Combination therapy for neoadjuvant treatment of cancer

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

[0001] TITLE: COMBINATION THERAPY FOR NEOADJUVANT TREATMENT OF CANCER

[0002] TECHNICAL FIELD

[0003] The present disclosure concerns fixed dosing of anti-clusterin antibodies, or an antigen binding fragments thereof for treatment of cancer. Methods of treating cancer with a combination therapy comprising an anti-clusterin antibody or an antigen binding fragment thereof and a chemotherapeutic combination comprising two or more antineoplastic agents are also disclosed herein. The present disclosure also provides treatment of metastatic colorectal cancer with an anticlusterin antibody or an antigen binding fragment thereof as a single agent or in combination with FOLFOX for resection of metastases.

[0004] BACKGROUND

[0005] The Applicant has developed anti-clusterin antibodies with potent epithelial-to- mesenchymal transition (EMT) inhibitory activity interfering with the binding of tumor-associated secreted clusterin (TA-sCLU) with LRP1, a cell surface receptor expressed in carcinoma cells whose expression is increased in tumor cells that overexpress TA-sCLU. TA-sCLU is a highly potent inducer of EMT. Its expression is induced by various stimuli in the tumor microenvironment, such as TGFP, and is expressed in various carcinomas. Overexpression of TA- sCLU induces the PI3K / AKT survival pathway through phosphorylation of AKT1 which is associated with tumor invasion, resistance to various classes of anti-cancer drugs and survival of tumor cells. AB-16B5 (a.k.a., humanized 16B5) has been shown to reduce metastatic invasion and increase responses to docetaxel in animal models. Treatment with AB-16B5 also increases intra-tumor immune infiltration. A Phase I trial has demonstrated that AB-16B5 can be administered safely to patients with advanced cancer. A recently conducted Phase II trial in patients with metastatic nonsmall cell lung cancer progressing following primary chemoimmunotherapy has shown that AB- 16B5 administered in combination with docetaxel can induce significant cancer cell cytotoxicity observed in tumor biopsies along with B- and a T-cell immune responses including the formation of tertiary lymphoid structures (TLS), which are markers of effective anti-tumor immune response. Although there have been many advances in the treatment of cancer, there remains a need for enhancing the immune response towards cancer cells. For example, current immunotherapies relying on anti-tumor T-cell response have generally not been efficacious in patients with metastatic colorectal cancer (CRC). The present application describes the use of an anti-clusterin antibody in combination with antineoplastic agents or chemotherapeutics combinations as neoadjuvant treatment. Such treatment may particularly be used prior to and / or after ablation of tumor or metastases with the aim of reducing persistence and / or recurrence. Combination therapy comprising an anti-clusterin antibody and antineoplastic agents is provided.

[0006] SUMMARY

[0007] Provided herein are methods of treating cancer in a human in need thereof comprising administering a therapeutically effective amount of an antibody that binds to human clusterin.

[0008] In some aspects, the disclosure provides a method for inhibiting, delaying, and / or reducing recurrence and / or growth of tumor(s) and / or for preventing and / or reducing persistence of tumor(s) in a subject having cancer by administering an antibody or an antigen binding fragment thereof that binds to clusterin at least prior to ablation of the tumor(s).

[0009] In other aspects, the disclosure provides a method for inhibiting, delaying, and / or reducing recurrence and / or growth of metastasi s(es) and / or for preventing and / or reducing persistence of metastasi s(es) in a subject having cancer by administering an antibody or an antigen binding fragment thereof that binds to clusterin at least prior to ablation of the metastasi s(es).

[0010] The method of the present disclosure may also involve administration of an antineoplastic agent or a chemotherapeutic combination of antineoplastic agents.

[0011] The administration may be performed at least prior to ablation of tumor(s) and / or metastasi s(es), after ablation of the tumor(s) and / or metastasi s(es) or prior to and after ablation of the tumor(s) and / or metastasi s(es). For example, the anti-clusterin antibody or antigen binding fragment thereof and the antineoplastic agent or chemotherapeutic combination may all be administered prior to ablation, after ablation or before and after ablation of the tumor(s) and / or metastasis(es).

[0012] The method of the present disclosure is particularly used for inhibiting, delaying, and / or reducing recurrence and / or growth of tumor(s) and / or liver metastasi s(es) and / or preventing and / or reducing persistence of tumor(s) and / or liver metastasi s(es) subsequent to ablation of the tumors and / or liver metastasis(es) in a subject having cancer. In some instances, the chemotherapeutic combination may comprise two or more antineoplastic agents and wherein at least one, at least two, at least three, at least four or at least five of the antineoplastic agents is selected from 5 -fluorouracil (5-FU), oxaliplatin, leucovorin, capecitabine or irinotecan. The antineoplastic agent(s) may be used in a therapeutically effective amount suitable for treating a given condition.

[0013] In other aspects, the disclosure provides a method of treating a subject having cancer comprising administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising two or more antineoplastic agents and wherein at least one of the antineoplastic agents is selected from 5-fluorouracil, oxaliplatin, leucovorin, capecitabine or irinotecan.

[0014] In some instances, the chemotherapeutic combination comprises at least one antineoplastic agent selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0015] In some instances, the chemotherapeutic combination comprises at least two antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0016] In some instances, the chemotherapeutic combination comprises at least three antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0017] In some instances, the chemotherapeutic combination comprises at least four antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0018] In some embodiments, the chemotherapeutic combination comprises at least 5- fluorouracil.

[0019] In some embodiments, the chemotherapeutic combination comprises oxaliplatin, leucovorin and 5-fluorouracil.

[0020] In an exemplary embodiment, the antibody or an antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as a first-line therapy.

[0021] In an exemplary embodiment, the antibody or an antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as a second-line therapy. In another exemplary embodiment, the antibody or an antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as neoadjuvant therapy and / or as an adjuvant therapy.

[0022] In some instances, the chemotherapeutic combination is suitable for treatment of colorectal cancer.

[0023] In some instances, the chemotherapeutic combination is selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX.

[0024] In a particular embodiment, the chemotherapeutic combination is FOLFOX. The anticlusterin antibody or an antigen binding fragment thereof and FOLFOX may be administered as a first-line therapy. The anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX may be administered as a neoadjuvant therapy and / or as an adjuvant therapy.

[0025] In a particular embodiment, the method of the present disclosure comprises administering an antibody or an antigen binding fragment that binds to secreted clusterin.

[0026] In some instances, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may bind to a polypeptide comprising an amino acid sequence comprising amino acid residues 228 to 449 of SEQ ID NO:42 or a portion thereof.

[0027] In some instances, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may bind to a polypeptide comprising an amino acid sequence comprising amino acid residues 375 to 449 of SEQ ID NO:42 or a portion thereof.

[0028] In some instances, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure may bind to a polypeptide comprising an amino acid sequence comprising amino acid residues 421 to 443 of SEQ ID NO:42 or a portion thereof.

[0029] In an exemplary embodiment, the anti-clusterin antibody or an antigen binding fragment thereof may comprise a light chain variable region (VL) 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 (VH) comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0030] In some instances, the CDR1, CDR2 and / or CDR3 correspond to the Kabat CDR1, CDR2, and / or CDR3. In other instances, the CDR1, CDR2 and / or CDR3 correspond to the IMGT CDR1, CDR2 and / or CDR3.

[0031] In another exemplary embodiment, the anti-clusterin antibody or an antigen binding fragment thereof may comprise a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 13.

[0032] In yet another exemplary embodiment, the anti-clusterin antibody or an antigen binding fragment thereof may comprise a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0033] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is an anti-clusterin antibody that 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.

[0034] In another exemplary embodiment, the anti-clusterin antibody or an antigen binding fragment thereof may be 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.

[0035] In a particular embodiment, the method of the present disclosure involves administration of a conventional antibody that binds to clusterin.

[0036] In certain embodiments, the anti-clusterin antibody or an antigen binding fragment thereof may be administered at a dose of between approximately 3 mg / kg to approximately 20 mg / kg.

[0037] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered at a dose of approximately 6 mg / kg., approximately 9 mg / kg or approximately 12 mg / kg. In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered in one or more fixed dose(s). In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered in one or more dose(s) independent of the patient’s weight.

[0038] For example, the anti-clusterin antibody or an antigen binding fragment thereof is administered in one or more fixed dose(s) selected between approximately 400 mg to approximately 1000 mg.

[0039] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered in one or more fixed dose(s) of approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0040] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg or approximately 1000 mg.

[0041] The anti-clusterin antibody or an antigen binding fragment thereof may be administered in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of between approximately 800 mg to approximately 400 mg.

[0042] The anti-clusterin antibody or an antigen binding fragment thereof may be administered in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of approximately 600 mg and / or of approximately 450 mg.

[0043] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly, once every two weeks, once every three weeks, once monthly.

[0044] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is generally administered once weekly.

[0045] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or more. In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks before and / or after ablation of the tumor(s) and / or metastasis(es).

[0046] In some embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of approximately 12 weeks before ablation of the tumor(s) and / or metastasis(es).

[0047] The anti-clusterin antibody or an antigen binding fragment thereof may be administered for example and without limitations via intravenous infusion.

[0048] In exemplary embodiments, FOLFOX is administered once every two weeks for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks or more.

[0049] For example, FOLFOX may be administered once every two weeks for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks before and / or after ablation of the tumor(s) and / or metastasis(es).

[0050] In some embodiments, the FOLFOX regimen comprises administration of oxaliplatin at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) at a dose of between approximately 200 mg / m2to approximately 400 mg / m2followed by at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m2.

[0051] In some embodiments, the FOLFOX regimen comprises administration of oxaliplatin at a dose of approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5- Fluorouracil (5-FU) at a dose of approximately 400 mg / m2followed by at a dose of approximately 2400 mg / m2.

[0052] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered intravenously at approximately 800 mg on day 1 and day 8 of each cycle and FOLFOX is administered on day 1 of cycle 1 to cycle 4 as follows: oxaliplatin at approximately 85 mg / m2IV bolus + leucovorin at approximately 400 mg / m2IV bolus + 5 -Fluorouracil (5-FU) at approximately 400 mg / m2IV bolus + 5-FU at approximately 2400 mg / m2continuous IV infusion over approximately 46 hours.

[0053] The method may also comprise ablation (by resection and / or thermo-ablation or else) of one or more tumors or metastasi s(es) after treatment with the anti-clusterin antibody or antigen binding fragment thereof and chemotherapeutics combination.

[0054] The ablation of one or more liver metastasi s(es) may be performed at approximately 4 to 6 weeks after cycle 4 of treatment or at approximately 2 to 4 weeks following the last dose of the antibody or an antigen binding fragment thereof that binds to clusterin.

[0055] In some instances, the method may comprise administering immunotherapy, chemotherapy and / or radiation therapy to the subject.

[0056] In other instances, the method may comprise administering an adjuvant therapy after tumor or metastasi s(es) ablation. Such adjuvant therapy may comprise for example, immunotherapy, chemotherapy and / or radiation therapy.

[0057] In some instances, the immunotherapy may involve administration of an antibody or an antigen binding fragment thereof that binds to clusterin, cetuximab, bevacizumab, panitumumab, an immune checkpoint inhibitor. Exemplary embodiments of immune checkpoint inhibitor include without limitations, pembrolizumab, nivolumab, atezolizumab and others.

[0058] In exemplary embodiments, the immunotherapy, chemotherapy and / or radiation therapy may be administered prior to the anti-clusterin antibody or antigen binding fragment thereof and chemotherapeutics combination.

[0059] In exemplary embodiments, the immunotherapy, chemotherapy and / or radiation therapy may be administered after to the anti-clusterin antibody or antigen binding fragment thereof and chemotherapeutics combination.

[0060] In exemplary embodiments, the immunotherapy, chemotherapy and / or radiation therapy may be administered in conjunction with the anti-clusterin antibody or antigen binding fragment thereof and chemotherapeutics combination. In some instances, the subject has received immunotherapy, chemotherapy and / or radiation therapy prior to treatment with the the anti-clusterin antibody or antigen binding fragment thereof and chemotherapeutics combination.

[0061] The method of the present disclosure may be amenable to the treatment of a solid tumor.

[0062] The method of the present disclosure provides for the treatment of colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer (non-small cell lung cancer), gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0063] The method of the present disclosure provides for the treatment of liver metastasi s(es) originating from or caused by colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer (non-small cell lung cancer), gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0064] The present disclosure particularly provides a method for treating liver metastasis in a subject having colorectal cancer.

[0065] In some instances, the method of the present disclosure is particularly used for treating a subject having colorectal carcinoma. In other instances, the method of the present disclosure is particularly used for treating a subject having liver metastasi s(es) originating from or caused by colorectal carcinoma. The subject may have, for example, an advanced colorectal cancer, such as stage III or stage IV colon adenocarcinoma or rectal adenocarcinoma.

[0066] In exemplary embodiments, the method of the present disclosure is aimed, for example, at treating a subject having tumors and / or liver metastasis(es) that are at least partially resectable or resectable.

[0067] The method of the present disclosure is aimed, for example, at treating a subject that is considered as a candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

[0068] In other instance, the present disclosure relates to a method for treating cancer in a subject in need thereof comprising administering one or more fixed dose(s) amount selected between approximately 400 mg to approximately 1000 mg of an anti-clusterin antibody or antigen binding fragment thereof that 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; a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 13 or; a light chain (L) having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain (H) having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0069] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof may comprise a constant region of an antibody or a portion thereof. In some embodiments, the anticlusterin antibody or antigen binding fragment thereof comprises a constant region which is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to a human IgGl or a portion thereof. In other embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a constant region which is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to a human IgG2 or a portion thereof. In further embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a constant region which is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to a human IgG3 or a portion thereof. In yet other embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a constant region which is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to a human IgG4 or a portion thereof.

[0070] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a constant region which is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to a human kappa constant region. In other embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a constant region which is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to a human lambda constant region.

