may result in an improvement in a symptom associated with the lung cancer.
  • administration of the combination therapy may result in a complete response (CR) as per RECIST 1.1 guidelines.
  • administration of the combination therapy may result in partial response (PR) as per RECIST 1.1 guidelines.
  • administration of the combination therapy may result in a stable disease (SD) as per RECIST 1.1 guidelines.
  • SD stable disease
  • the combination therapy is used or for use as long as a clinical benefit is observed.
  • the combination therapy is used or for use until tumor progression is observed.
  • the combination therapy is used or for use until unmanageable toxicity occurs.
  • administration of the anti-clusterin antibody or antigen binding fragment thereof may be maintained after cessation of the combination therapy. In some embodiments, administration of the anti-clusterin antibody or antigen binding fragment thereof may be maintained after the appearance of clinical benefits.
  • the combination therapy is for use in a subject as described herein.
  • the subject is a human subject.
  • the subject is an adult (i.e., > 18 years of age).
  • the subject has or is selected for having NSCLC.
  • the subject has or is selected for having metastatic NSCLC.
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that is not eligible for or would unlikely benefit from treatment comprising an immune checkpoint antibody.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that progressed after treatment comprising an immune checkpoint antibody.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC such as metastatic NSCLC that progressed after chemotherapy.
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with immune checkpoint antibody and chemotherapy combination treatment.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with immune checkpoint antibody and a platinum-containing doublet treatment.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • NSCLC such as metastatic NSCLC
  • the doublet treatment may be provided simultaneously. In accordance with the present disclosure, the doublet treatment may be provided sequentially.
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an anti-PD-1 immune checkpoint antibody.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an PD-L1 immune checkpoint antibody.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an anti-PD-Ll immune checkpoint antibody and a platinum-containing doublet treatment.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab alone or in combination with platinum-based chemotherapy.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having NSCLC, such as metastatic NSCLC, that has failed prior treatment with pembrolizumab alone or in combination with platinum-based chemotherapy.
  • NSCLC such as metastatic NSCLC
  • the subject has or is selected for having a PD-L1 tumor proportion score (TPS) of > 50%.
  • TPS tumor proportion score
  • the subject has or is selected for having a PD-L1 tumor proportion score (TPS) of ⁇ 50%. In some embodiments, the subject has or is selected for having a PD-L1 tumor proportion score (TPS) of between 1 to 49 %.
  • TPS PD-L1 tumor proportion score
  • the subject has or is selected for having a PD-L1 tumor proportion score of ⁇ 1%.
  • the subject has or is selected for having a tumor that has poor infdtration of immune cells.
  • the level of immune cell infdtration may be determined by a trained pathologist or scientist.
  • the level of immune cell infdtration may be determined by imaging using computer-based quantification of tumor biopsy.
  • the subject has or is selected for having one or more lesions having an EMT signature or showing signs of an EMT signature.
  • the EMT signature of the tumor may be determined by a trained pathologist or scientist.
  • the EMT signature of the tumor may be determined by imaging using computer-based quantification of tumor or tumor biopsy.
  • the EMT signature may be assessed by one or more EMT biomarkers.
  • an EMT signature may be associated with the acquisition of mesenchymal markers and/or with attenuation of epithelial markers especially associated with EMT type 3 (see Zeisber, M. and E. G. Neilson, The Journal of Clin Investig, 119:1429- 1437 (2009)).
  • EMT biomarkers include for example, cell-surface proteins such as, for example, N- cadherin, OB-cadherin, a5pi integrin, aVp6 integrin, syndecan-1, cytoskeletal markers such as, for example, FSP1, a-SMA, vimentin, B-catenin, a 1(1) collagen, al (III) collagen, fibronectin, laminin 5, transcription factors such as, for example, snaill, snail2, ZEB1, CBF- A/KAP-1 complex, twist, LEF-1, Ets-1.
  • cell-surface proteins such as, for example, N- cadherin, OB-cadherin, a5pi integrin, aVp6 integrin, syndecan-1
  • cytoskeletal markers such as, for example, FSP1, a-SMA, vimentin, B-catenin, a 1(1) collagen, al (III) collagen, fibronectin, laminin 5, transcription factors such as, for example, snaill
  • mircroRNAs such as, for example, miRlOb, miR-21 (acquired markers), E-cadherin, ZO-1, cytokeratin, al (IV) collagen, laminin- 1 (attenuated markers) (see Zeisber, M. and E. G. Neilson, The Journal of Clin Investig, 119:1429-1437 (2009)).
  • the subject in need has a tumor that expresses or secretes clusterin.
  • the subject has or is selected for having stage III NSCLC.
  • the subject has or is selected for having stage IV NSCLC. In some embodiments, the subject does not receive concurrent anti-cancer treatment other than the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel.
  • the subject has or is selected for not being immunosuppressed.
  • the subject has or is selected for not having 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.
  • the subject has or is selected for not having received an immunosuppressive medication within 7 days prior to treatment.
  • the subject has or is selected for not having received prior treatment with docetaxel.
  • the method of the present disclosure comprises administering one or more cycles of treatment to a subject in need.
  • the method comprises administering to the subject in need, at least one initial cycle of treatment and at least one subsequent cycle of treatment.
  • the initial cycle(s) of treatment and subsequent cycle(s) of treatment may be the same or different.
  • the initial cycle(s) of treatment may include a given dose of the anti -clusterin antibody or antigen binding fragment thereof, while the subsequent cycle(s) of treatment may include a different dose of the anti-clusterin antibody or antigen binding fragment thereof.
  • the initial cycle(s) of treatment may include a given dose of docetaxel, while the subsequent cycle(s) of treatment may include a different dose of docetaxel.
  • the time interval between the anti-clusterin antibody or antigen binding fragment thereof and docetaxel may be different in the initial cycle(s) of treatment and in the subsequent cycle(s) of treatment.
  • the initial cycle of treatment comprises at least one dose of an anti-clusterin antibody or antigen binding fragment thereof and at least one dose of taxane such as docetaxel.
  • the initial cycle of treatment comprises two doses of an anti-clusterin antibody or antigen binding fragment thereof and one dose of taxane such as docetaxel.
  • the initial cycle of treatment comprises three doses of an anti-clusterin antibody or antigen binding fragment thereof and one dose of taxane such as docetaxel.
  • the initial cycle of treatment comprises four doses of an anti-clusterin antibody or antigen binding fragment thereof and one dose of taxane such as docetaxel.
  • the subsequent cycle of treatment comprises at least one dose of an anti-clusterin antibody or antigen binding fragment thereof and at least one dose of taxane such as docetaxel.
  • the subsequent cycle of treatment comprises two doses of an anti -clusterin antibody or antigen binding fragment thereof and one dose of taxane such as docetaxel.
  • the subsequent cycle of treatment comprises three doses of an anti-clusterin antibody or antigen binding fragment thereof and one dose of taxane such as docetaxel.
  • the subsequent cycle of treatment comprises four doses of an anti-clusterin antibody or antigen binding fragment thereof and one dose of taxane such as docetaxel.
  • the initial cycle of treatment and subsequent cycle of treatment each comprise at least one dose of the anti-clusterin antibody or antigen binding fragment thereof and at least one dose of docetaxel.
  • one cycle of treatment is approximately 21 days. In other embodiments, one cycle of treatment is more than 21 days, such as for example, approximately one month or more (e.g., approximately 28-31 days). In other embodiments, one cycle of treatment is less than 21 days, such as for example, approximately 2 weeks (e.g., approximately 13-16 days).
  • the subject is treated for one or more cycles of treatment.
  • one cycle of treatment may last approximately 21 days and may include administration of the anti-clusterin antibody or antigen binding fragment thereof once every three weeks (approximately) and administration of docetaxel once every three weeks (approximately).
  • one cycle of treatment therefore comprises administration of one dose of the anti -clusterin antibody or antigen binding fragment thereof and one dose of docetaxel every 21 days (approximately).
  • one cycle of treatment may last approximately 14 days and may include administration of the anti-clusterin antibody or antigen binding fragment thereof once every two weeks (approximately) and administration of docetaxel once every two weeks (approximately). In such a case, one cycle of treatment therefore comprises administration of one dose of the anti-clusterin antibody or antigen binding fragment thereof and one dose of docetaxel every 14 days (approximately). In some embodiments, one cycle of treatment may last approximately 1 month and may include administration of the anti-clusterin antibody or antigen binding fragment thereof once per month (approximately) and administration of docetaxel once per month (approximately). In such a case, one cycle of treatment therefore comprises administration of one dose of the anti-clusterin antibody or antigen binding fragment thereof and one dose of docetaxel every month (approximately).
  • one cycle of treatment is approximately 21 days and consists in administration of the anti-clusterin antibody or antigen binding fragment thereof once weekly and administration of docetaxel once every three weeks.
  • the initial cycle of treatment and/or subsequent cycle of treatment may each independently comprise administering the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week, once every two weeks, or once every three weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 to 100 mg/m 2 once every two weeks or once every three weeks.
  • the method comprises administering docetaxel at a dose of approximately 75 mg/m 2 once every three weeks and administering the anti -clusterin antibody or antigen binding fragment thereof per week, once every two weeks or once every three weeks.
  • the method comprises administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administering docetaxel at a dose of approximately 75 mg/m 2 once every three weeks.
  • the method comprises administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every three weeks and administering docetaxel at a dose of approximately 75 mg/m 2 once every three weeks.
  • the method of the present disclosure may comprise administering to a subject in need, a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week and administration of docetaxel at a dose of approximately 50 mg/m 2 to 100 mg/m 2 once every three weeks and; b) at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once every three weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 to 100 mg/m 2 once every three weeks.
  • the method of the present disclosure may comprise administering to a subject in need, a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks and; b) at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once every three weeks and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks.
  • the method of the present disclosure may comprise administering to a subject in need, a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks and; b) at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every three weeks and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks.
  • the method comprises administering docetaxel at a dose of approximately 50 mg/m 2 once every two weeks and administering the anti -clusterin antibody or antigen binding fragment thereof once per week, once every two weeks or once every three weeks.
  • the method comprises administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administering docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the method comprises administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every two weeks and administering docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the method of the present disclosure may comprise administering to a subject in need, a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks and; b) at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once every two weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the method of the present disclosure may comprise administering to a subject in need, a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks and; b) at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every two weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the subject is treated for at least one cycle of treatment.
  • the subject is treated for at least one initial cycle of treatment and at least one subsequent cycle of treatment.
  • the subject is treated for at least two cycles of treatment. In an exemplary embodiment, the subject is treated for at least two initial cycles of treatment. In an exemplary embodiment, the subject is treated for at least two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least one initial cycle of treatment and at least two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least two initial cycles of treatment and at least two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least two initial cycles of treatment and more than two subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for more than two initial cycles of treatment and more than two subsequent cycles of treatment.
  • the subject is treated for at least three cycles of treatment. In an exemplary embodiment, the subject is treated for at least three initial cycles of treatment. In an exemplary embodiment, the subject is treated for at least three subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least three initial cycles of treatment and at least three subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least three initial cycles of treatment and more than three subsequent cycles of treatment.
  • the subject is treated for at least four cycles of treatment. In an exemplary embodiment, the subject is treated for at least four initial cycles of treatment. In an exemplary embodiment, the subject is treated for at least four subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least four initial cycles of treatment and at least four subsequent cycles of treatment. In an exemplary embodiment, the subject is treated for at least four initial cycles of treatment and more than four subsequent cycles of treatment.
  • 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.
  • 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 initial cycles of treatment.
  • 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 initial and/or subsequent cycles of treatment.
  • the treatment cycles are consecutive.
  • the treatment cycles are uninterrupted.
  • the treatment cycles are interrupted.
  • 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, the treatment is interrupted after a certain period of time determined by a physician or clinician.
  • the combination therapy is administered for at least two consecutive cycles.
  • the combination therapy is administered for at least three consecutive cycles.
  • the combination therapy is administered for at least four consecutive cycles.
  • the combination therapy is administered for at least five consecutive cycles.
  • the combination therapy is administered for at least six consecutive cycles.
  • the combination therapy is administered for at least seven consecutive cycles.
  • the combination therapy is administered for at least eight consecutive cycles. In accordance with the present disclosure the combination therapy is administered for at least nine consecutive cycles.
  • the combination therapy is administered for at least ten consecutive cycles.
  • the combination therapy is administered for at least eleven consecutive cycles.
  • the combination therapy is administered for at least twelve consecutive cycles.
  • a clinical benefit may be observed or measured after two cycles of treatment.
  • a clinical benefit may be observed or measured after three cycles of treatment.
  • a clinical benefit may be observed or measured after four cycles of treatment.
  • a clinical benefit may be observed or measured after five cycles of treatment.
  • a clinical benefit may be observed or measured after more than five cycles of treatment.
  • the combination therapy is administered as long as a clinical benefit is observed or measured.
  • the combination therapy is administered until tumor progression.
  • the combination therapy is administered until unmanageable toxicity occurs.
  • administration of the anti-clusterin antibody or antigen binding fragment thereof is maintained after the appearance of clinical benefits.
  • 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 a taxane such as, for example, docetaxel for use in combination therapy and a package insert comprising instructions for treating a subject as described herein.
  • 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 a taxane such as, for example, docetaxel for use in combination therapy and a package insert comprising instructions for treating a subject as described herein.
  • the package insert states that the combination therapy is intended for treatment of a subject having NSCLC or metastatic NSCLC.
  • Figure 1 table showing the percentage of reduction of target lesions, the duration of patients on treatment as the best response as per RECIST 1.1 (PT; Patient, BR; Best response, PD-L1; PD-L1 tumor proportion score, PR; Partial response, SD; Stable disease, PD; progressive disease, AE; adverse event).
  • Figure 2 histology analyses of pre- (a and c) and on-treatment (b and d) biopsies from two patients under study. Tumor sections were stained with hematoxylin and eosin.
  • amino acid numbering indicated for the dimerization domain are in accordance with the EU numbering system.
  • subject refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, sheep, horse or primate) having lung cancer such as without limitation, a non-small cell lung cancer, metastatic non-small cell lung cancer and/or a subject having stage III to IV non-small cell lung cancer.