[0071] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a Fc region of a human antibody or a portion thereof. For example, the Fc region is from a human IgGl, a human IgG2, a human IgG3 or a human IgG4.

[0072] In some embodiments, the fixed dose amount is as disclosed herein and may be for example and without limitations, approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0073] The method of treating cancer may involve administering a fixed dose of the anti-clusterin antibody or antigen binding fragment thereof. The fixed dose of the anti-clusterin antibody or antigen binding fragment thereof may be administered as a single therapy or in combination with one or more antineoplastic agent, chemotherapeutic combination or with radiation therapy.

[0074] The method of the present disclosure may further comprise administering cellular therapy to the subject. Accordingly, in certain embodiments, the subject may receive a preparation of tumor infiltrating lymphocytes (TILs) subsequent to ablation of the one or more tumors and / or metastasis(es). In some instances, the preparation of tumor infiltrating lymphocytes is obtained from the subject’s metastasi s(es) or tumor (autologous TILs). The TILs preparation may be obtained by isolating and expanding tumor infiltrating lymphocytes. The tumor infiltrating lymphocytes may comprise, for example, CD3+PD1+T cells. The administration of TILs may be performed subsequent to lymphodepletion of the subject.

[0075] In some embodiments, the cellular therapy comprises immune cells isolated from the individual. In some embodiments, the immune cells may be genetically modified or not.

[0076] In some embodiments, the method may further comprise administering IL-2 to the subject.

[0077] In some instances, the antineoplastic agent may be selected from an alkylating agent, an anti-metabolite, an alkaloid, an anti-tumor antibiotic or combination thereof. Exemplary embodiments of antineoplastic agent include, for example, from altretamine, busulfan, carboplatin, oxaliplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5 -fluorouracil, 6-mercaptopurine, azacytidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, vincristine, vinblastine, vinorelbine, taxanes (e.g., paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel), etoposide, teniposide, irinotecan, topotecan, daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, valrubicin, capecitabine or leucovorin.

[0078] In some instances, the cancer is a carcinoma.

[0079] In some instances, the cancer is for example, colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer (non-small cell lung cancer), gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0080] The method of the present disclosure may result in an improved prognostic for the subject.

[0081] The method of the present disclosure may result in minimal residual disease detection after tumor(s) or metastasi s(es) resection.

[0082] The method of the present disclosure may result in minimal residual disease detection after colorectal liver metastasis resection.

[0083] The method of the present disclosure may result in a complete response, partial response or stable disease in accordance with RECIST 1.1 criteria.

[0084] In further aspects the disclosure provides a combination therapy comprising a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX, whereby the antibody or antigen binding fragment thereof that binds to clusterin 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; a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to with the amino acid sequence set forth in SEQ ID NO: 13 or; a light chain (L) 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 (V) having an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 15.

[0085] In exemplary embodiments, the combination therapy comprises the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX.

[0086] In some instances, the pharmaceutical composition comprises a fixed dose amount of the anti-clusterin antibody selected between approximately 400 mg to approximately 1000 mg.

[0087] In exemplary embodiments, the pharmaceutical composition comprises a fixed dose amount of the anti-clusterin antibody of approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0088] The combination therapy of the present disclosure may comprise FOLFOX.

[0089] In some instances, FOLFOX comprises oxaliplatin for administration at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin for administration at a dose of approximately 400 mg / m2and 5-Fluorouracil (5-FU) for administration at a dose of between approximately 200 mg / m2to approximately 400 mg / m2and for administration at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m2.

[0090] In other instances, FOLFOX comprises oxaliplatin for administration at a dose of approximately 85 mg / m2, leucovorin for administration at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) for administration at a dose of approximately 400 mg / m2and for administration at a dose of approximately 2400 mg / m2.

[0091] In exemplary embodiments, the combination therapy is for use in the treatment of colorectal cancer and / or in liver metastasis(es) hepatectomy.

[0092] The present application therefore provides a combination therapy comprising an anticlusterin antibody and FOLFOX and its use for treating colorectal cancer patients with liver metastasis(es). In other aspects the disclosure provides an article of manufacture comprising one or more vial(s) containing a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin formulated for administration by intra-venous infusion at a fixed dose amount selected between approximately 400 mg to approximately 1000 mg.

[0093] The article of manufacturing of the present disclosure may comprise a fixed dose amount of approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0094] In some embodiments, the fixed dose amount of the antibody or antigen binding fragment thereof that binds to clusterin is provided as a single unit dose. Accordingly, the article of manufacture may comprise a single unit dose of the anti-clusterin antibody or antigen binding fragment thereof.

[0095] In some embodiments, the article of manufacture may further comprise one or more vial(s) containing one or more antineoplastic agent(s).

[0096] In exemplary embodiments, the article of manufacturing is a kit.

[0097] In further aspects the disclosure provides a unit dose form comprising an antibody or an antigen binding fragment thereof that binds to clusterin provided as a single unit dose, wherein the single unit dose comprises a fixed dose amount selected from between approximately 400 mg to approximately 1000 mg of the antibody or an antigen binding fragment thereof that binds to clusterin, 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; a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 13 or; a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0098] The unit dose form of the present disclosure may be, for example, a unit package comprising one or more single unit doses of the anti-clusterin antibody or antigen binding fragment thereof for single administration.

[0099] The unit dose form may comprise, for example, one or more single unit doses comprising a fixed dose of approximately 800 mg, approximately 600 mg and / or approximately 450 mg of the anti-clusterin antibody or antigen binding fragment thereof.

[0100] In some embodiments, the single unit doses is for single administration.

[0101] In some embodiments, unit dose form may further comprise an antineoplastic agent or chemotherapeutics combination. In some embodiment, the unit dose form may comprise FOLFOX.

[0102] DETAILED DESCRIPTION

[0103] Definitions

[0104] Unless indicated otherwise, the amino acid numbering indicated are in accordance with the EU numbering system.

[0105] The use of the terms "a" and "an" and "the" and similar referents in the context of describing embodiments (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0106] Unless specifically stated or obvious from context, as used herein the term “or” is understood to be inclusive and covers both “or” and “and”.

[0107] The term “and / or” where used herein is to be taken as specific disclosure of each of the specified features or components with or without the other.

[0108] The term "ablation" refers to a procedure or treatment that involves the partial or complete removal or destruction tumor cells. In the context of cancer, “ablation” is performed to eliminate or reduce the size of the tumor or metastasi s(es) by surgery (e.g., surgical resection) or by other means including without limitations by thermal ablation, radiofrequency ablation, microwave ablation, laser ablation, cryoablation, high-intensity focused ultrasound, embolization, needleablation.

[0109] 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.

[0110] As used herein, the term “affinity” refers to the strength of non-covalent interaction between a binding agent or antigen binding domain(s) thereof and an antigen. “Affinity” is represented, for example, by KD value, i.e., the ratio of dissociation rate to association rate (k off / k on) when the binding between the antigen and the binding agent (e.g., antibody such as single domain antibody) reaches equilibrium. The affinity may be determined by using any conventional method known in the art, including but are not limited to, surface plasmon resonance method, microscale thermophoresis method, HPLC-MS method and flow cytometry (such as FACS) method. An antibody generally has a KD value of <10 '6M (e.g., < 5x10 '7M, < 2x10 '7M,

[0111] < 10 -7M, < 5x10 -8M, < 2x10 -8M, < 10 ’8M, < 5x10 '9M, < 4x10 ’9M, <3 xlO ’9M, < 2x10 '9M, or <10 '9M and any value <10 '6). Preferably, an antibody has a KD value in the nanomolar range or lower (e.g., < 9x10 '9M, < 8x10 '9M, < 7x10 '9M, < 6x10 '9M, < 5x10 '9M, < 4x10 '9M, < 3x10 "9M, < 2x10 "9M, < 1x10 "9M or lower e.g., < 1x10 '10M, < 1x101M, < 1x10 "12M). Even more preferably, an antibody has a KD value in the picomolar range or lower (e.g., < 9x102M,

[0112] < 8x102M, < 7x102M, < 6x102M, < 5x102M, < 4x102M, < 3x102M, < 2x102M,

[0113] < 1x10 "12M or lower).

[0114] The term “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, diabody, 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. As used herein 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.

[0115] The term “antibody or an antigen binding fragment thereof that binds to clusterin’’ and “anti-clusterin antibody or an antigen binding fragment thereof’ are used interchangeably. It is to be understood herein that an anti-clusterin antibody or an antigen binding fragment thereof encompasses an antibody or an antigen binding fragment thereof that is capable of binding to at least human tumor-associated secreted clusterin (human TA-sCLU) while being optionally able to bind to human clusterin analogs or orthologs. Particularly, an anti-clusterin antibody or an antigen binding fragment thereof encompasses an antibody or an antigen binding fragment thereof that is capable of binding to amino acid residues 23-449 of SEQ ID NO:42 or to a portion thereof including for example and without limitations amino acid residues 228 to 449, 375 to 449, 421 to 443 of SEQ ID NO:42.

[0116] As used herein the term “analog” refers to a gene or protein that is an isotype of a particular gene or protein or a variant occurring in nature or man-made.

[0117] The term “antigen binding fragment(s)” as used in the expression “antibody or antigen binding fragment thereof’ refers to a fragment of the antibody that encompasses the antigen binding domain (CDRs or variable region(s)) and that may incorporate or not, other portion(s) of the antibody such as for example amino acid residues of the hinge region, amino acid residues of a constant region, portion of a Fc region. An “antigen binding fragment(s)” thus comprises a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHI domains; antigen binding domains linked to CH3, CH2-CH3 with or without hinge region. Regardless of structure, an antigen binding fragment binds to the same antigen that is recognized by the complete antibody.

[0118] The term “antineoplastic effect” refers to the ability of a substance to inhibit or prevent the growth and / or spread of tumors or malignant cells.

[0119] The term “antineoplastic agent” is understood to mean a substance producing an antineoplastic effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that an “agent” may be a single compound or a combination or composition of two or more compounds.

[0120] The term “at least” with respect to a given value intends to include the value and superior values. For example, the term “at least 80%” includes “at least 80%”, “at least 81%”, “at least 82%”, “at least 83%”, “at least 84%”, “at least 85%”, “at least 86%”, “at least 87%”, “at least 88%” “at least 89%”, “at least 90%”, “at least 91%”, “at least 92%”, “at least 93%”, “at least 94%”, “at least 95%”, “at least 96%”, “at least 97%”, “at least 98%”, “at least 99%”, “at least 99.1%”, “at least 99.2%”, at least 99.3%”, at least 99.4%”, at least 99.5%”, at least 99.6%”, at least 99.7%”, at least 99.8%”, at least 99.9%”, and 100%.

[0121] The term “carcinoma” refers to a type of cancer that originates from cells lining the internal or external surfaces of the body. A “carcinoma” is typically derived from epithelial cells that cover the surfaces of the skin, organs, glands, and other structures.

[0122] The term “CDR” refers to a complementarity determining region of an antibody. A conventional antibody has typically three light chain variable region CDRs; CDR1, CDR2 and CDR3 (a.k.a., CDRL1, CDRL2, CDRL3 respectively) on each light chain and three heavy chain variable region CDRs; CDR1, CDR2 and CDR3 (a.k.a., CDRH1, CDRH2, CDRH3 respectively) on each heavy chain. A single domain antibody typically has three CDRs on each heavy chainCDRl, CDR2 and CDR3 (a.k.a., CDRH1, CDRH2, CDRH3 respectively). The location of “CDR” in a conventional antibody may be determined with the Kabat numbering scheme scheme (e.g., Kabat, J Immunol., 147: 1709-19 (1991); Chothia C, Lesk AM, J Mol Biol. Aug 20;196(4):901-17 (1987)), Chotia numbering scheme or IMGT numbering scheme (e.g., Lefranc, M.-P., The Immunologist, 7, 132-136 (1999)).

[0123] The term “clusterin’’ refers to a human clusterin and to analogs or orthologs that have at least 75% sequence identity. An example of “clusterin’’ is provided in amino acid 23-449 of SEQ ID NO:42.

[0124] The term “combination therapy” refers to a therapy that uses two or more therapeutic substances such as two or more antineoplastic agents. It is to be understood herein that the therapeutic substances of a “combination therapy” may be administered separately (separate times, separate mode of administration, etc.) as part of one or more cycles of treatment. Exemplary embodiments of therapeutic substances include, without limitations, anti-clusterin antibody or antigen binding fragments thereof and antineoplastic agents.

[0125] As used herein, the term “competing for binding”, “compete for binding”, “compete(s) with” or “competing with” refers to the ability of a first antibody or antigen-binding fragment thereof (e.g., single domain antibody or antigen binding fragment thereof) to inhibit the binding interaction between clusterin and a second anti-clusterin antibody to any detectable degree.

[0126] The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. The term “consisting of’ is to be construed as close-ended.

[0127] The term “EMT signature” as used herein 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.

[0128] The term “first-line therapy” refers to the initial or primary treatment that a subject receives for its current condition. A therapy is considered a “first-line therapy” if the patient has not received treatment for the same condition in the previous 6 months period.

[0129] The term “second-line therapy” refers to a subsequent treatment that a subject receives for its current condition. A therapy is considered a “second-line therapy” if the patient has received treatment for the same condition in the previous 6 months period.

[0130] The term “fixed dose” refers to a specific and predetermined amount of therapeutic substance that is prescribed or administered to individuals without adjustment based on individual variations such as weight, age, and / or health conditions.

[0131] The term “functional immune system” with respect to a subject means that the immune system of the subject is essentially not affected by cancer or by medication or that the subject is not immunosuppressed.

[0132] As used herein, the term " identity" with reference to sequence indicates the degree of identical nucleotides or amino acid residues between two nucleic acid sequences or two amino acid sequences when best compared. An “identity” may be assessed over the entire length of a sequence or over a particular portion. A sequence identity may be at least 85 %, 90 % or 95 %, preferably at least 95 %. Non-limiting examples include 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 95 %, 96 %, 97 %, 98 %, 99 % and 100 %. Unless specifically mentioned, the percentage of identity expressed herein such as in the expression “% identical” is with respect to the entire length of the sequence.

[0133] The term “liver metastases” or the plural form “liver metastases” refer to cancer cells that have spread from a primary (original) site to the liver.

[0134] The term “metastasis” or the plural form “metastases” refer to cancer cells that have spread from a primary (original) site to another site.

[0135] The term “minimal residual disease” refers to a small number of residual tumor cells in the body during or after treatment, representing the persistence of the tumor.

[0136] The term "neoadjuvant" refers to treatment that is administered before the primary cancer treatment. A “neoadjuvant” therapy is typically provided before surgery, with the goal of shrinking tumors or rendering them more manageable before the surgical intervention.

[0137] As used herein the term “ortholog” with respect to a particular gene or protein refers to a gene or protein of a distinct species.

[0138] The term “persistence” in the context of tumor(s) or metastasi s(es) refers to remaining tumors or metastases after treatment or removal.

[0139] The term “reducing persistence” in the context of tumor(s) or metastasis(es) refers to a decrease in the likelihood that the tumor(s) or metastasis(es) to persist. Such reduction is determined on an individual basis or a population basis. As such, the likelihood of persistence may be determined based on available statistic for a particular situation.

[0140] The term “reducing recurrence” in the context of tumor(s) or metastasi s(es) refers to a decrease in the likelihood that the tumor(s) or metastasi s(es) comes back. Such reduction is determined on an individual basis or a population basis. As such, the likelihood of recurrence may be determined based on available statistic for a particular situation. The term “reducing recurrence” encompasses reducing regrowth of tumor(s) or metastasi s(es) after their treatment or ablation or reducing growth of new tumor(s) or metastasi s(es) subsequent to the ablation of tumor(s) or metastasis(es).

[0141] The term “recurrence” in the context of tumor(s) or metastasi s(es) refers to regrowth of tumors or metastases after treatment or growth of new tumor(s) or metastasi s(es) after treatment. The term “recurrence” encompasses regrowth of tumor(s) or metastasi s(es) after their ablation or growth of new tumor(s) or metastasi s(es) subsequent to the ablation of tumor(s) or metastasis(es).

[0142] As used herein the term “single unit dose” or “single-use” refers to a dose or use of a medication that is meant for a single patient, for a single case, single administration (e.g. injection, infusion). A “single unit dose” is generally provided in a single vial or single container.

[0143] The term “specific binding” or “specifically binds” as used herein refers to a non-random binding reaction between two molecules, such as for example between an antibody and an antigen. Specific binding can be characterized in binding affinity, A KD value of <10 '6M (e.g., <5x10 ’7M, <2x10 -7M, <10 -7M, <5x10 '8M, < 2x10 '8M, <10 '8M, <5x10 '9M, <4x10 ’9M, <3x10 ’9M, <2x10 '9M, or <10 '9M and any value <10 '6) can indicate specific binding between a binding agent (e.g., antibody such as single domain antibody) and clusterin (e.g., human clusterin such as human TA-sCLU).

[0144] The term “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. The term “subject” is used herein interchangeably with “individual” or “patient.”

[0145] The term “therapeutically 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.

[0146] The term “therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term "treat" or “treating” for purposes of this disclosure refers to the action of providing a treatment (such as the combination therapy disclosed herein) to a subject. As used herein, the term “treat,” or “treating” refers to any method used to partially or completely alleviate, 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 therapeutically effective in some subjects having the particular disease, disorder, and / or condition but have no effects in others that have nevertheless received treatment.

[0147] It is to be understood herein, that expressions referring to ranges of values in the format such as “from A to B”, include each individual value and any sub-range comprised and including such ranges. For example, the expression “from 1 to 10” includes sub-ranges such as and without limitations, “from 2 to 10”, “from 3 to 10”, “from 4 to 10”, “from 5 to 10”, “from 6 to 10”, “from 7 to 10”, “from 8 to 10”, “from 9 to 10”, “from 2 to 9”, “from 3 to 9”, “from 4 to 9”, “from 5 to 9”, “from 6 to 9”, “from 7 to 9”, “from 8 to 9”, “from 2 to 8”, “from 3 to 8”, “from 4 to 8”, “from 5 to 8”, “from 6 to 8”, “from 7 to 8”, “from 2 to 7”, “from 3 to 7”, “from 4 to 7”, “from 5 to 7”, “from 6 to 7”, “from 2 to 6”, “from 3 to 6”, “from 4 to 6”, “from 5 to 6”, “from 2 to 5”, “from 3 to 5”, “from 4 to 5”, “from 2 to 4”, “from 2 to 3”, and any individual values comprised between and including 1 and 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0148] BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1: Tumor Volume (Day 22) in a Syngeneic CT26 CRC Mouse Model.

[0150] Figure 2: Tumor Weight (Day 26) in a Syngeneic CT26 CRC Mouse Model.

[0151] Figure 3: Premedication and Clinical Management of Infusion Related Reactions.

[0152] Figure 4: Anti-Emetic Prophylactic and Post-Treatment Medication.

[0153] Figure 5: Trial schema.

[0154] Figure 6- Part A to Part C: Schedule of Activities.

[0155] Figure 7: Histopathological response scoring scheme.

[0156] Figure 8A: Graphic showing carcinoembryonic Antigen (CEA) levels (ug / L) as measured during the course of treatment for patient 001. Figure 8B: Graphic showing CEA levels (ug / L) as measured during the course of treatment for patient 004.

[0157] Exemplary embodiments of anti-clusterin antibodies or antigen binding fragments thereof

[0158] An exemplary embodiment of human clusterin comprises amino acid residues 23-449 of SEQ ID NO:42 or a portion thereof. Amino acid residues 1-22 of human clusterin, which correspond to the signal sequence, are cleaved off during the maturing process. The polypeptide becomes glycosylated in the endoplasmic reticulum and golgi-apparatus and is subsequently cleaved by a furin-like proprotein convertase between Arg227 and Ser228 to produce an N- terminal a-chain and a C-terminal P-chain which are interlinked by disulfide bonds. Finally, mature sCLU is secreted as a heterodimeric complex of two 40-45 kDa subunits (from Philipp Rohne et al., BioMol Concepts 2016;7(l): 1-15).

[0159] The anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable binding to human clusterin or to a portion thereof.

[0160] In an exemplary embodiment, the antibody or antigen binding fragment thereof of the present disclosure may bind to a polypeptide comprising the amino acid sequence set forth in amino acid residues 228 to 449 of SEQ ID NO:42 or to a portion thereof.

[0161] In another exemplary embodiment, the antibody or antigen binding fragment thereof of the present disclosure may bind to a polypeptide comprising the amino acid sequence set forth in amino acid residues 375 to 449 of SEQ ID NO:42 or to a portion thereof.

[0162] In yet another exemplary embodiment, the antibody or antigen binding fragment thereof of the present disclosure may bind to a polypeptide comprising the amino acid sequence set forth in amino acid residues 421 to 443 of SEQ ID NO:42 or to a portion thereof.

[0163] In certain embodiments, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of inhibiting epithelial to mesenchymal transition in carcinoma cells.

[0164] For example, in some embodiments, the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of binding to amino acids 421 and 443 or to an epitope comprised within amino acids 421 and 443 of human clusterin (SEQ ID NO: 42 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).

[0165] Anti-clusterin antibodies or antigen binding fragments thereof of the present disclosure are exemplified in Table 15 or comprise the CDRs, variable regions or full chains exemplified in Table 15

[0166] In some embodiments, the CDRs are identified using methods known to a person skilled in the art and which are reviewed in Antibody Engineering Vol. 2, Chapter 3 by Andrew C.R. Martin, the entire content of which is incorporated herein by reference.

[0167] In particular embodiments, all CDRs are identified using the Kabat definition which is the most commonly used definition (Wu and Kabat, 1970).

[0168] In particular embodiments, all CDRs are identified using the IMGT definition.

[0169] In particular embodiments, all CDRs are identified using the contact definition (MacCallum et al., 1996) which is likely to be the most useful for people wishing to perform mutagenesis to modify the affinity of an antibody since these are residues which take part in interactions with antigen.

[0170] In particular embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13.

[0171] In some exemplary embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 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.

[0172] In some exemplary embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6.

[0173] In some exemplary embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO: 7, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:8, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:9.

[0174] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 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 or as set forth in SEQ ID NO: 7, a CDRH2 having the amino acid sequence set forth in SEQ ID NO: 5 or as set forth in SEQ ID NO: 8, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6 or as set forth in SEQ ID NO:9.

[0175] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0176] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO: 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.

[0177] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0178] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing with an antibody comprising a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 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:42 or a portion thereof (amino acid sequence 421-443).

[0179] In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to 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% identical to 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.

[0180] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 13.

[0181] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 13.

[0182] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 13.

[0183] In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to 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 at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to 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. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0184] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence identical the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 15.

[0185] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is capable of competing with an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 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:42 or a portion thereof.

[0186] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is an antibody or antigen binding fragment thereof that is capable of competing with an anti-clusterin antibody or antigen binding fragment thereof of the present disclosure for the binding of a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:42 or a portion thereof.

[0187] In yet further particular embodiments, the anti-clusterin antibody or antigen binding fragment thereof may be able to compete with one or more of the antibody(ies) or antigen binding fragment(s) thereof listed in Table 15.

[0188] A particular embodiment of anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is AB-16B5 (a.k.a., humanized 16B5) comprising two light chains (SEQ ID NO: 14 and two heavy chains (SEQ ID NO: 15).

[0189] In an exemplary embodiment, the present disclosure more specifically relates to an antibody or antigen binding fragment thereof that 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 a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:42 or a portion thereof.

[0190] Exemplary embodiments of antibodies or antigen binding fragment thereof that competes with AB-16B5 (humanized 16B5) includes for example and without limitations, antibodies identified as 16B5 (i.e., murine 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 15.

[0191] In particular embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO:30 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO:31.

[0192] In some exemplary embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 19, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:20, a CDRL3 having the amino acid sequence set forth in SEQ ID NO:21.

[0193] In some exemplary embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:22, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:23, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:24.

[0194] In some exemplary embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:25, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:26, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:27.

[0195] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO: 19, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:20, a CDRL3 having the amino acid sequence set forth in SEQ ID NO:21 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:22 or as set forth in SEQ ID NO:25, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:23 or as set forth in SEQ ID NO:26, and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:24 or as set forth in SEQ ID NO:27.

[0196] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO:28 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% identical to the amino acid sequence set forth in SEQ ID NO:29.

[0197] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:28 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:29.

[0198] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:28 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:29.

[0199] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO:30 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% identical to the amino acid sequence set forth in SEQ ID NO:31.

[0200] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:30 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:31. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:30 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:31.

[0201] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO:32 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO:33.

[0202] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:32 and a heavy chain having an amino acid sequence at least 90% identity with the amino acid sequence set forth in SEQ ID NO:33.

[0203] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:32 and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:33.

[0204] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO:36 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% identical to the amino acid sequence set forth in SEQ ID NO:37.

[0205] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:36 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:37. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:36 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:37.

[0206] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO:38 or in SEQ ID NO:39 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% identical to the amino acid sequence set forth in SEQ ID NO:40.

[0207] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO:38 or in SEQ ID NO:39 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:40.

[0208] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:38 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:40.

[0209] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:39 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO:40.

[0210] Variations within one or more of the CDR(s), one or more of the framework regions and / or one or more of the variable regions are also contemplated as described herein.

[0211] In some embodiments, the antibody heavy chain may comprise amino acids residues of a constant region of an IgGl, IgG2, IgG3 or IgG4 subtype including for example, constant region of naturally occurring human IgGl, IgG2, IgG3 or IgG4. In certain embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a human IgGl constant region or a portion thereof.

[0212] In certain embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a human IgG2 constant region or a portion thereof.

[0213] In certain embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a human IgG3 constant region or a portion thereof.

[0214] In certain embodiments, the anti-clusterin antibody or antigen binding fragment thereof comprises a human IgG4 constant region or a portion thereof.

[0215] Variations within the constant region are also contemplated as described herein.

[0216] Exemplary embodiments of variants

[0217] Variants of the sequences disclosed herein are also encompassed by the present disclosure. Such variants include analogs or orthologs. The present disclosure therefore encompasses variants of the antibody or antigen binding fragments disclosed herein.

[0218] The variation may occur in a variable region of the antibody (including in one or more of the framework regions and / or CDRs) or in a constant region. Typically, variation in one or more framework regions of the antibody may be introduced without significantly affecting the antibody activity in a negative manner.

[0219] Variations include amino acid substitution, addition or deletion. In some instances, the present disclosure encompasses antibody variants having one, two, three, four, five, six, seven, eight, nine, ten, and up to twenty-five amino acid substitution in the light chain variable domain and / or in the heavy chain variable domain. Such substitution includes conservative or nonconservative amino acid substitutions. In an exemplary embodiment, an antibody variant will contain conservative amino acid substitutions and non-conservative amino acid substitutions.

[0220] For example, naturally occurring residues are divided into groups based on common side chain properties. Conservative substitutions may be made by exchanging an amino acid from one of the groups listed below (group 1 to 6) for another amino acid of the same group. Nonconservative substitutions will entail exchanging a member of one of these groups for another. (group 1) hydrophobic: norleucine, methionine (Met), Alanine (Ala), Valine (Vai), Leucine (Leu), Isoleucine (He)

[0221] (group 2) neutral hydrophilic: Cysteine (Cys), Serine (Ser), Threonine (Thr), Asparagine (Asn), Glutamine (Gin),

[0222] (group 3) acidic: Aspartic acid (Asp), Glutamic acid (Glu)

[0223] (group 4) basic: Histidine (His), Lysine (Lys), Arginine (Arg)

[0224] (group 5) residues that influence chain orientation: Glycine (Gly), Proline (Pro); and

[0225] (group 6) aromatic: Tryptophan (Trp), Tyrosine (Tyr), Phenylalanine (Phe)

[0226] Other exemplary embodiments of conservative substitutions are shown in Table 1 under the heading of "preferred substitutions". If such substitutions result in an undesired property, then more substantial changes, denominated "exemplary substitutions" in Table 1, or as further described below in reference to amino acid classes, may be introduced and the products screened.