  • non-small cell lung cancer e.g., metastatic non-small cell lung cancer and/or a subject having stage III to IV non-small cell lung cancer.
  • subject is used herein interchangeably with “individual” or “patient.”
  • antibody is used in the broadest sense and encompasses various antibody formats and structures, including any immunoglobulin, monoclonal antibody, polyclonal antibody, bivalent antibody, monovalent antibody, bispecific antibody, multiple specific (multi-specific) antibody, conventional antibody, single domain antibody, single chain antibody, heavy chain only antibody, nanobody, full-length antibody, humanized antibody, chimeric antibody that binds to a specific antigen, and any antigen binding fragment that exhibits the desired antigen binding activity.
  • An antibody can be naturally occurring (native) or the results or recombination technologies.
  • the term “conventional antibody” has the same format as a naturally occurring human antibody. It is to be understood herein that the sequence of a conventional antibody may be partially and/or totally derived from a non-human animal antibody or from a human antibody and therefore encompasses without limitations, monoclonal, chimeric, human and humanized antibody.
  • treat refers to the action of providing a treatment (such as the combination therapy disclosed herein) to a subject.
  • a treatment such as the combination therapy disclosed herein
  • treating refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity, reduce incidence, stabilize, and/or manage one or more symptoms and/or features of a particular disease, disorder, and/or condition and/or to obtain or maintain a clinical benefit as defined per RECIST 1.1 guidelines. It is to be understood that a treatment may be effective in some subjects having the particular disease, disorder, and/or condition but have no effects in others that have nevertheless received treatment.
  • terapéuticaally effective refers to a treatment that results in partial or complete alleviation, amelioration, relief, inhibition, prevention, delay in onset, reduction of severity, reduction in incidence, stabilization and/or improved management of one or more symptoms and/or features of a particular disease, disorder, and/or condition, and/or that results in a clinical benefit as defined per RECIST 1.1 guidelines for some subjects.
  • EMT signature refers to changes that are indicative of a loss of epithelial phenotype and/or acquisition of a mesenchymal phenotype that are observable at the cellular level and/or observable or measurable at the genetic level or protein level.
  • 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 +/- 4 percent, within +/- 3 percent, within +/- 2 percent or within +/- 1 percent of a given value or range.
  • 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.
  • 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, that the subject is immunocompetent or that the subject is not immunosuppressed.
  • treatment comprising an immune checkpoint antibody refers to treatment with an immune checkpoint antibody as monotherapy or in combination therapy.
  • the present disclosure provides a combination therapy that includes an anti -clusterin antibody or antigen binding fragment thereof and a taxane. More particularly, the present disclosure provides a combination therapy that includes an anti-clusterin antibody or antigen binding fragment thereof and a docetaxel.
  • the present disclosure provides a method of treating a subject having lung cancer (e.g., lung carcinoma, with the combination therapy disclosed herein.
  • lung cancer e.g., lung carcinoma
  • the present disclosure provides a method of treating a subject having non-small cell lung cancer with the combination therapy disclosed herein.
  • the present disclosure provides a method of treating a subject having metastatic non-small cell lung cancer with the combination therapy disclosed herein.
  • the present disclosure also relates to a method of treating a subject having non-small cell lung cancer with the combination therapy disclosed herein so as to obtain a clinical benefit.
  • the present disclosure further relates to a method of treating a subject having metastatic non-small cell lung cancer with the combination therapy disclosed herein so as to obtain a clinical benefit.
  • the present disclosure also relates to a method of procuring a clinical benefit to a subject having non-small cell lung cancer with the combination therapy disclosed herein.
  • the present disclosure further relates to a method of procuring a clinical benefit to a subject having metastatic non-small cell lung cancer with the combination therapy disclosed herein.
  • the method may comprise administering the combination therapy in a dosage sufficient to result in a clinical benefit.
  • the method may comprise administering the combination therapy for period of time sufficient to result in a clinical benefit.
  • the method may comprise administering the combination therapy according to a schedule of treatment sufficient to result in a clinical benefit.
  • the method may comprise administering the combination therapy according to a treatment regimen sufficient to result in a clinical benefit.
  • the method of the present disclosure comprises administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane.
  • the method of the present disclosure comprises administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a therapeutically effective dose.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a safe dose.
  • docetaxel is administered at a therapeutically effective dose.
  • docetaxel is administered at a safe dose.
  • docetaxel is administered at a dose sufficient to allow chemotherapy -induced immunogenic modulation of tumor.
  • docetaxel is administered at an administration interval sufficient to allow chemotherapy-induced immunogenic modulation of tumor.
  • the method comprises administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg and docetaxel at a dose of approximately 60 mg/m 2 to 100 mg/m 2
  • 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
  • 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.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 3.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 4.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 4.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 5.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 5.0 mg/kg.
  • 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 istered at a dose of 6.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 7.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 7.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 8.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 8.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 9.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 9.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 10.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 10.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 11.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 11.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 12.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 12.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 13.0 mg/kg. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 13.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 14.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 14.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 15.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 15.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 16.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 16.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 17.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 17.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 18.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 18.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 19.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of 19.0 mg/kg.
  • the anti-clusterin antibody or antigen binding fragment thereof istered at a dose of approximately 20.0 mg/kg. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of 20.0 mg/kg.
  • docetaxel is administered at a dose of between approximately 50 mg/m 2 to approximately 100 mg/m 2 such as for example, 60 mg/m 2 to approximately 100 mg/m 2 , 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 50 mg/m 2 to approximately 75 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
  • docetaxel is administered at a dose of approximately 50 mg/m 2
  • docetaxel is administered at a dose of approximately 60 mg/m 2 .
  • docetaxel is administered at a dose of approximately 65 mg/m 2 .
  • docetaxel is administered at a dose of approximately 70 mg/m 2 .
  • docetaxel is administered at a dose of approximately 75 mg/m 2 .
  • docetaxel is administered at a dose of approximately 80 mg/m 2 .
  • 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
  • docetaxel is administered at a dose of approximately 95 mg/m 2 .
  • docetaxel is administered at a dose of approximately 100 mg/m 2 .
  • An exemplary embodiment of a method of the present disclosure is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic nonsmall cell lung cancer comprising administering a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel, where the anti -clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 .
  • a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel
  • the anti -clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg to approximately 20 mg/kg and
  • Another exemplary embodiment of a method of the present disclosure is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non- small cell lung cancer comprising administering a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel, where the anti -clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel
  • the anti -clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complement
  • Another exemplary embodiment of a method of the present disclosure is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non- small cell lung cancer comprising administering a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel, where the anti -clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2
  • Yet another exemplary embodiment of a method of the present disclosure is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic nonsmall cell lung cancer comprising administering a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg to approximately 20 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 .
  • a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at
  • a further exemplary embodiment of a method of the present disclosure is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non- small cell lung cancer comprising administering a combination therapy comprising an anticlusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • CDRs complementarity determining regions
  • a further exemplary embodiment of a method of the present disclosure is a method of treating a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel so as to obtain a clinical benefit, where the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and docetaxel is administered at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once weekly.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered twice weekly.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once every four weeks.