[0227] One of skill in the art will recognize that certain amino acids are less positively charged, are neutral, are negatively charged or have a reduced charge in comparison to other amino acids. Amino acids can be categorized based on net charge as indicated by an amino acid’s isoelectric point. The isoelectric point is the pH at which the average net charge of the amino acid molecule is zero. When pH>pI, an amino acid has a net negative charge, and when the pH<pI, an amino acid has a net positive charge. In some embodiments, the measured pl value for an antibody is between about 3 and 9 (e.g. 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, and 9) and any values in between. In some embodiments, the measured pl value for an antibody is between about 4 and 7 (e.g. 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0), and any values in between. Exemplary isoelectric points of amino acids are shown in Table 1 below. Generally amino acids with positive electrically charged side chains include, for example, Arginine (R), Histidine (H), and Lysine (K). Amino acids with negative electrically charged side chains include, for example, Aspartic Acid (D) and Glutamic Acid (E). Amino acids with polar properties include, for example, Serine (S), Threonine (T), Asparagine (N), Glutamine (Q), and Cysteine (C), Tyrosine (Y) and Tryptophan (W). Non-polar amino acids include, for example, Alanine (A), Valine (V), Isoleucine (I), Leucine (L), Methionine (M), Phenylalanine (F), Glycine (G) and Proline (P). In some embodiments, the isoelectric point of an antibody is modified via amino acid substitution. See, e.g. US20110076275. In some embodiments, modifying the isoelectric point of a polypeptide comprising an antibody results in a change in the antibody’s half-life.

[0228] Table 1. Exemplary amino acid substitutions

[0229] Generally, the degree of similarity and identity between variable chains is determined herein using the Blast2 sequence program (Tatiana A. Tatusova, Thomas L. Madden (1999), "Blast 2 sequences - a new tool for comparing protein and nucleotide sequences", FEMS Microbiol Lett. 174:247-250) using default settings, i.e., blastp program, BLOSUM62 matrix (open gap 11 and extension gap penalty 1; gapx dropoff 50, expect 10.0, word size 3) and activated filters.

[0230] Percent identity will therefore be indicative of amino acids which are identical in comparison with the original peptide and which may occupy the same or similar position.

[0231] Percent similarity will be indicative of amino acids which are identical and those which are replaced with conservative amino acid substitution in comparison with the original peptide at the same or similar position.

[0232] Variants of the present disclosure may therefore comprise a sequence that is at least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical with that of an original or reference sequence or a portion of an original sequence.

[0233] In an exemplary embodiment, mutations in one or more CDR(s), variable region or constant region may be performed by amino acid substitution. Exemplary embodiments of substitutions include conservative amino acid substitutions or non-conservative amino acid substitutions. Exemplary substitutions are provided in Table 1.

[0234] In some embodiments, polypeptide chains having an amino acid sequence which is at least 75%, 80% 85%, 90%, 95%, 99% identical or less than 100% identical to a given amino acid sequence, may have amino acid substitutions, additions or deletions that are generally located outside of the complementarity determining regions.

[0235] In some embodiments, a variant may have at least 80% sequence identity with a sequence disclosed herein. In other embodiments, a variant may have at least 85% sequence identity with a sequence disclosed herein. In yet embodiments, a variant may have at least 90% sequence identity with a sequence disclosed herein. In further embodiments, a variant may have at least 95% sequence identity with a sequence disclosed herein. In other embodiments, a variant may have at least 99% sequence identity with a sequence disclosed herein.

[0236] In other embodiments, the variations may occur in the constant region. In an exemplary embodiment, the constant region may be mutated so as to modulate ADCC activity. In another exemplary embodiment, the constant region may be mutated so as to modulate ADCP activity. In another exemplary embodiment, the constant region may be mutated so as to improve ADCP activity. In yet other exemplary embodiment, the constant region may be mutated so as to improve internalization. In yet other exemplary embodiment, the constant region may be mutated so as to improve stability.

[0237] Exemplary and non-limiting embodiments of mutations in the constant region (e.g., Fc region) that improves one or more effector functions are encompassed by the present disclosure, exemplary embodiments of which, are provided in the Table 2 (List of Mutations Antibodies (Basel). 2020 Nov 17;9(4):64, the entire content of which is incorporated herein by reference).

[0238] Table 2

[0239] Pharmaceutical composition, dosage and article of manufacturing The present disclosure therefore provides a pharmaceutical composition comprising an anticlusterin antibody or an antigen binding fragment thereof and a pharmaceutically acceptable carrier. In some embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is formulated for intra-venous administration. The anti-clusterin antibody or an antigen binding fragment thereof is provided, for example, as an injectable solution at a concentration of 10 mg / mL.

[0240] The present disclosure provides for the administration of a therapeutically effective dose of an anti-clusterin antibody or an antigen binding fragment thereof.

[0241] In some instances, the dose of the anti-clusterin antibody or an antigen binding fragment thereof is adjusted for the patient’s weight.

[0242] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is provided in one or more fixed dose(s) independent of the patient’s weight.

[0243] The anti-clusterin antibody or an antigen binding fragment thereof may be administered once per week or less frequently.

[0244] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered at dose of between approximately 3 mg / kg to approximately 20 mg / kg.

[0245] Accordingly, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of between approximately 3 mg / kg and approximately 20 mg / kg, such as for example, between approximately 4 mg / kg and approximately 20 mg / kg, between approximately 5 mg / kg and approximately 20 mg / kg, between approximately 6 mg / kg and approximately 20 mg / kg, between approximately 6 mg / kg and approximately 18 mg / kg, between approximately 6 mg / kg and approximately 17 mg / kg, between approximately 6 mg / kg and approximately 16 mg / kg, between approximately 6 mg / kg and approximately 15 mg / kg, between approximately 6 mg / kg and approximately 14 mg / kg, between approximately 6 mg / kg and approximately 13 mg / kg, between approximately 6 mg / kg and approximately 12 mg / kg, between approximately 7 mg / kg and approximately 18 mg / kg, between approximately 7 mg / kg and approximately 17 mg / kg, between approximately 7 mg / kg and approximately 16 mg / kg, between approximately 7 mg / kg and approximately 15 mg / kg, between approximately 7 mg / kg and approximately 14 mg / kg, between approximately 7 mg / kg and approximately 13 mg / kg, between approximately 7 mg / kg and approximately 12 mg / kg, between approximately 8 mg / kg and approximately 18 mg / kg, between approximately 8 mg / kg and approximately 17 mg / kg, between approximately 8 mg / kg and approximately 16 mg / kg, between approximately 8 mg / kg and approximately 15 mg / kg, between approximately 8 mg / kg and approximately 14 mg / kg, between approximately 8 mg / kg and approximately 13 mg / kg, between approximately 8 mg / kg and approximately 12 mg / kg, between approximately 9 mg / kg and approximately 18 mg / kg, between approximately 9 mg / kg and approximately 17 mg / kg, between approximately 9 mg / kg and approximately 16 mg / kg, between approximately 9 mg / kg and approximately 15 mg / kg, between approximately 9 mg / kg and approximately 14 mg / kg, between approximately 9 mg / kg and approximately 13 mg / kg, between approximately 9 mg / kg and approximately 12 mg / kg, between approximately 10 mg / kg and approximately 18 mg / kg, between approximately 10 mg / kg and approximately 17 mg / kg, between approximately 10 mg / kg and approximately 16 mg / kg, between approximately 10 mg / kg and approximately 15 mg / kg, between approximately 10 mg / kg and approximately 14 mg / kg, between approximately lOmg / kg and approximately 13 mg / kg, or between approximately 10 mg / kg and approximately 12 mg / kg.

[0246] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 3.0 mg / kg or at a dose of 3.0 mg / kg.

[0247] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 4.0 mg / kg at a dose of 4.0 mg / kg.

[0248] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 5.0 mg / kg or at a dose of 5.0 mg / kg.

[0249] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 6.0 mg / kg or at a dose of 6.0 mg / kg.

[0250] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 7.0 mg / kg or at a dose of 7.0 mg / kg.

[0251] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 8.0 mg / kg or at a dose of 8.0 mg / kg.

[0252] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 9.0 mg / kg or at a dose of 9.0 mg / kg.

[0253] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 10.0 mg / kg or at a dose of 10.0 mg / kg. In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 11.0 mg / kg or at a dose of 11.0 mg / kg.

[0254] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 12.0 mg / kg or at a dose of 12.0 mg / kg.

[0255] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 13.0 mg / kg or at a dose of 13.0 mg / kg.

[0256] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 14.0 mg / kg or at a dose of 14.0 mg / kg.

[0257] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 15.0 mg / kg or at a dose of 15.0 mg / kg.

[0258] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 16.0 mg / kg or at a dose of 16.0 mg / kg.

[0259] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 17.0 mg / kg or at a dose of 17.0 mg / kg.

[0260] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 18.0 mg / kg or at a dose of 18.0 mg / kg.

[0261] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 19.0 mg / kg or at a dose of 19.0 mg / kg.

[0262] In some embodiments, the anti-clusterin antibody or antigen binding fragment thereof is administered at a dose of approximately 20.0 mg / kg or at a dose of 20.0 mg / kg.

[0263] In other instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered in one or more fixed dose(s) selected between approximately 400 mg to approximately 1000 mg.

[0264] In some embodiments, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is selected amongst approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0265] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 1000 mg. In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 950 mg.

[0266] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 900 mg.

[0267] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 850 mg.

[0268] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 800 mg.

[0269] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 750 mg.

[0270] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 700 mg.

[0271] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 650 mg.

[0272] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 600 mg.

[0273] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 550 mg.

[0274] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 500 mg.

[0275] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 450 mg.

[0276] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 400 mg.

[0277] In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 350 mg. In some instances, the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 300 mg.

[0278] The anti-clusterin antibody or an antigen binding fragment thereof is provided in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of between approximately 800 mg to approximately 400 mg.

[0279] In some instances, all doses are approximately 800 mg.

[0280] The anti-clusterin antibody or an antigen binding fragment thereof is provided in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of approximately 600 mg and / or of approximately 450 mg.

[0281] In addition to the active ingredients, a pharmaceutical composition may contain pharmaceutically acceptable carriers comprising water, PBS, salt solutions, gelatins, oils, alcohols, and other excipients and auxiliaries that facilitate processing of the active compounds into preparations that may be used pharmaceutically. In other instances, such preparations may be sterilized.

[0282] As used herein, "pharmaceutical composition" includes a therapeutically effective amounts of the agent (e.g., anti-clusterin antibody or antigen binding fragment thereof, or antineoplastic agent) together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvant and / or carriers.

[0283] Such compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g., Tris-HCl., acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts). Solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, etc., or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g., pol oxamers or pol oxamines). Other embodiments of the compositions of the invention incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal, oral, vaginal, rectal routes.

[0284] In some embodiments the pharmaceutical composition is formulated for administration parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially or intratumorally.

[0285] The present disclosure also relates to an article of manufacture comprising one or more vial(s) or container(s) (e.g., infusion bottle) containing a pharmaceutical composition of the anticlusterin antibody or an antigen binding fragment thereof formulated for administration at a fixed dose amount selected between approximately 400 mg to approximately 1000 mg. The article of manufacturing comprises the number of vials or container(s) necessary to provide one fixed dose amount of the anti-clusterin antibody or antigen binding fragment thereof. The article of manufacturing may comprise more than one fixed dose amount of the anti-clusterin antibody or antigen binding fragment thereof. In some embodiments, the article of manufacturing is for singleuse.

[0286] In some embodiments, the article of manufacture is a vial or a container (e.g., infusion bottle) containing a pharmaceutical composition of the anti-clusterin antibody or an antigen binding fragment thereof.

[0287] Injection vials typically have a capacity of between 6 to 100 mL whereas infusion bottles typically have a capacity of between 70 and 500 mL. Generally, all vials or containers of a given production line essentially have the same volume.

[0288] A dose of 800 mg of a solution at a concentration 10 mg / mL will require one or more vial(s) or container(s) that can fit a total of at least 80 mL. A dose of 800 mg may therefore be provided as 8 vials each containing approximately 10 mL of the solution, 4 vials each containing approximately 20 mL of the solution, 2 vials each containing approximately 40 mL of the solution, one vial containing approximately 80 mL of the solution. In the case of administration by infusion, it may be advantageous that the fixed-dose be provided in a single vial or container such as an infusion bottle.

[0289] During manufacturing, a small amount of the excess solution is generally added as overfill to ensure that the dose volume is fully extractable from the vial or container. Therefore, it is to be understood herein that the vial or container may contain a larger volume than the volume stated for the single dose unit.

[0290] The article of manufacture of the present disclosure comprises one or more vial(s) or container(s) comprising a fixed dose amount of approximately 800 mg, approximately 600 mg and / or approximately 450 mg of the anti-clusterin antibody or antigen binding fragment thereof.

[0291] Accordingly in some embodiments, the article of manufacture may comprise a fixed dose of approximately 800 mg of the anti-clusterin antibody or antigen binding fragment thereof provided as a single unit dose.

[0292] In other embodiments, the article of manufacture may comprise a fixed dose of approximately 600 mg of the anti-clusterin antibody or antigen binding fragment thereof provided as a single unit dose.

[0293] In yet other embodiments, the article of manufacture may comprise a fixed dose of approximately 450 mg of the anti-clusterin antibody or antigen binding fragment thereof provided as a single unit dose.

[0294] The article of manufacture may further comprise vials or containers containing the one or more antineoplastic agent(s) to be administered with the anti-clusterin antibody or antigen binding fragment thereof.

[0295] The present disclosure also relates to a unit dose form comprising one or more single unit doses of an anti-clusterin antibody or antigen binding fragment thereof.

[0296] In some embodiments, the unit dose form is a package (e.g., unit package) comprising one or more single unit doses of the anti-clusterin antibody or antigen binding fragment thereof. The package may further comprise instructions for the use of the anti-clusterin antibody or antigen binding fragment thereof.

[0297] The package may also comprise one or more single unit doses of the one or more antineoplastic agent(s) to be administered with the anti-clusterin antibody or antigen binding fragment thereof. Accordingly, the package may further comprise instructions for the use of the antineoplastic agents in combination with the anti-clusterin antibody or antigen binding fragment thereof.

[0298] In some embodiments the single unit dose comprises a fixed dose amount of selected between approximately 400 mg to approximately 1000 mg. In particular embodiments, the single unit dose comprises a fixed dose amount of approximately 800 mg. In other particular embodiments, the single unit dose comprises a fixed dose amount of approximately 600 mg. In yet other particular embodiments, the single unit dose comprises a fixed dose amount of approximately 450 mg.

[0299] In some embodiments, the single unit dose is provided in a single vial or container. In other embodiments, the single unit dose is provided in one or more vial(s) or container(s). In some embodiments, the single unit dose is for single-use or single administration.

[0300] Exemplary embodiments of subjects

[0301] In some embodiments, the subject is preferably a human subject.

[0302] In exemplary embodiments, the subject is a subject having cancer. In some embodiments the subject may have, for example, colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer (non-small cell lung cancer), gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0303] In a particular embodiment, the subject has or is selected for having colon carcinoma.

[0304] In certain embodiments, the subject has or is selected for having a stage III colon carcinoma. In certain embodiments, the subject has or is selected for having a stage IV colon carcinoma.

[0305] In a particular embodiment, the subject has or is selected for having a rectal adenocarcinoma.

[0306] In certain embodiments, the subject has or is selected for having a stage III rectal adenocarcinoma. In certain embodiments, the subject has or is selected for having a stage IV rectal adenocarcinoma. In some embodiments, the subject may have one or more tumors that are partially resectable or resectable.

[0307] In some embodiments, the subject has or is selected for having one or more metastases. The subject may preferably have or may be selected for having one or more partially resectable or resectable metastases. The subject may have or may be selected for having a metastasis amenable for biopsy.

[0308] The subject may have, for example, liver-dominant metastases Accordingly, the subject may have at least one or multiple liver metastases.

[0309] In some embodiments, the subject is a candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

[0310] In some embodiments, the subject may have had resection of their primary colon or rectal adenocarcinoma in the past.

[0311] In some embodiments, the subject may have a partially resectable or resectable primary cancer.

[0312] In some embodiments, the subject may have received prior chemotherapy for metastatic disease or not. In some embodiments, the subject is selected for not having received prior chemotherapy for metastatic disease.

[0313] In some embodiments, the subject may have received prior adjuvant chemotherapy and / or radiotherapy following resection of primary tumor or not.

[0314] In some embodiments, the subject has or is selected for having at least one measurable lesion according to RECIST 1.1 ((Eisenhauer, E.A., et al., European Journal of Cancer 45:228-247 (2009)).

[0315] Preferably, the subject should have recovered from the toxic effects resulting from the most recent cancer treatment to Grade 1 or less or from the complications and / or toxicity of major surgery before being considered for treatment with the combination therapy described herein.

[0316] In some embodiments, the subject is selected for having a life expectancy of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or more than one year.

[0317] In some embodiments, the subject has or is selected for having adequate organ and / or immune function.

[0318] In some embodiments, the subject has or is selected for having a functional immune system.

[0319] In some embodiments, the subject has or is selected for having one or more lesions that are immunologically cold.

[0320] In some embodiments, the subject is or selected for being immunocompetent.

[0321] In some embodiments, the subject has or is selected for not being immunosuppressed.

[0322] In some embodiments, 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.

[0323] In accordance with the present disclosure, the subject in need has a tumor that expresses or secrete clusterin.

[0324] In some embodiments, 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.

[0325] In some embodiments, the subject may optionally have not received concurrent administration of anti-VGFR, anti-EGFR, anti-VEGF or other biological or targeted therapy with neoadjuvant FOLFOX.

[0326] In some embodiments, the subject may optionally be selected for not having a defective DNA mismatch repair (MMR-deficient) primary colorectal tumor.

[0327] In some embodiments, the subject may optionally be selected for not having hereditary colorectal cancer such as for example, familial colonic polyposis or Lynch syndrome. In some embodiments, the subject may optionally be selected for not having another malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer.

[0328] In some embodiments, the subject may optionally be selected for not being expected to require any other form of systemic or localized antineoplastic therapy while on the trial. This includes maintenance therapy with another agent or radiation therapy.

[0329] In some embodiments, the subject may optionally be selected for not receiving a dose > 10 mg / day of prednisone (or equivalent) within 7 days prior to the first dose of study treatment or any other form of immunosuppressive medication.

[0330] In some embodiments, the subject may optionally be selected for not having a pre-existing peripheral sensitive neuropathy with functional impairment.

[0331] In some embodiments, the subject may optionally be selected for not having clinically significant electrocardiogram (ECG) abnormalities.

[0332] In some embodiments, the subject may optionally be selected for not having received or to receive a live vaccine with 30 days prior to the first dose of trial treatment.

[0333] In some embodiments, the subject may optionally be selected for not having a known history of human immunodeficiency (HIV).

[0334] In some embodiments, the subject may optionally be selected for not having an active Hepatitis B or C infection.

[0335] In some embodiments, the subject may optionally be selected for not having an active infection requiring antibiotic therapy.

[0336] In some embodiments, the subject may optionally be selected for not having a known history of alcohol or other substance abuse within the last year.

[0337] In some embodiments, the subject may optionally be selected for not having a known hypersensitivity to FOLFOX.

[0338] In some embodiments, the subject may optionally be selected for not being pregnant or lactating or who are not expecting to conceive or father children within the projected duration of treatment through 90 days after the last dose of AB-16B5 or 180 days after the last dose of FOLFOX.

[0339] Exemplary embodiments of antineoplastic agents

[0340] Examplary embodiments of antineoplastic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK7; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'=-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0341] Particular embodiments of antineoplastic agents include for example, altretamine, busulfan, carboplatin, oxaliplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5-fluorouracil, 6-mercaptopurine, azacytidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, vincristine, vinblastine, vinorelbine, taxanes (paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel), etoposide, teniposide, irinotecan, topotecan, daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, valrubicin, capecitabine or leucovorin.

[0342] In some embodiments, antineoplastic agents are provided as a chemotherapeutic combination for administration together with the anti-clusterin antibody or antigen binding fragment disclosed herein. Selected antineoplastic agents include 5-fluorouracil (5-FU), oxaliplatin, leucovorin, capecitabine and irinotecan.

[0343] In some instances, the chemotherapeutic combination comprises at least one antineoplastic agent amongst 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0344] In some instances, the chemotherapeutic combination comprises at least two antineoplastic agents amongst 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0345] In some instances, the chemotherapeutic combination comprises at least three antineoplastic agents amongst 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan. In some instances, the chemotherapeutic combination comprises at least four antineoplastic agents amongst 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0346] In some embodiments, the chemotherapeutic combination comprises at least 5- fluorouracil.

[0347] In some embodiments, the chemotherapeutic combination comprises oxaliplatin, leucovorin and 5-fluorouracil.

[0348] The antineoplastic agent may be used in a therapeutically effective amount suitable for treating a given condition.

[0349] CAPECITABINE: Capecitabine, 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, is an antineoplastic agent used for example, for treatment of colorectal cancer and breast cancer. Capecitabine is converted into 5 -Fluorouracil in the body. Generally, the dose of capecitabine is between approximately 1000 mg / m2to 2000 mg / m2(usually 1000 mg / m2taken twice daily (per os (PO) morning and evening). In some embodiments, the dose of capecitabine is approximately 500 mg / m2, approximately 600 mg / m2, approximately 700 mg / m2, approximately 800 mg / m2, approximately 900 mg / m2, approximately 1000 mg / m2, approximately 1100 mg / m2, approximately 1200 mg / m2, approximately 1300 mg / m2, approximately 1400 mg / m2, approximately 1500 mg / m2, approximately 1600 mg / m2, approximately 1700 mg / m2, approximately 1800 mg / m2, approximately 1900 mg / m2, approximately 2000 mg / m2, approximately 2100 mg / m2, approximately 2200 mg / m2, approximately 2300 mg / m2, approximately 2400 mg / m2, or approximately 2500 mg / m2.

[0350] 5-FLUOROURACIL: 5-FU, 5-fluoro-2,4-(lH,3H) pyrimidinedione is an antineoplastic agent used as a single agent or in combination with other antineoplastic agents (chemotherapeutic combination) in the treatment of carcinomas, such as for example, breast cancer, colon cancer, rectal cancer, stomach cancer and pancreas cancer. Other fluoropyrimidine analogs include 5- fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate. In some embodiments, the dose of 5-Fluorouracil (5-FU) is initially between approximately 200 mg / m2to approximately 500 mg / m2. Generally, the initial dose of 5-FU is approximately 400 mg / m2and is administered intravenously (IV) and often taken once per cycle of 14 days. In some embodiments, 5- fuorouracil is administered at a dose of 400 mg / m2, IV bolus (IV push) after leucovorin and then at a dose of 2400 mg / m2IV continuous infusion over 46 hours (5mL / h). In case of toxicity, the dose of fluorouracil may be reduced for example by 20% or may be reduced for example, from 400 mg / m2to 320 mg / m2or 200 mg / m2, or from 2400 mg / m2to 2000 mg / m2or 1600 mg / m2.

[0351] In some embodiments, the dose of 5-FU is approximately 100 mg / m2, approximately 150 mg / m2, approximately 200 mg / m2, approximately 250 mg / m2, approximately 300 mg / m2, approximately 350 mg / m2, approximately 400 mg / m2, approximately 450 mg / m2, approximately 500 mg / m2or approximately 550 mg / m2.

[0352] In some embodiments, the dose of 5 -Fluorouracil (5-FU) is subsequently between approximately 1600 mg / m2to approximately 3000 mg / m2. Generally, the subsequent dose of 5-FU is administered by continuous intravenous infusion (CIVI) at a dose of approximately 2400 mg / m over approximately 46 hours once per cycle of 14 days. In some embodiments, the subsequent dose of 5-FU is approximately 1000 mg / m2, approximately 1100 mg / m2, approximately 1200 mg / m2, approximately 1300 mg / m2, approximately 1400 mg / m2, approximately 1500 mg / m2, approximately 1600 mg / m2, approximately 1700 mg / m2, approximately 1800 mg / m2approximately 1900 mg / m2, approximately 2000 mg / m2, approximately 2100 mg / m2approximately 2200 mg / m2, approximately 2300 mg / m2, approximately 2400 mg / m2approximately 2500 mg / m2, approximately 2600 mg / m2, approximately 2700 mg / m2approximately 2800 mg / m2, approximately 2900 mg / m2, approximately 3000 mg / m2approximately 3100 mg / m2, approximately 3200 mg / m2, approximately 3300 mg / m2approximately 3400 mg / m2, or approximately 3500 mg / m2.

[0353] IRINOTECAN: Irinotecan HC1, (4S)-4,1 l-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-lH-pyrano[3',4',6,7]indolizino[l,2-b]quinoline-3,14(4H,12H)-dione hydrochloride is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I-DNA complex. Irinotecan is an antineoplastic agent used for example, for the treatment of metastatic cancer of the colon or rectum and small cell lung cancer. Generally, the dose of irinotecan is between approximately 150 mg / m2to approximately 180 mg / m2. Generally, irinotecan is administered intravenously (IV) once per cycle of 14 days. In some embodiments, the dose of irinotecan is approximately 100 mg / m2, approximately 110 mg / m2, approximately 120 mg / m2, approximately 130 mg / m2, approximately 140 mg / m2, approximately 150 mg / m2, approximately 160 mg / m2, approximately 170 mg / m2, approximately 180 mg / m2, approximately 190 mg / m2, approximately 200 mg / m2.

[0354] OXALIPLATIN: (SP-4-2)-[(lR,2R)-l,2-cyclohexanediamine-N,N'] [ethane-dioato(2-)- 0,0'] platinum, is an antineoplastic agent used for example, for treatment of colorectal cancer, pancreatic cancer, gastric cancer by intravenous infusion and generally in combination with other antineoplastic agents. In some embodiments, the dose of oxaliplatin is between approximately 50 mg / m2to approximately 130 mg / m2. Generally, oxaliplatin is administered intravenously (IV) at a dose of approximately 85 mg / m once per cycle of 14 days. In some embodiments, oxaliplatin is administered at a dose of 85 mg / m2IV in 250-500 mL D5W over 120 minutes. In case of toxicity, the dose of oxaliplatin may be decreased for example to 75 mg / m2, 65 mg / m2or 50 mg / m2. In case of persistent neurotoxicity (> grade 3 or grade 4) oxaliplatin may be discontinued. In some embodiments, the dose of oxaliplatin is approximately 20 mg / m2, approximately 30 mg / m2, approximately 40 mg / m2, approximately 50 mg / m2, approximately 60 mg / m2, approximately 70 mg / m2, approximately 80 mg / m2, approximately 90 mg / m2, approximately 100 mg / m2, approximately 110 mg / m2, approximately 120 mg / m2, approximately 130 mg / m2, approximately 140 mg / m2, approximately 150 mg / m2. Oxaliplatin may be administered, for example, as IV bolus or as intravenous infusion (IVI).