  • docetaxel is administered every week.
  • docetaxel is administered every two weeks.
  • docetaxel is administered every three weeks.
  • docetaxel is administered every four weeks.
  • docetaxel is administered once per week.
  • docetaxel is administered once every two weeks.
  • docetaxel is administered once every three weeks.
  • docetaxel is administered once every four weeks.
  • docetaxel is administered once every five weeks.
  • docetaxel is administered once every six weeks.
  • 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.
  • one treatment cycle is approximately 7 days.
  • essentially all treatment cycles are approximately 7 days.
  • each treatment cycles are approximately 7 days. In accordance with the present disclosure, the subject may thus receive a treatment cycle every 7 days.
  • one treatment cycle is approximately 14 days.
  • essentially all treatment cycles are approximately 14 days.
  • each treatment cycles are approximately 14 days.
  • the subject may thus receive a treatment cycle every 14 days.
  • one treatment cycle is approximately 21 days.
  • essentially all treatment cycles are approximately 21 days.
  • each treatment cycles are approximately 21 days.
  • the subject may thus receive a treatment cycle every 21 days.
  • one treatment cycle is approximately 28 days.
  • essentially all treatment cycles are approximately 28 days.
  • each treatment cycles are approximately 28 days.
  • the subject may thus receive a treatment cycle every 28 days.
  • the combination therapy is administered in one or more cycles of treatment including administration of the anti-clusterin antibody or antigen binding fragment thereof on days 1, 8 and 15 and administration of docetaxel on day 1.
  • interval of administration of the anti-clusterin antibody or antigen binding fragment thereof and docetaxel may be changed without significantly changing the effect of the combination therapy.
  • the anti-clusterin antibody or antigen binding fragment thereof may be administered on days 1, 7 and 14 and docetaxel may be administered on day 1.
  • the anti-clusterin antibody or antigen binding fragment thereof may be administered on days 1, 7 and 16 and docetaxel may be administered on day 1.
  • the anti-clusterin antibody or antigen binding fragment thereof may be administered on days 1, 8 and 16 and docetaxel may be administered on day 1.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel every three weeks.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every two weeks and administration of docetaxel every two weeks.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every two weeks and administration of docetaxel every three weeks.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every three weeks and administration of docetaxel every three weeks.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel every month.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every two weeks and administration of docetaxel every month.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every month and administration of docetaxel every month.
  • one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every two months and administration of docetaxel every two months. In an exemplary embodiment, one treatment cycle consists in administration of the anti-clusterin antibody or antigen binding fragment thereof every three months and administration of docetaxel every three months.
  • the method comprises administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg and docetaxel at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 every two to three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and docetaxel is administered at a dose of approximately 75 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and docetaxel is administered at a dose of approximately 60 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg and docetaxel is administered at a dose of approximately 50 mg/m 2 every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 9 mg/kg and docetaxel is administered at a dose of approximately 75 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 9 mg/kg and docetaxel is administered at a dose of approximately 60 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 9 mg/kg and docetaxel is administered at a dose of approximately 50 mg/m 2 every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6 mg/kg and docetaxel is administered at a dose of approximately 75 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6 mg/kg and docetaxel is administered at a dose of approximately 60 mg/m 2 every three weeks. In exemplary embodiments the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6 mg/kg and docetaxel is administered at a dose of approximately 50 mg/m 2 every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg and docetaxel is administered at a dose of approximately 75 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg and docetaxel is administered at a dose of approximately 60 mg/m 2 every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3 mg/kg and docetaxel is administered at a dose of approximately 50 mg/m 2 every two weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered once per week on same day.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered once per week on same day.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered every 2 weeks on same day.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered every 3 weeks on same day.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are administered every 4 weeks on same day.
  • the method comprises administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week and docetaxel at a dose of approximately 50 mg/m 2 to 100 mg/m 2 once every two to three weeks.
  • 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 exemplary 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.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12 mg/kg once weekly and docetaxel is administered at a dose of approximately 50 mg/m 2 once every three weeks.
  • 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.
  • 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.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 9 mg/kg once weekly and docetaxel is administered at a dose of approximately 50 mg/m 2 once every three weeks.
  • 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.
  • 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.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6 mg/kg once weekly and docetaxel is administered at a dose of approximately 50 mg/m 2 once every three weeks.
  • 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.
  • 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. In exemplary 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 50 mg/m 2 once every three weeks.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel may be 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 may be administered on same day and separately.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel may be administered sequentially.
  • the anti-clusterin antibody or antigen binding fragment thereof and/or docetaxel may be administered by infusion.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered over the entire course of the treatment period.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered at each cycle of treatment.
  • 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.
  • a subject may receive at least one treatment cycle.
  • a subject may receive at least two treatment cycles.
  • a subject may receive at least three treatment cycles.
  • a subject may receive at least four treatment cycles. In accordance with the present disclosure, a subject may receive four or more treatment cycles.
  • a subject may receive at least five treatment cycles.
  • a subject may receive at least six treatment cycles.
  • a subject may receive at least seven treatment cycles.
  • a subject may receive at least eight treatment cycles.
  • a subject may receive at least nine treatment cycles.
  • a subject may receive at least ten treatment cycles.
  • a subject may receive at least eleven treatment cycles.
  • a subject may receive at least twelve treatment cycles.
  • a subject may receive at least thirteen treatment cycles.
  • a subject may receive at least fourteen treatment cycles.
  • a subject may receive at least fifteen treatment cycles.
  • a subject may receive at least sixteen treatment cycles.
  • a subject may receive at least seventeen treatment cycles. In accordance with the present disclosure, a subject may receive at least eighteen treatment cycles.
  • a subject may receive at least nineteen treatment cycles.
  • a subject may receive at least twenty treatment cycles.
  • a subject may receive more than twenty treatment cycles.
  • a subject may receive at least one treatment cycle comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least two treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least three treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least four treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive four or more treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least five treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least six treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least seven treatment each cycles comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least eight treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least nine treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least ten treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least eleven treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive at least twelve treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • a subject may receive more than twelve treatment cycles each comprising administration of the anti-clusterin antibody or antigen binding fragment thereof once per week and administration of docetaxel once every three weeks.
  • the treatment cycles are consecutive. In accordance with the present disclosure, all treatment cycles are consecutive.
  • the treatment cycles are uninterrupted.
  • 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.
  • Treatment may be reinitiated afterward.
  • At least one treatment cycle is interrupted.
  • more than one treatment cycles are interrupted.
  • 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.
  • the method particularly involves administering an anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2) and SEQ ID NO:6 (CDRH3).
  • the method particularly involves administering an anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID N0:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2) and SEQ ID NO:9 (CDRH3).
  • the method particularly involves administering an anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13.
  • the method particularly involves administering anti -clusterin antibody or antigen binding fragment thereof comprises a light chain having the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered by infusion over approximately a 1-hour time frame.
  • docetaxel is administered by infusion over approximately a 1- hour time frame.
  • 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.
  • 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.
  • the combination therapy or medicament may be used for subjects having non-small cell lung cancer such as metastatic NSCLC or stage III to IV NSCLC.