[0355] LEUCOVORIN: Leucovorin is an antineoplastic agent and one of several active, chemically reduced derivatives of folic acid. It is also known as calcium folinate or 5-formyl tetrahydrofolic acid and is used for example, to increase levels of folic acid under conditions favoring folic acid inhibition and is known to enhance the activity of fluorouracil. It is provided for intramuscular injection or intravenous injection. Commercially available leucovorin is usually composed of a 1 : 1 racemic mixture of the dextrorotary and levorotary isomers but the levo-isomer known as levoleucovorin is also available. Generally, the dose of leucovorin is between approximately 200 mg / m2to approximately 500 mg / m2. Generally, leucovorin is administered intravenously (IV) at a dose of approximately 400 mg / m2once per cycle of 14 days. In some embodiments, leucovorin is administered at a dose of 400 mg / m2IV diluted in 250 mL D5W over 120 minutes concurrently with oxaliplatin. Leucovorin may be administered, for example, as IV bolus or as intravenous infusion (IVI). In some embodiments, the dose of leucovorin is approximately 100 mg / m2, approximately 150 mg / m2, approximately 200 mg / m2, approximately 250 mg / m2, approximately 300 mg / m2, approximately 350 mg / m2, approximately 400 mg / m2, approximately 450 mg / m2, approximately 500 mg / m2, approximately 550 mg / m2, approximately 600 mg / m2.

[0356] In some instances, the chemotherapeutic combination is selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX.

[0357] In a particular embodiment, the chemotherapeutic combination is FOLFOX.

[0358] In some embodiments, the FOLFOX regimen comprises administration of oxaliplatin at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) at a dose of between approximately 200 mg / m2to approximately 400 mg / m2followed by at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m2.

[0359] In certain embodiments, the FOLFOX treatment regimen may comprise for example, FOLFOX4.

[0360] In certain embodiments, the FOLFOX treatment regimen may comprise for example, FOLFOX 6.

[0361] In certain embodiments, the FOLFOX treatment regimen may comprise for example, FOLFOX 7.

[0362] In certain embodiments, the FOLFOX treatment regimen may comprise for example, modified FOLFOX 6.

[0363] In certain embodiments, the FOLFOX treatment regimen may comprise for example, modified FOLFOX 7.

[0364] In some embodiments, the FOLFOX regimen comprises oxaliplatin at a dose of approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5- FU) at a dose of approximately 400 mg / m2followed by at a dose of approximately 2400 mg / m2.

[0365] The present application therefore provides a combination therapy comprising an anticlusterin antibody and FOLFOX. In some embodiments, the FOLFIRI regimen comprises leucovorin, 5 -fluorouracil and irinotecan. In exemplary embodiments, the FOLFIRI regimen comprises administration of leucovorin at a dose of approximately 200 mg / m2, irinotecan at a dose of approximately 180 mg / m2and fluorouracil at a dose of approximately 400 mg / m2followed by a dose of approximately 2400 to 3000 mg / m2(Solimando, D. A. et al., Hospital Pharmacy, Vol. 40 (5): 393-398).

[0366] In some embodiments, the FOLFIRINOX regimen comprises leucovorin, irinotecan, oxaliplatin and 5 -fluorouracil.

[0367] In exemplary embodiments, the FOLFIRINOX regimen comprises administration of oxaliplatin at a dose of approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2, irinotecan at a dose of approximately 180 mg / m2and fluorouracil at a dose of approximately 400 mg / m2followed by a dose of approximately 2400 mg / m2(Jao, M.E. et al., JHOP, 2022, vol 12(6), pp. 334-339).

[0368] In some embodiments, the XELOX regimen comprises oxaliplatin at a dose of 130 mg / m2(IV infusion on day 1) and capecitabine 1000 mg / m2 twice daily (per os) on days 1-14 of a 21 days cycle generally for 8 cycles.

[0369] Exemplary embodiments of methods

[0370] The present disclosure provides methods of treating cancer in a human in need thereof comprising administering a therapeutically effective amount of an antibody that binds to human clusterin.

[0371] In some instances, the method is for inhibiting, delaying, and / or reducing recurrence and / or growth of tumor(s) and / or for preventing and / or reducing persistence of tumor(s) in a subject having cancer by administering an antibody or an antigen binding fragment thereof that binds to clusterin at least prior to ablation of the tumor(s).

[0372] In other instances, the method is for inhibiting, delaying, and / or reducing recurrence and / or growth of metastasi s(es) and / or for preventing and / or reducing persistence of metastasi s(es) in a subject having cancer by administering an antibody or an antigen binding fragment thereof that binds to clusterin at least prior to ablation of the metastasis(es).

[0373] The method of the present disclosure may also involve administration of an antineoplastic agent or a chemotherapeutic combination of antineoplastic agents. In some instances, the administration is performed at least prior to ablation of tumor(s) and / or metastasis(es). In other instances, the administration is performed after ablation of the tumor(s) and / or metastasis(es). In yet other instances, the administration is performed prior to and after ablation of the tumor(s) and / or metastasis(es). For example, the anti-clusterin antibody or antigen binding fragment thereof and the antineoplastic agent or chemotherapeutic combination may all be administered prior to ablation, after ablation or before and after ablation of the tumor(s) and / or metastasi s(es). Such administration may involve sequential or simultaneous administration of the antibody of the antineoplastic agent(s).

[0374] In an exemplary embodiment, the method is used for inhibiting recurrence of tumor(s).

[0375] In an exemplary embodiment, the method is used for delaying recurrence of tumor(s).

[0376] In an exemplary embodiment, the method is used for reducing recurrence or reducing the risk of recurrence of tumor(s).

[0377] In an exemplary embodiment, the method is used for inhibiting growth of tumor(s).

[0378] In an exemplary embodiment, the method is used for delaying growth of tumor(s).

[0379] In an exemplary embodiment, the method is used for reducing growth of tumor(s).

[0380] In an exemplary embodiment, the method is used for preventing persistence of tumor(s).

[0381] In an exemplary embodiment, the method is used for reducing persistence of tumor(s).

[0382] In an exemplary embodiment, the method is used for inhibiting recurrence of metastasis(es).

[0383] In an exemplary embodiment, the method is used for delaying recurrence of metastasis(es).

[0384] In an exemplary embodiment, the method is used for reducing recurrence or reducing the risk of recurrence of metastasis(es).

[0385] In an exemplary embodiment, the method is used for inhibiting growth of metastasis(es).

[0386] In an exemplary embodiment, the method is used for delaying growth of metastasi s(es).

[0387] In an exemplary embodiment, the method is used for reducing growth of metastasis(es).

[0388] In an exemplary embodiment, the method is used for preventing persistence of metastasis(es). In an exemplary embodiment, the method is used for reducing persistence of metastasis(es).

[0389] The method of the present disclosure is particularly used for inhibiting, delaying, and / or reducing recurrence and / or growth of tumor(s) and / or liver metastasi s(es) and / or preventing and / or reducing persistence of tumor(s) and / or liver metastasi s(es) subsequent to ablation of the tumors and / or liver metastasis(es) in a subject having colorectal cancer or rectal adenocarcinoma.

[0390] The method of the present disclosure particularly encompasses administering an anticlusterin antibody or an antigen binding fragment thereof and a chemotherapeutic combination comprising more than one antineoplastic agent.

[0391] In an exemplary embodiment, the antibody or an antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as a first-line therapy.

[0392] In another exemplary embodiment, the antibody or an antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as neoadjuvant therapy.

[0393] In some instances, the chemotherapeutic combination may comprise two or more antineoplastic agents and wherein at least one, at least two, at least three, at least four or at least five of the antineoplastic agents is selected from 5 -fluorouracil (5-FU), oxaliplatin, leucovorin, capecitabine or irinotecan. The antineoplastic agent(s) may be used in a therapeutically effective amount suitable for treating a given condition.

[0394] In other aspects, the disclosure provides a method of treating a subject having cancer comprising administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising two or more antineoplastic agents and wherein at least one of the antineoplastic agents is selected from 5-fluorouracil, oxaliplatin, leucovorin, capecitabine or irinotecan.

[0395] In some embodiments, the method of the present disclosure therefore comprises administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising at least one antineoplastic agent selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan. In other embodiments, the method of the present disclosure therefore comprises administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising at least two antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0396] In yet other embodiments, the method of the present disclosure therefore comprises administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising at least three antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0397] In further embodiments, the method of the present disclosure therefore comprises administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising at least four antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.

[0398] In particular embodiments, the method of the present disclosure therefore comprises administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising at least 5- fluorouracil and another antineoplastic agent. For example, the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and 5- FU / leucovorin.

[0399] In other particular embodiments, the method of the present disclosure therefore comprises administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and chemotherapeutic combination comprising oxaliplatin, leucovorin and 5-fluorouracil.

[0400] In some instances, the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and FOLFOX. In a particular embodiment, the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX may be administered as a first-line therapy. In other particular embodiment, the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX may be administered as a neoadjuvant therapy. In some embodiments, the FOLFOX treatment regimen is FOLFOX4, FOLFOX 6 or, FOLFOX 7 or modified versions of the regimen (e.g., modified FOLFOX 6, modified FOLFOX 7).

[0401] An exemplary embodiment of modified FOLFOX 6 includes administration of oxaliplatin via 2-h intravenous infusion (IVI) at a dose of 85 mg / m2. Then, Leucovorin is administered via 2- h IVI at a dose of 400 mg / m2, followed by a 5-FU bolus at a dose of 400 mg / m2on day 1, and then 5-FU is administered via 46 to 48-h IVI a dose of 2400 mg / m2from day 1. Once cycle of modified FOLFOX 6 is 2 weeks.

[0402] In other instances, the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and FOLFIRI.

[0403] In yet other instances, the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and FOLFIRINOX.

[0404] In further instances, the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and XELOX.

[0405] In some embodiments, the method comprises administering at least one cycle of treatment wherein one cycle of treatment consists of approximately 7 days.

[0406] In some embodiments, the method comprises administering at least one cycle of treatment wherein one cycle of treatment consists of approximately 14 days (e.g., 13-16 days).

[0407] In some embodiments, the method comprises administering at least one cycle of treatment wherein one cycle of treatment consists of approximately 21 days.

[0408] In some embodiments, the method comprises administering at least one cycle of treatment wherein one cycle of treatment consists of approximately 28 days or approximately 1 month.

[0409] In some embodiments, the method comprises administering at least one cycle of treatment wherein one cycle of treatment consists of approximately 2, 3, 4, 5 or 6 months.

[0410] The method of the present disclosure comprises administering one or more cycles of treatment to a subj ect in need. Typically, the subj ect is treated for more than one cycle of treatment. In some embodiments, the method comprises administering two, three, four, five, six cycles of treatment. In some embodiments, the method comprises administering more than six cycles of treatment (e.g., seven, eight, nine, ten or more).

[0411] In some embodiments, 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. For example, 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.

[0412] The initial cycle(s) of treatment and subsequent cycle(s) of treatment may also vary in length from one another. For example, the initial cycle(s) of treatment may be 14 days and the subsequent cycle(s) of treatment may be more than 14 days.

[0413] In another example, the initial cycle(s) of treatment may include a given antineoplastic agent or chemotherapeutic combination, while the subsequent cycle(s) of treatment may include a different antineoplastic agent or chemotherapeutic combination.

[0414] In yet another example, the initial cycle(s) of treatment may include a given dose of antineoplastic agent, while the subsequent cycle(s) of treatment may include a different dose of the antineoplastic agent.

[0415] In a particular exemplary embodiment, one cycle of treatment consists in 14 days. In another particular exemplary embodiment, each cycle of treatment consists in 14 days.

[0416] The anti-clusterin antibody or antigen binding fragment thereof may be administered, for example, on day 1 and 8 of each 14 days cycle. The chemotherapeutic combination may be administered, for example, on day 1 of each 14 days cycle.

[0417] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly, once every two weeks, once every three weeks, once monthly.

[0418] In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered once per week.

[0419] In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered once every two weeks. In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered once every three weeks.

[0420] In accordance with the present disclosure, the anti-clusterin antibody or antigen binding fragment thereof is administered once every four weeks.

[0421] It is to be understood herein that the frequency of treatment (i.e., once per week, every two weeks, every three weeks, every four weeks and the like) is not strict and allow some variation. For example, a physician may decide to administer a dose ahead of the schedule or delay the dose by a few days or longer. As well, it is also possible that one or more doses be skipped without affecting treatment.

[0422] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is generally administered once weekly.

[0423] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10, months, at least 11 months, at least 1 year or more.

[0424] In exemplary embodiments, the antibody or an antigen binding fragment thereof that binds to clusterin is administered as neoadjuvant therapy. For instances, the the anti-clusterin antibody or an antigen binding fragment thereof is administered before ablation of the tumor(s) or metastasis(es).

[0425] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks before ablation of the tumor(s) and / or metastasis(es). In particular embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of approximately 12 weeks before ablation of the tumor(s) and / or metastasis(es).

[0426] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten cycles of approximately 2 weeks, before ablation of the tumor(s) or metastasi s(es).

[0427] In particular embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for at least six cycles of 2 weeks before ablation of the tumor(s) and / or metastasis(es).

[0428] In other instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered as an adjuvant therapy. For instances, the the anti-clusterin antibody or an antigen binding fragment thereof is administered after ablation of the tumor(s) or metastasi s(es).

[0429] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks after ablation of the tumor(s) and / or metastasis(es).

[0430] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten cycles of approximately 2 weeks, after ablation of the tumor(s) or metastasis(es).

[0431] In particular embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of at least 12 weeks after ablation of the tumor(s) and / or metastasis(es).

[0432] In yet other instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered for a period of approximately 13, 14, 16, 17, 18, 19 or 20 weeks before and / or after ablation of the tumor(s) or metastasi s(es).

[0433] The anti-clusterin antibody or an antigen binding fragment thereof may be administered for example and without limitations via intravenous infusion.

[0434] In some embodiments, the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof each week for a period of between 1 to at 12 weeks. In some embodiments, the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof each week for more than 12 weeks. In some embodiments, the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof each two weeks for a period of between 1 to at 12 weeks. In some embodiments, the method comprises administering the anti-clusterin antibody or antigen binding fragment thereof each two weeks for more than 12 weeks.

[0435] In some instances, FOLFOX is administered once every two weeks, once every three weeks, once monthly, once every two months.

[0436] In some instances, FOLFOX is generally administered once every two weeks.