  • the anti-clusterin antibody or antigen binding fragment thereof and docetaxel are both administered essentially over the entire course of the treatment period.
  • the combination therapy may be used in NSCLC patients that progressed after treatment with an immune checkpoint antibody either alone or in combination with chemotherapy.
  • the combination therapy may be used in NSCLC patients with no evidence of PD-L1 expression (e.g., tumor proportion score (TPS) ⁇ 1%) or with low expression of PD-L1 (e.g., tumor proportion score (TPS) ⁇ 15%, i.e., including ⁇ 5%, ⁇ !%, ⁇ !% and 0%).
  • TPS tumor proportion score
  • TPS tumor proportion score
  • the combination therapy may be used in NSCLC that is not eligible for or would unlikely benefit from treatment comprising an immune checkpoint antibody.
  • the present disclosure relates to a combination therapy for use in a method of treating NSCLC such as metastatic NSCLC by promoting infiltration of immune cells in one or more lesions.
  • the present disclosure relates to a combination therapy for use in a method of treating NSCLC such as metastatic NSCLC by promoting infiltration of immune cells in one or more lesions that has low expression of PD-L1 or no evidence of PD-L1 expression.
  • the anti -clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of inhibiting epithelial to mesenchymal transition.
  • the anti -clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of binding to amino acids 421 and 443 or 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: 41 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).
  • Such anticlusterin antibodies or antigen binding fragments thereof are exemplified in Table 3 or comprise the CDRs, variable regions or full chains exemplified in Table 3.
  • WO2011/063523 which describes a combination of an anti -clusterin antibody and a taxane
  • the present application provides evidence that the use of a combination therapy, particular doses or dosages, treatment regimen and/or schedule of administration described herein can induce tumor regression or stabilization of tumor growth in NSCLC patients.
  • the anti -clusterin antibody or antigen binding fragment thereof is an antibody or antigen binding fragment thereof that is capable of competing with an anticlusterin 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:18.
  • clusterin e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)
  • TA-sCLU tumor-associated sCLU
  • 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.
  • all CDRs are identified using the Kabat definition which is the most commonly used definition (Wu and Kabat, 1970).
  • 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.
  • 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 3.
  • the anti -clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • 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: 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.
  • 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.
  • the anti -clusterin antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO: 7, a CDRH2 having the amino acid sequence set forth in SEQ ID NO: 8, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:9.
  • 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: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 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.
  • 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: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 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:7, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:8, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:9.
  • 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: 10 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: 11.
  • 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: 10 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: 11.
  • the anti -clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 11.
  • 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: 10 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 11 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: 18.
  • clusterin e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)
  • 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: 12 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identity with the amino acid sequence set forth in SEQ ID NO: 13 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 13.
  • 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: 14 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 14 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: 15 or is identical to or comprises the amino acid sequence set forth in SEQ ID NO: 15.
  • 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: 12 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: 13.
  • 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: 12 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: 13.
  • the anti -clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 13.
  • 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: 12 and a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 13 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: 18.
  • clusterin e.g., secreted clusterin (sCLU) or tumor-associated sCLU (TA-sCLU)
  • TA-sCLU tumor-associated sCLU
  • 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: 14 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:15.
  • 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: 14 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:15.
  • 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: 14 and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 15.
  • 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: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15 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: 18.
  • clusterin e.g., secreted clusterin (sCLU) or tumor- associated sCLU (TA-sCLU)
  • 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 3.
  • the anti -clusterin antibody or antigen binding fragment thereof is humanized 16B5.
  • the anti -clusterin antibody or antigen binding fragment thereof is a humanized 16B5 biosimilar.
  • the anti-clusterin antibody or antigen binding fragment thereof may be able to compete with one or more of the antibodies or antigen binding fragments thereof listed in Table 3.
  • Exemplary embodiments of antibodies or antigen binding fragment thereof that competes with AB-16B5 includes for example and without limitations, antibodies identified as 16B5, 21B12, 20E11, 11E2 and 16C11 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.
  • Such anti-clusterin antibodies or antigen binding fragments thereof are exemplified in Table 3.
  • Exemplary embodiments of subject The combination therapy disclosed herein is administered to a subject in need.
  • the combination therapy disclosed herein is generally administered to a human subject.
  • the subject has cancer.
  • the subject is a subject having cancer and having a functional immune system.
  • the subject is a subject having cancer and adequate organ and immune function.
  • the subject has non-small cell lung cancer.
  • the subject has metastatic NSCLC.
  • the subject has stage III to IV NSCLC.
  • the subject has or is selected for having NSCLC that progressed after treatment comprising an immune checkpoint antibody.
  • the subject has or is selected for having NSCLC that progressed after chemotherapy.
  • the subject has received prior treatment with chemotherapy.
  • the subject has or is selected for having NSCLC that is not eligible for or would unlikely benefit from treatment that comprises immune checkpoint antibody.
  • a subject may be characterized as being not eligible for treatment with a PD-1 or PD- L1 immune checkpoint inhibitor based on objective criteria such as for example, prior failure of treatment comprising a PD-1 or PD-L1 immune checkpoint inhibitor, level of expression of PD-1 or PD-L1, level of immune cell infiltration in the tumor environment and the like.
  • a subject may be characterized as being unlikely to benefit from treatment with a PD- 1 or PD-L1 immune checkpoint inhibitor based on subjective criteria such as, physician assessment of risks and benefits, overall clinical condition of the subject, and the like.
  • the subject has or is selected for having NSCLC that has failed prior treatment with an immune checkpoint antibody and a platinum-containing doublet treatment. In some embodiments, the subject has or is selected for having NSCLC that has failed prior treatment comprising an anti-PD-1 immune checkpoint antibody.
  • the subject has or is selected for having NSCLC that has failed prior treatment comprising an PD-L1 immune checkpoint antibody.
  • the subject has or is selected for having NSCLC that has failed prior treatment comprising an anti-PD-1 or PD-L1 immune checkpoint antibody.
  • the subject has or is selected for having NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • the subject has or is selected for having NSCLC that has failed prior treatment with an anti-PD-Ll immune checkpoint antibody and a platinum-containing doublet treatment.
  • the subject has or is selected for having NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • the doublet treatment may be provided simultaneously.
  • the doublet treatment may be provided sequentially.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • the subject has or is selected for having NSCLC that has failed prior treatment with immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab alone or in combination with platinum-based chemotherapy.
  • immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab alone or in combination with platinum-based chemotherapy.
  • the subject has or is selected for having NSCLC that has failed prior treatment with pembrolizumab alone or in combination with platinum-based chemotherapy. In other embodiments, the subject has or is selected for having metastatic NSCLC that progressed after treatment comprising an immune checkpoint antibody.
  • the subject has or is selected for having metastatic NSCLC that progressed after chemotherapy.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with immune checkpoint antibody and chemotherapy treatment.
  • the subject has or is selected for having metastatic NSCLC that is not eligible for or would unlikely benefit from treatment that comprises immune checkpoint antibody.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with immune checkpoint antibody and a platinum-containing doublet treatment.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment comprising an anti-PD-1 immune checkpoint antibody.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment comprising an PD-L1 immune checkpoint antibody.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment comprising an anti-PD-1 or PD-L1 immune checkpoint antibody.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with an anti-PD-1 immune checkpoint antibody and a platinum- containing doublet treatment.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with an anti-PD-Ll immune checkpoint antibody and a platinum- containing doublet treatment.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment. In some embodiments, the subject has or is selected for having metastatic NSCLC that has failed prior treatment with an anti-PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab alone or in combination with platinum-based chemotherapy.
  • immune checkpoint antibody selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab alone or in combination with platinum-based chemotherapy.
  • the subject has or is selected for having metastatic NSCLC that has failed prior treatment with pembrolizumab alone or in combination with platinum-based chemotherapy.
  • the subject may have or may be selected for having one or more characteristics described herein and/or exemplified below.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of > 50%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of ⁇ 50%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of between 1% to 49%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of ⁇ 15%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of ⁇ 5%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of ⁇ 1%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of ⁇ 1%.
  • the subject has or is selected for having one or more lesions with a PD-L1 tumor proportion score of 0%.
  • the tumor proportion score is determined at baseline. In some embodiments, the tumor proportion score is determined prior to administration of the combination therapy.
  • the tumor proportion score is determined after first-line therapy.
  • the tumor proportion score is determined at the onset of the combination therapy.
  • the PD-L1 tumor proportion score is determined by a scientist or pathologist.
  • the PD-L1 tumor proportion score is determined in accordance with drug regulator’s guidance (e.g., FDA, EMA and the like).
  • drug regulator e.g., FDA, EMA and the like.
  • the subject has or is selected for having one or more lesions that are immunologically cold.
  • the subject has or is selected for having one or more lesions with poor infiltration of immune cells.
  • the level of immune cell infiltration may be determined by a trained pathologist.
  • the level of immune cell infiltration may be determined by computer-based quantification of tumor biopsy imaging.
  • the subject has or is selected for having one or more lesions having an EMT signature or showing signs of an EMT signature.
  • the EMT signature may be determined by a trained pathologist.
  • the EMT signature may be determined by computer- based quantification of tumor or tumor biopsy imaging.
  • the subject is a subject having non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer and is selected based on the following non-exhaustive and non-limitative criteria: a) The subject has failed prior therapy with an immune checkpoint antibody either alone or in combination with chemotherapy; b) The subject has a one or more lesions with poor infiltration of immune cells; c) The subject has one or more lesions having an EMT signature or showing signs of an EMT signature; d) The subject has one or more criteria listed in any one of a) to c).
  • non-small cell lung cancer such as, for example, metastatic non-small cell lung cancer and is selected based on the following non-exhaustive and non-limitative criteria: a) The subject has failed prior therapy with an immune checkpoint antibody either alone or in combination with chemotherapy; b) The subject has a one or more lesions with poor infiltration of immune cells; c) The subject has one or more lesions having an EMT signature or showing signs of an EMT signature; d) The subject
  • the subject is a subject having non-small cell lung cancer such as, for example metastatic non-small cell lung cancer and is selected based on the following non-exhaustive and non-limitative criteria; a) The subject has not received prior therapy with an anti-PD-Ll antibody either alone or in combination with platinum-based chemotherapy; b) The subject has one or more lesions with a PD-L1 tumor proportion score of ⁇ 15%; c) The subject has one or more lesions with poor infdtration of immune cells; d) The subject has one or more lesions having an EMT signature or showing signs of an EMT signature or; e) The subject has one or more criteria listed in any one of a) to d).
  • non-small cell lung cancer such as, for example metastatic non-small cell lung cancer and is selected based on the following non-exhaustive and non-limitative criteria; a) The subject has not received prior therapy with an anti-PD-Ll antibody either alone or in combination with platinum-based chemotherapy; b) The subject has one or more les
  • a subject may thus be selected based on one criterion or a combination of criteria disclosed herein.
  • the subject has a functional immune system and/or an adequate organ and immune function.
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and has not received prior therapy with an anti-PD-Ll antibody.
  • NSCLC such as metastatic non-small cell lung cancer
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and one or more lesions with a PD-L1 tumor proportion score of ⁇ 15%.
  • NSCLC such as metastatic non-small cell lung cancer
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 15% and has not received prior therapy with an anti-PD-Ll antibody.
  • NSCLC such as metastatic non-small cell lung cancer
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 15% and for having one or more lesions with poor infdtration of immune cells.
  • NSCLC such as metastatic non-small cell lung cancer
  • PD-L1 tumor proportion score of ⁇ 15%
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 1%.
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 1% and has not received prior therapy with an anti-PD-Ll antibody.
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 1% and for having one or more lesions with poor infdtration of immune cells.
  • NSCLC such as metastatic non-small cell lung cancer
  • PD-L1 tumor proportion score of ⁇ 1%
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and that has failed prior therapy with an immune checkpoint antibody either alone or in combination with chemotherapy.
  • NSCLC such as metastatic non-small cell lung cancer
  • the subject has or is selected for having NSCLC, such as metastatic non-small cell lung cancer, that has failed first-line, second-line, third-line or subsequent line therapy.
  • NSCLC such as metastatic non-small cell lung cancer
  • the combination therapy is administered as a first-line therapy in a subject having or selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 15%.
  • the combination therapy is administered as a first-line therapy in a subject having or is selected for having NSCLC, such as metastatic non-small cell lung cancer, and a PD-L1 tumor proportion score of ⁇ 1%.
  • the combination therapy is administered as a second-line therapy in a subject having NSCLC, such as metastatic non-small cell lung cancer, and that has failed prior therapy with an immune checkpoint antibody either alone or in combination with chemotherapy.
  • NSCLC such as metastatic non-small cell lung cancer
  • the combination therapy is administered as a second-line therapy in a subject having NSCLC, such as metastatic non-small cell lung cancer, and that has failed prior therapy with an immune checkpoint antibody either alone or in combination with chemotherapy.
  • NSCLC such as metastatic non-small cell lung cancer
  • the subject in need has a tumor that expresses or secrete clusterin.
  • 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.
  • the subject in need may have received corticosteroids prior to treatment.
  • the subject is or selected for being immunocompetent.
  • the subject has or is selected for not being immunosuppressed.
  • the subject has or is selected for not having received an immunosuppressive medication within 7 days prior to treatment.
  • the subject in need is a subject that has not received prior treatment with docetaxel.
  • subjects that has failed prior treatment includes subjects having progressive disease.
  • subjects that has failed prior treatment includes subjects having undesired side effects associated with the prior treatment.
  • the subject has not received prior treatment with docetaxel.
  • PD-L1 expression may be determined using methods known to a person skilled in the art.
  • the PD-L1 tumor proportion score is assessed with the 22C3 antibody (Agilent Technologies, Carpinteria, CA, code SK006).
  • the PD-L1 TPS is assessed with the 28-8 antibody (Agilent Technologies, Carpinteria, CA, code SK005; Abeam, Toronto, Canada, Cat. No. Ab205921).
  • PD-L1 TPS is assessed with the SP263 antibody Roche Diagnostic Ref. 740-4907.