[0437] In exemplary embodiments, FOLFOX is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10, months, at least 11 months, at least 1 year or more.

[0438] In some embodiments, FOLFOX may be administered for a period of at least 12 weeks. In other embodiments, FOLFOX may be administered for a period of 12 weeks.

[0439] In some instances, FOLFOX is administered as a neoadjuvant therapy. For instances, FOLFOX is administered before ablation of the tumor(s) or metastasis(es).

[0440] In some instances, FOLFOX is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks before ablation of the tumor(s) and / or metastasis(es).

[0441] In some instances, FOLFOX is administered once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten cycles of approximately 2 weeks before ablation of the tumor(s) or metastasis(es).

[0442] In other instances, FOLFOX is administered as an adjuvant therapy. For instances, FOLFOX is administered after ablation of the tumor(s) or metastasis(es).

[0443] In some instances, FOLFOX is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, after ablation of the tumor(s) or metastasi s(es).

[0444] In some instances, FOLFOX is administered once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten cycles of approximately 2 weeks, after ablation of the tumor(s) or metastasis(es).

[0445] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX combination is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10, months, at least 11 months, at least 1 year or more. Treatment may however be interrupted for a certain period of time.

[0446] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX combination is administered for a period of at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks before ablation of the tumor(s) and / or metastasi s(es).

[0447] In some embodiments, the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX combination is administered for a period of approximately 12 weeks before ablation of the tumor(s) and / or metastasi s(es).

[0448] In some instances, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten cycles of approximately 2 weeks and FOLFOX is administered once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten cycles of approximately 2 weeks.

[0449] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly or once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six cycles of approximately 2 weeks, and FOLFOX is administered once every two weeks for at least one, at least two, at least three, at least four, at least five, at least six cycles of approximately 2 weeks before and / or after ablation of the tumor(s) or metastasis(es).

[0450] In some embodiments, the anti-clusterin antibody or an antigen binding fragment thereof and FOLFOX combination are administered for the same number of cycles.

[0451] In some embodiments, the number of cycles of the anti-clusterin antibody or an antigen binding fragment thereof treatment and FOLFOX treatment are different.

[0452] The method of the present disclosure comprises treating the subject for at least 4 cycles of FOLFOX (cycle 1 to cycle 4) and for at least 6 cycles of the anti-clusterin antibody or an antigen binding fragment thereof (cycle 1 to cycle 6), whereby each cycle is approximately 14 days (approximately two weeks).

[0453] In some embodiments, the method of the present disclosure comprises treating the subject for 4 cycles of FOLFOX (cycle 1 to cycle 4) and for 6 cycles of the anti-clusterin antibody or an antigen binding fragment thereof (cycle 1 to cycle 6), whereby each cycle is approximately 14 days (approximately two weeks).

[0454] In exemplary embodiments, the anti-clusterin antibody or an antigen binding fragment thereof is administered intravenously at a dose of approximately between 400 mg to 1000 mg on day 1 and day 8 of each cycle and FOLFOX is administered on day 1 of cycle 1 to cycle 4 as follows: oxaliplatin at approximately 85 mg / m2IV bolus + leucovorin at approximately 400 mg / m2IV bolus + 5 -Fluorouracil (5-FU) at approximately 400 mg / m2IV bolus + 5-FU at approximately 2400 mg / m2continuous IV infusion over approximately 46 hours.

[0455] In a particular embodiment, the anti-clusterin antibody or an antigen binding fragment thereof is administered intravenously at a dose of approximately 800 mg on day 1 and day 8 of each cycle and FOLFOX is administered on day 1 of cycle 1 to cycle 4 as follows: oxaliplatin at approximately 85 mg / m2IV bolus + leucovorin at approximately 400 mg / m2IV bolus + 5- Fluorouracil (5-FU) at approximately 400 mg / m2IV bolus + 5-FU at approximately 2400 mg / m2continuous IV infusion over approximately 46 hours.

[0456] In some embodiments, the ablation of one or more liver metastasis(es) may be performed at approximately 4 to 6 weeks after cycle 4 of treatment. In some embodiments, the ablation of one or more liver metastasis(es) may be performed later than the 4 to 6 weeks after cycle 4 of treatment. In some instances, the ablation may be performed 2 months, 3 months, 4 months, 5 months, 6 months after treatment or later.

[0457] In some embodiments, the ablation of one or more liver metastasis(es) may be performed approximately 2 to 4 weeks following the last dose of the antibody or an antigen binding fragment thereof that binds to clusterin.

[0458] In some embodiments, the ablation of one or more liver metastasis(es) may be performed later than 2 to 4 weeks following the last dose of the anti-clusterin antibody or an antigen binding fragment thereof. In some instances, the ablation may be performed 2 months, 3 months, 4 months, 5 months, 6 months after the last dose of the anti-clusterin antibody or an antigen binding fragment thereof or later.

[0459] The method of the present disclosure comprises administering a fixed dose of the anticlusterin antibody or antigen binding fragment thereof. The fixed dose of anti-clusterin antibody or antigen binding fragment thereof may be used for single therapy or in combination with one or more antineoplastic agent(s), chemotherapeutic combination or with radiation therapy.

[0460] Accordingly, the method of the present disclosure comprises providing one or more single unit dose of the anti-clusterin antibody or antigen binding fragment thereof and administering a fixed dose amount of the anti-clusterin antibody or antigen binding fragment thereof.

[0461] In some embodiments, the method of the present disclosure comprises administering a fixed dose of the anti-clusterin antibody or antigen binding fragment thereof provided in one or more vial(s) or container(s) for single-use.

[0462] The method of the present disclosure further provides using a single unit dose of the anticlusterin antibody or antigen binding fragment thereof for treatment of a subject in need. The single unit dose comprises a single dose. In some embodiments, a single unit dose of the anti-clusterin antibody or antigen binding fragment thereof is used at each treatment cycles.

[0463] The method of the present disclosure may further comprise administering cellular therapy to the subject. Exemplary embodiments of cellular therapy and methods are provided, for example, in publication No. WO2022 / 226641 the entire content of which is incorporated herein by reference. Accordingly, in certain embodiments, the subject may receive a preparation of tumor infiltrating lymphocytes (TILs). The TILs may be administered subsequent to ablation of the one or more tumors and / or metastasis(es). In some instances, the preparation of tumor infiltrating lymphocytes is obtained from the subject’s metastasi s(es) or tumor (autologous TILs). The TILs preparation may be obtained by isolating and expanding tumor infiltrating lymphocytes.

[0464] The tumor infiltrating lymphocytes may comprise, for example, CD3+PD1+T cells. The administration of TILs may be performed subsequent to lymphodepletion of the subject. In some instances, IL-2 is administered to the subject together with cellular therapy.

[0465] The method of the present disclosure is intended for treating a subject as described herein.

[0466] Accordingly, the method of the present disclosure is intended for treating a subject having a tumor or metastasis that is partially resectable or resectable, a subject that is a candidate to neoadjuvant FOLFOX followed by partial hepatectomy, a subject having a cold tumor, a subject having colorectal cancer (e.g., stage III or stage IV) and / or a subject having a liver metastasis that is partially resectable or resectable.

[0467] The present disclosure also relates to a method for promoting / inducing (formation, enrichment, apparition of) tertiary lymphoid structures (TLS) in the microenvironment of one or more tumors and / or of one or more metastases in a subject in need thereof. The promotion / induction of TLS may be used for the treatment of cancer.

[0468] In some embodiments, the method comprises administering an antibody or antigen binding fragment thereof that binds clusterin.

[0469] In particular embodiments, methods of the present disclosure are carried out with AB-16B5 (a.k.a. humanized 16B5). In particular embodiments, methods of the present disclosure are carried out with AB-16B5 in combination with one or more antineoplastic agents described herein.

[0470] In other embodiments, methods of the present disclosure are carried out in subjects as described herein.

[0471] In some embodiments, the methods of the present disclosure provides one or more clinical benefits. In some embodiments,

[0472] Exemplary embodiments of monitoring / prognosis methods The present disclosure also relates to methods of monitoring response to a treatment that comprises an antibody or an antigen binding fragment thereof that binds to clusterin.

[0473] In some embodiments, the method of monitoring may comprise quantifying the levels of CEA in a sample obtained from the subject. In some embodiments, the sample may be a blood sample. In other embodiments, the sample may be a serum sample.

[0474] In some embodiments, reduction of the levels of CEA compared to base-line (e.g., at screening, before treatment) may be indicative of response to treatment.

[0475] In some embodiments, reduction of the levels of CEA compared to base-line (e.g., at screening, before treatment) may be indicative of at least partial efficacy.

[0476] In other embodiments, reduction of the levels of CEA compared to base-line (e.g., at screening, before treatment) may be indicative of at least partial regression of one or more tumors and / or of one or more metastases.

[0477] In some embodiments, CEA levels is measured in subjects having colorectal cancer, breast cancer, lung cancer, pancreatic cancer, stomach cancer, liver cancer, liver metastasis, ovarian cancer.

[0478] In some embodiments, the method of monitoring may comprise detecting tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases of the subject.

[0479] In some embodiments, the presence of TLS in the tumor microenvironment may be indicative of response to treatment.

[0480] In some embodiments, the abundance of TLS in the tumor microenvironment may be indicative of response to treatment.

[0481] In some embodiments, detection of TLS may be performed by obtaining a biopsy from a tumor or metastasis.

[0482] The present disclosure also relates to a method for prognosis of cancer comprising detecting tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases of a subj ect treated with an antibody or an antigen binding fragment thereof that binds to clusterin. In some embodiments, the presence of tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases is indicative of favorable prognosis.

[0483] In exemplary embodiments, the presence of TLS may be indicative of a favorable clinical response.

[0484] In exemplary embodiments, the presence of TLS may be indicative of increased likelihood of clinical benefit(s).

[0485] In exemplary embodiments, the presence of TLS may be indicative increased likelihood of remission.

[0486] In exemplary embodiments, the presence of TLS may be indicative of increased likelihood of disease-free survival.

[0487] In exemplary embodiments, the presence of TLS may be indicative of increased likelihood overall survival.

[0488] EXAMPLE 1- Evaluation of the Immunostimulatory Efficacy of Murine Anti-sCLU Antibody 16B5 in Combination with Fluorouracil / Oxaliplatin in a Mouse CT26 Syngeneic Model of Colorectal Cancer

[0489] An internally developed protocol with the CT26 mouse syngeneic model of colorectal cancer was used to evaluate the ability of the murine anti-TA sCLU 16B5 mAb (murine 16B5) in combination with FOX to stimulate an immune response. Briefly, this model consists of implanting a number of CT26 murine colorectal carcinoma cells directly into the liver which in turn permits their metastasis at the usual sites observed in advanced CRC (e.g., lung, peritoneal and surrounding liver). The objectives of the study were to determine if the combination of 16B5 and FOX would reduce the capacity of the CT26 tumor to metastasize locally and at distant sites and increase response to treatment with FOX as well as to isolate tumor infiltrating lymphocytes (TILs) from the liver tumor.

[0490] Four (4) groups, each consisting of 5 female Balb / c mice were assigned to this study. All animals received intra-hepatic and subcutaneous implantations of CT26 murine colorectal carcinoma cells in Matrigel (defined as Day 1). Treatment started on Day 11 for all animals. Animals from Group 1 received IP treatment of saline twice weekly. Group 2 animals received 5-FU at 50 mg / kg IP and oxaliplatin 2.5 mg / kg IP (FOX) weekly. Animals from Groups 3 received 16B5 at 10 mg / kg IP twice weekly while animals from Group 4 received the combination of 16B5 10 mg / kg IP twice weekly and FOX weekly. The volume of the subcutaneous tumor was monitored twice weekly using a caliper. All animals were sacrificed at Day 22 postimplantation. The intra-hepatic and subcutaneous tumors were surgically resected at sacrifice.

[0491] On Day 22, the abdominal cavity and lungs were examined, and it was found that all animals treated with the combination of FOX and 16B5 (Group 4) were devoid of metastases while all animals from the other groups had metastases.

[0492] The statistical analyses were conducted on the subcutaneous tumor volume at sacrifice (Day 22) using an analysis of variance (ANOVA) including treatment as fixed effect. Each treatment group was compared to the saline group (Group 1). The comparisons were tested using Sidak’s method to control for multiplicity of testing at alpha of 0.05.

[0493] A statistically significant difference in the subcutaneous tumor volume was observed only when comparing Group 4 (FOX + 16B5) to Group 1 (saline) (adjusted p=0.0346) (Figure 1). Indeed, the average tumor volume of the animals treated with the combination of FOX and 16B5 was 55% smaller than that of the control animals. Although there was no statistically significant difference between the tumor volume of Group 3 animals (16B5) when compared to Group 1 animals (saline) (adjusted p=0.3813), their average tumor volume was 30% smaller (Figure 1).

[0494] EXAMPLE 2- Evaluation of the Efficacy of the Combination of 16B5, FOX and TILs in a Mouse CT26 Syngeneic Model of Colorectal Cancer

[0495] The CD3+PD-1+T cells expanded from the liver implanted tumors of animals treated with (murine) 16B5 and FOX from the experiment described in Example 1 were used in an adaptive immune cell therapy protocol in the CT26 mouse syngeneic model of colorectal cancer described previously.

[0496] The objective of the study was to evaluate if the addition of TILs to treatment with FOX and 16B5 would result in a better therapeutic response in comparison to treatment with the combination of FOX and 16B5 without TILs. Five (5) groups, each consisting of 8 female Balb / c mice were assigned to this study. All animals received intra-hepatic implantations of CT26 murine colorectal carcinoma cells in Matrigel (defined as Day 1). Treatment started on Day 5 for all animals.