  • the PD-L1 TPS is assessed with the SP142 antibody (Abeam, Toronto, Canada, Cat. No. Ab228462).
  • the PD-L1 TPS is assessed with the 73-10 antibody (clone MKP1A07310; Merck KGaA, Darmstadt, Germany; Abeam, Toronto, Canada, Cat. No. Ab228415).
  • the PD-L1 expression may be assessed using an anti-PD-Ll antibody suitable for the type of carcinoma that the subject has.
  • the PD-L1 expression is usually assessed in tumor cells. However, the PD-L1 expression may be assessed both in tumor cells and in tumor-infiltrating immune cells.
  • the PD-L1 expression is assessed by immunohistochemistry.
  • the PD-L1 expression is assessed by fluorescence assays, such as for example, by quantitative fluorescence or fluorescence in-situ hybridization.
  • the assay is an assay approved by at least one regulatory body.
  • the assay is a United States Food and Drug Administration (FDA) - approved diagnostic test (Dx).
  • FDA United States Food and Drug Administration
  • Dx diagnostic test
  • the assay is an FDA-approved test for research (Rx).
  • the assay is based on PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA, code SK006).
  • the assay is based on PD-L1 IHC 28-8 pharmDx ((Agilent Technologies, Carpinteria, CA, code SK005)).
  • the assay is based on Ventana PD-L1 (SP263) (Roche Diagnostic Ref. 740-4907).
  • the immunohistochemistry assay is performed in accordance with manufacturer’s instructions.
  • the assay uses Autostainer Link 48 immunohistochemistry platform (Dako).
  • the assay uses the Omnis immunohistochemistry platform (Dako).
  • the assay is performed with the Bond-Ill immunohistochemistry platform (Leica).
  • the assay uses the BenchMark ULTRA immunohistochemistry platform (Ventana).
  • the assay results are interpreted using the manufacturer’s interpretation manual. Exemplary assays are described in Munari, E., et al., 2021, Marchetti, A. et al., 2017, Yoshikawa, K. et al., 2021, the entire content of all of which is incorporated herein by reference.
  • the absence or presence of immune cells in the tumor microenvironment may be confirmed by tumor biopsy.
  • 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).
  • 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.
  • 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.
  • 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”.
  • kits 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 a taxane for use in combination therapy and a package insert comprising instructions for treating a subject in need.
  • kits 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 anti-clusterin antibody or antigen binding fragment thereof and docetaxel are provided in separate containers.
  • the antibody or antigen binding fragment thereof is as described herein.
  • the package insert states that the combination therapy is intended for treatment of a subject as described herein.
  • the package insert states that the combination therapy is intended for treatment of a subject having NSCLC.
  • the package insert states that the combination therapy is intended for treatment of a subject having metastatic NSCLC such as for example, stage III- IV NSCLC.
  • the package insert states that the combination therapy is intended for treatment of a subject having NSCLC that progressed after treatment comprising an immune checkpoint antibody.
  • the package insert states that the combination therapy is intended for treatment of a subject having NSCLC that has failed prior treatment with immune checkpoint antibody and a platinum-containing doublet treatment.
  • the package insert states that the combination therapy is intended for treatment of a subject having metastatic NSCLC that progressed after a first-line treatment comprising an immune checkpoint antibody.
  • the package insert states that the combination therapy is intended for treatment of a subject having metastatic NSCLC that has failed prior treatment comprising an immune checkpoint antibody and a platinum-containing doublet treatment.
  • a method of treating a subject having lung cancer comprising administering the combination therapy disclosed herein.
  • a method of treating a subject having non-small cell lung cancer comprising administering the combination therapy disclosed herein.
  • 3. A method of treating a subject having non-small cell lung cancer, the method comprising administering the combination therapy disclosed herein so as to obtain and/or maintain a clinical benefit.
  • combination therapy comprises an anti-clusterin antibody or antigen binding fragment thereof and a taxane.
  • a method of procuring a clinical benefit to a subject having non-small cell lung cancer comprising administering the combination therapy disclosed herein.
  • a method of procuring a clinical benefit to a subject having non-small cell lung cancer in a method of treatment comprising administering a combination therapy for at least two cycles of treatment, each cycle of treatment comprising administration of the anticlusterin antibody at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week and administration of a taxane at a dose of approximately 60mg/m 2 and 100mg/m2 once every three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a method of procuring a clinical benefit to a subject having non-small cell lung cancer in a method of treatment comprising administering a combination therapy for at least two cycles of treatment, each cycle of treatment comprising administration of the anticlusterin antibody at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks, wherein the anticlusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a method of treating a subject having non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane, wherein the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a method of treating a subject having non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane so as to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a method of treating non-small cell lung cancer in a subject in need thereof comprising administering a combination therapy for at least two cycles of treatment, each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week, once every two weeks, or once every three weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 to approximately 100 mg/m 2 once every two to three weeks, wherein the anti -clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a method of treating a subject having non-small cell lung cancer comprising administering a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week, once every two weeks, once every three weeks, once every four weeks and docetaxel at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 once every two to three weeks so as to obtain a clinical benefit, wherein the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a method of treating non-small cell lung cancer in a subject in need thereof comprising administering a combination therapy for at least two cycles of treatment, each cycle of treatment comprising administration of the anti-clusterin antibody at a dose of approximately 12 mg/kg once per week, once every two weeks, once every three weeks or once every four weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 once every two to three weeks, wherein the anti -clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the immune checkpoint antibody is selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab.
  • each of the initial cycle of treatment and subsequent cycle of treatment comprises at least one dose of the anti-clusterin antibody or antigen binding fragment thereof and at least one dose of docetaxel.
  • the method comprises administering docetaxel at a dose of approximately 75 mg/m 2 once every three weeks and administering the anti-clusterin antibody or antigen binding fragment thereof once per week, once every two weeks or once every three weeks.
  • the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every three weeks and administering docetaxel at a dose of approximately 75 mg/m 2 once every three weeks.
  • the method comprises administering: a. at least one initial cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks and; b. at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once every three weeks and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks. 138. The method of any one of the preceding embodiments, wherein the method comprises administering: a.
  • At least one initial cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks and; b. at least one subsequent cycle of treatment comprising administering the anticlusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every three weeks and administration of docetaxel at a dose of approximately 75 mg/m 2 once every three weeks.
  • the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administering docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every two weeks and administering docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the method comprises administering: a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks and; b) at least one subsequent cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 3 mg/kg to approximately 20 mg/kg once every two weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • the method comprises administering: a) at least one initial cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks and; b) at least one subsequent cycle of treatment comprising administering the anti -clusterin antibody or antigen binding fragment thereof at a dose of approximately 12 mg/kg once every two weeks and administration of docetaxel at a dose of approximately 50 mg/m 2 once every two weeks.
  • anticlusterin antibody or antigen binding fragment thereof is capable of binding to amino acids 421 and 443 or to an epitope comprised within amino acids 421 and 443 of a C-terminal portion of aB-subunit of human clusterin.
  • anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2) and SEQ ID NO:6 (CDRH3).
  • anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO: 8 (CDRH2) and SEQ ID NO:9 (CDRH3).
  • the anticlusterin antibody or antigen binding fragment thereof comprises: a.
  • 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: 12 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: 13 or; b. a light chain having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 14 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:15.
  • anticlusterin antibody or antigen binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13.
  • anticlusterin antibody or antigen binding fragment thereof comprises a light chain having the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15.
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane.
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane for treatment of lung cancer.
  • a therapeutically effective combination therapy comprising an anti -clusterin antibody or antigen binding fragment thereof and a taxane for use in the treatment of nonsmall cell lung cancer (NSCLC) in a subject in need thereof.
  • NSCLC nonsmall cell lung cancer
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane for use in treatment of a subject having non-small cell lung cancer, wherein the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO:13.
  • CDRs complementarity determining regions
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and a taxane for use in procuring a clinical benefit to a subject having non-small cell lung cancer, wherein the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • a combination therapy comprising an anti-clusterin antibody or antigen binding fragment thereof and docetaxel for use in procuring a clinical benefit to a subject having non-small cell lung cancer, wherein the anti-clusterin antibody or antigen binding fragment thereof is formulated for administration at a dose of approximately 12 mg/kg and comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13 and docetaxel is formulated for administration at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 .
  • CDRs complementarity determining regions
  • a combination therapy for use in procuring a clinical benefit to a subject having non-small cell lung cancer wherein the combination therapy is used for at least two cycles of treatment each cycle of treatment comprising administration of the anti -clusterin antibody at a dose of approximately 3 mg/kg to approximately 20 mg/kg once per week and administration of a taxane at a dose of approximately 60mg/m 2 to 100mg/m 2 once every three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13. 263.
  • CDRs complementarity determining regions
  • a combination therapy for use in procuring a clinical benefit to a subject having non-small cell lung cancer wherein the combination therapy is used for at least two cycles of treatment each cycle of treatment comprising administration of the anti -clusterin antibody at a dose of approximately 12 mg/kg once per week and administration of docetaxel at a dose of approximately 50 mg/m 2 to approximately 75 mg/m 2 once every three weeks, wherein the anti-clusterin antibody comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.
  • CDRs complementarity determining regions
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:4 (CDRH1), SEQ ID NO:5 (CDRH2) and SEQ ID NO:6 (CDRH3).
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:1 (CDRL1), in SEQ ID NO:2 (CDRL2) and in SEQ ID NO: 3 (CDRL3) and a heavy chain variable region comprising CDRs having the amino acid sequence set forth in SEQ ID NO:7 (CDRH1), SEQ ID NO:8 (CDRH2) and SEQ ID NO:9 (CDRH3).
  • the anti-clusterin antibody or antigen binding fragment thereof comprises: a. 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: 12 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: 13 or; b. a light chain having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 14 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:15. 321.
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13.
  • anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 15.
  • Example 1- PHASE II CLINICAL STUDY DESIGN The Applicant is evaluating 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 PD-L1 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/m 2 once every 3 weeks.
  • AB-16B5 herein referred to as humanized 16B5
  • ORR objective response rate
  • 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.
  • EMT epithelial to mesenchymal transition
  • An exploratory objective of this study is to evaluate disease response using iRECIST in subjects pursuing treatment beyond progression.
  • 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-PD-1 or PD-L1 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 profile 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).
  • RECIST Solid Tumors
  • ORR objective response rate
  • PFS progression free survival
  • 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.
  • 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).
  • mTPI modified toxicity probability interval method
  • 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.
  • DLTs dose limiting toxicity
  • a DLT is defined as a Grade > 3 non-hematologic toxicity occurring during Cycle 1 of therapy.
  • the following hematologic toxicities are considered as a DLT:
  • DLTs DLTs that are clearly and incontrovertibly due to disease progression or to extraneous causes are not to be considered DLTs.
  • non-hematologic toxicities are not to be considered DLTs:
  • De-escalation of AB-16B5 is performed if more than 3 DLTs are observed in the first 8 subjects treated.
  • 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.
  • 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.
  • PD-1 or PD-L1 immune checkpoint antibody and a platinum-containing doublet treatment, administered simultaneously or sequentially.

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PCT/CA2023/050151 2022-02-07 2023-02-06 Combination therapy for use in treatment of non-small cell lung cancer Ceased WO2023147673A1 (en)

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US18/729,922 US20250108110A1 (en) 2022-02-07 2023-02-06 Combination therapy for use in treatment of non-small cell lung cancer
EP23749327.5A EP4475885A4 (en) 2022-02-07 2023-02-06 POLYTHERAPY INTENDED FOR USE IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER
AU2023216333A AU2023216333A1 (en) 2022-02-07 2023-02-06 Combination therapy for use in treatment of non-small cell lung cancer.
JP2024546456A JP2025505652A (ja) 2022-02-07 2023-02-06 非小細胞肺がんの治療における使用のための併用療法
MX2024009671A MX2024009671A (es) 2022-02-07 2023-02-06 Terapia de combinación para uso en el tratamiento del cáncer de pulmón de células no pequeñas.
IL314600A IL314600A (en) 2022-02-07 2023-02-06 Combination therapy for use in treatment of non-small cell lung cancer
CA3243096A CA3243096A1 (en) 2022-02-07 2023-02-06 POLYTHERAPY INTENDED FOR USE IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER
CN202380028327.7A CN118900700A (zh) 2022-02-07 2023-02-06 用于治疗非小细胞肺癌的联合疗法

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EA034462B1 (ru) * 2009-11-24 2020-02-11 Алетиа Байотерапьютикс Инк. Антикластериновые антитела и антигенсвязывающие фрагменты и их использование для уменьшения объема новообразований
US9822170B2 (en) * 2012-02-22 2017-11-21 Alethia Biotherapeutics Inc. Co-use of a clusterin inhibitor with an EGFR inhibitor to treat cancer
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* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "AB-16B5 Combined With Docetaxel in Subjects With Metastatic Non-Small Cell Lung Cancer (EGIA-002)", CLINICALTRIALS.GOV; NCT04364620, 28 April 2020 (2020-04-28), XP093084222, Retrieved from the Internet <URL:https://classic.clinicaltrials.gov/ct2/show/NCT04364620?term=NCT04364620&draw=2&rank=1> [retrieved on 20230921] *
MA XIAOKUN, ZOU LIYUAN, LI XING, CHEN ZHANHONG, LIN QU, WU XIANGYUAN: "MicroRNA-195 regulates docetaxel resistance by targeting clusterin in prostate cancer", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, FR, vol. 99, 1 March 2018 (2018-03-01), FR , pages 445 - 450, XP093084225, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2018.01.088 *
See also references of EP4475885A4 *
TAN JUOFANG, GUO WEI, YANG SU, HAN DINGPEI, LI HECHENG: "The multiple roles and therapeutic potential of clusterin in non-small-cell lung cancer: a narrative review", TRANSLATIONAL LUNG CANCER RESEARCH, SOCIETY FOR TRANSLATIONAL CANCER RESEARCH (STCR), HONG KONG, vol. 10, no. 6, 1 June 2021 (2021-06-01), Hong Kong , pages 2683 - 2697, XP093084224, ISSN: 2218-6751, DOI: 10.21037/tlcr-20-1298 *

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