[0497] Animals from Group 1 received IP treatment of saline twice weekly. Group 2 animals received 5- FU at 50 mg / kg IP and oxaliplatin 2.5 mg / kg IP (FOX) weekly. Animals from Groups 3 received 16B5 at 10 mg / kg IP twice weekly. Animals from Group 4 and 5 received the combination of 16B5 10 mg / kg IP twice weekly and FOX weekly. For Group 5 animals, lymphodepletion was performed at Day 13 with cyclophosphamide treatment at 100 mg / kg IP. These animals were administered 1.1 million TILs intravenously on Day 14 and received 1.5 pg IL-2 IP twice daily from Day 14 to Day 17. The CD3+ PD1+ T cells selected by fluorescence- activated cell sorting (FACS) were grown in 24-well G-Rex in Human T cell Expansion Media, Xeno-Free (R&D Systems) containing anti-CD3 and anti-CD28 monoclonal antibodies, mercaptoethanol and a combination of cytokines (undisclosed). One animal in Group 1 was sacrificed on Day 2 due to complications following the surgery. One animal in Group 3 was sacrificed on Day 20 due to a large volume of ascites in the abdominal cavity and enlarged liver. All other animals were sacrificed on Day 26.

[0498] At sacrifice, the abdominal cavity, lungs and liver were examined for metastases. Remarkably, all eight animals treated with TILs (Group 5; FOX + 16B5 + TILs) were devoid of metastases. Moreover, metastases were observed more frequently in the abdominal cavity, lungs and liver in saline treated animals (Group 1; 6 / 7) and in those treated with 16B5 alone (Group 3; 5 / 7) than in the animals treated with FOX (Group 2; 3 / 8) or the combination of 16B5 and FOX (Group 4; 3 / 8).

[0499] The statistical analyses were conducted on the hepatic tumor weight at sacrifice (Day 26) using an analysis of variance (ANOVA) including treatment as fixed effect. A natural log transformation was performed on the data in order to meet the assumptions of normality and homogeneity of variance. Each treatment group was compared to the saline group (Group 1). A comparison between Groups 2 and 5 and between Groups 4 and 5 was also performed. The comparisons were tested using Sidak’s method to control for the multiplicity of testing at alpha of 0.05. Liver tumor weight was highly variable within Group 1 (saline) and within Group 3 (16B5) animals. A statistically significant difference in tumor weight was observed between the animals from Group 1 (saline) and those of Group 5 (FOX + 16B5 + TILs) (adjusted p<0.0001). There was also a statistically significant difference in tumor weight between Group 2 (FOX) and Group 5 (adjusted p=0.0004) as well as between Group 4 (FOX + 16B5) and Group 5 (FOX + 16B5 + TILs) (adjusted p=0.0002) (Figure 2). These results show that TILs treatment combined with an EMT inhibitor could offer a potential approach in increasing the efficacy of standard-of-care chemotherapy. In fact, animals treated with the TILs (Group 5) had minuscule tumors averaging 0.0234 g while tumors from the animals treated with FOX alone (Group 2) or FOX + 16B5 without the TILs (Group 4) had an average weight of 0.216 g and 0.226 g, respectively. The average weight of the tumors in animals of Group 1 (saline) was 0.736 g.

[0500] Some immune biomarkers were investigated on the resected liver tumors after dissociation by flow cytometry. Results indicated the presence of myeloid-derived suppressor cells (MDSCs) and very few T lymphocytes in Group 1 (saline) and in Group 2 (FOX) animals while animals that were treated with 16B5 alone (Group 3) and those treated with the combination of 16B5 + FOX (Group 4) had tumors that were devoid of MDSCs but were infiltrated with T cells mostly positive for CD8. Moreover, although the tumors from the animals treated with TILs (Group 5) were very small, flow cytometry results indicated a strong presence of CD8+T cells.

[0501] Taken together the results indicate that treatment with 16B5 allowed the creation of an inflammatory tumor microenvironment in CT26 tumors when combined with FOX. The addition of TILs to the combination of 16B5 and FOX produced a significant anti-tumoral immune cell response resulting in an elimination of colorectal carcinoma cells at levels rarely observed in mouse syngeneic cancers, offering a potential setting for curative treatment of metastatic CRC.

[0502] EXAMPLE 3- A Proof-of-Concept Phase II Trial to Evaluate AB-16B5 Combined with FOLFOX Administered as Neoadjuvant Treatment Prior to Resection of Colorectal Cancer Liver Metastasis

[0503] 1. INTRODUCTION

[0504] 1.1- PURPOSE OF THE TRIAL

[0505] Colorectal cancer (CRC) is the second leading cause of cancer death after lung cancer. Globally, between 1990 and 2019, CRC incident cases more than doubled to 2.2 million and deaths increased to 1.1 million. More than 50% of CRC patients will develop liver metastases. Patients with CRC with liver dominant metastases can be treated by surgical resection. Chemotherapy with FOLFOX is usually administered preoperatively to gain metastatic disease control and potentially reduce the size of the metastases to perform parenchymal sparing hepatectomy. Five-year overall survival rates in CRC patients with resected liver metastases are approximately 50 %, but 80% of patients recur within 2-3 years after surgery. Patients with unresectable CRC metastases invariably have a fatal prognosis. Significant unmet needs thus remain for patients with metastatic CRC.

[0506] Current immunotherapies relying on anti-tumor T-cell response have generally not been efficacious in patients with metastatic CRC. One of the possible reasons is the high proportion of CRC bearing high TGFP levels in the tumor microenvironment leading to a mesenchymal tumor phenotype combined with direct inhibition of tumor-infiltrating T lymphocytes (TIL). Accordingly, results from mouse studies demonstrate that liver metastases recruit immunosuppressive macrophages that promote antigen-specific T cell apoptosis within the liver resulting in a systemic loss of T cells and diminished immunotherapy efficacy. Given its mechanism of action, AB-16B5 may improve T-cell infiltration in CRC liver metastases and cytotoxicity toward cancer cells by reversing the TGFP mesenchymal imprint, in a synergistic manner with FOLFOX, known to produce immunogenic cancer cell death and to increase TIL infiltration.

[0507] The proposed trial will test the hypothesis that the combination of AB-16B5 with FOLFOX administered prior to CRC liver metastases resection will inhibit EMT while producing a significant anti-tumoral immune cell response and clearance of cancer cells thereby improving the pathological response of the resected colorectal liver metastases. These results will be compared to historical data obtained in a pre-operative FOLFOX neo-adjuvant systemic chemotherapy population.

[0508] If positive, the results of this pilot trial should lead to testing the efficacy of novel immunotherapeutic strategies in patients with metastatic CRC, such as adoptive TIL transfer immunotherapy. In term, a pharmacological way of converting an immune-cold into an immune- hot tumor could lead to higher efficacy of immunotherapy in this common malignancy.

[0509] 1.2- SUMMARY OF BENEFITS AND RISKS

[0510] Benefit Summary Five-year overall survival rates in CRC patients with resected liver metastases are approximately 50%, but 80% of patients recur within 2-3 years after surgery. Given its mechanism of action, AB-16B5 may improve T-cell infiltration in CRC liver metastases and cytotoxicity toward cancer cells by reversing the TGFP mesenchymal imprint, in a synergistic manner with FOLFOX. This could enhance the efficacy of neoadjuvant FOLFOX and therefore improve the prognosis of CRC patients following liver metastases resection.

[0511] Risk Summary and Mitigation Strategy

[0512] AB-16B5 has never been administered in combination with FOLFOX chemotherapy nor prior to surgery. AB-16B5 did not enhance the toxicity of docetaxel when administered concomitantly in patients with advanced non-small cell lung cancer. Although AB-16B5 inhibits type 3 EMT which occurs in progressive carcinomas, it is unlikely that it perturbs type 2 EMT which plays a major role in wound healing by promoting re-epithelializationl2. Liver resection will occur approximately 2 to 4 weeks following the last dose of AB-16B5. Pharmacokinetic modeling predicts that AB-16B5 will have been completely cleared from the plasma prior to surgery. Surgical complications will be monitored in real time during the clinical trial to ensure that AB-16B5 does not increase complication rates post hepatectomy.

[0513] Overall Benefit:Risk Conclusion

[0514] The recurrence rate of CRC patients following neoadjuvant FOLFOX chemotherapy and resection of liver metastases remains high. AB-16B5 may enhance the efficacy of neoadjuvant FOLFOX and therefore improve the prognosis of CRC patients following hepatectomy. AB- 16B5 could potentially however increase FOLFOX toxicity and hepatectomy complication rates. These risks will be monitored closely in this single institution trial to ensure patient safety. The benefit risk ratio appears acceptable considering the current prognosis of CRC patients following liver metastases resection.

[0515] 2. TRIAL OBJECTIVES, ENDPOINTS AND ESTIMANDS Table 3: Primary Objectives

[0516] Table 4: Secondary Objective

[0517] Table 5: Exploratory Objectives

[0518] 3. TRIAL DESIGN

[0519] 3.1 -DESCRIPTION OF TRIAL DESIGN

[0520] The Applicant has designed an open-label, single-arm, single-center proof-of-concept Phase II trial of AB-16B5 in combination with FOLFOX-based preoperative neoadjuvant systemic chemotherapy in participants with resectable liver-dominant metastases and candidate to neoadjuvant FOLFOX followed by partial hepatectomy. AB-16B5 is a humanized type 2 immunoglobulin (IgG2) conventional antibody composed of two light chains having the amino acid sequence set forth in SEQ ID NO: 14 and two heavy chains having the amino acid sequence SEQ ID NO: 15. Approximately 17 participants will be enrolled in this trial and will receive 4 cycles of FOLFOX (Cycle 1 to Cycle 4) as preoperative systemic chemotherapy and 6 cycles of AB-16B5 (Cycle 1 to Cycle 6). One cycle of treatment will consist of 14 days (2 weeks). AB-16B5 will be administered intravenously (IV) at 800 mg on Day 1 and Day 8 of each cycle. FOLFOX will be administered on Day 1 of Cycle 1 to Cycle 4 as follows: oxaliplatin 85 mg / m2IV bolus + leucovorin 400 mg / m2IV bolus + 5 -Fluorouracil (5-FU) 400 mg / m2IV bolus + 5-FU 2400 mg / m2continuous IV infusion over 46 hours. Participants will undergo liver metastasis resection with or without primary cancer resection following recovery from preoperative neoadjuvant systemic chemotherapy.

[0521] 3.2- RATIONALE FOR TRIAL DESIGN

[0522] Patients with stage IV colon or rectal adenocarcinoma with liver-dominant metastases are currently treated with neoadjuvant FOLFOX chemotherapy followed by partial hepatectomy. Pathologic scoring of the treated liver metastases in the hepatectomy specimen is predictive of prognosis. The Rubbia-Brandt score will be used as the primary pathological grading system. Approximately 3 out of 15 patients following standard neoadjuvant FOLFOX chemotherapy will have a Rubbia- Brandt TRG score of 1 and 2, which portend a good prognosis, with the remaining patients having Rubbia-Brandt TRG scores of 3 to 5, which are associated with poor prognoses. An increased number of patients with a Rubbia-Brandt TRG score of 1 and 2 following AB-16B5 co- administration with neoadjuvant FOLFOX would support a broadened examination of the liver metastases. If positive, the results of this pilot trial should lead to testing the efficacy of novel immunotherapeutic strategies in patients with metastatic CRC, such as adoptive TIL transfer immunotherapy.

[0523] 3.3- ACCESS TO TRIAL INTERVENTION AFTER END OF TRIAL

[0524] Not applicable.

[0525] 3.4 -START OF TRIAL AND END OF TRIAL The overall trial begins when the first participant (or their legally acceptable representative) provides documented informed consent. The overall trial ends when the last participant completes the last surgery follow-up, withdraws consent, or is lost to follow-up. Participants will be considered enrolled in the trial if they meet all eligibility criteria and proceed to trial intervention on Cycle 1 Day 1.

[0526] 4. TRIAL POPULATION

[0527] The trial population will include participants > 18 years of age diagnosed with stage IV colon or rectal adenocarcinoma with liver-dominant metastases candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

[0528] 4.1- SELECTION OF TRIAL POPULATION

[0529] The trial population will include participants > 18 years of age diagnosed with stage IV colon or rectal adenocarcinoma with liver-dominant metastases candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

[0530] 4.2- RATIONALE FOR TRIAL POPULATION

[0531] The recurrence rate of CRC patients following neoadjuvant FOLFOX chemotherapy and resection of liver metastases remains high. There is thus an unmet medical need in this patient population. AB-16B5 may enhance the efficacy of neoadjuvant FOLFOX and therefore improve the prognosis of CRC patients following hepatectomy.

[0532] 4.3- TRIAL INCLUSION CRITERIA

[0533] Participants (male or non-pregnant female) must be > 18 years of age on the day of signing the informed consent.

[0534] Participants with stage IV colon or rectal adenocarcinoma with resectable liver-dominant metastases and candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

[0535] Participants may have had resection of their primary colon or rectal adenocarcinoma in the past or will have their primary cancer resected at the same time as the liver metastases resection or after liver metastases resection. Participants must not have received prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy and radiotherapy following resection of primary tumor is acceptable if completed at least 12 months prior to trial enrolment.

[0536] For multiple liver metastases, participants may undergo liver metastases needle-ablation of some metastases combined with surgical resection of others, as long as at least one metastasis is surgically resected.

[0537] Participants with at least one measurable lesion according to RECIST 1.1.

[0538] Participants must have a liver metastasis amenable for biopsy with no contraindication for biopsy. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of < 2.

[0539] Participants must have recovered from the toxic effects resulting from the most recent cancer treatment to Grade 1 or less. If the participants underwent major surgery, they must have recovered from the complications and / or toxicity. Participants must have a life expectancy of at least 3 months.

[0540] Participants must have adequate organ and immune function as indicated in the table below:

[0541] Table 6:

[0542] Female participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to the first dose of trial treatment.

[0543] Participants (both male and female) of reproductive potential willing to practice highly effective methods of contraception throughout the trial and for up to 90 days after the last dose of trial medication. Abstinence is acceptable if this is the participant’s usual lifestyle.

[0544] Female participants are not considered of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following:

[0545] 45 years of age and has not had menses for more than 2 years Amenorrheic for < 2 years without hysterectomy and oophorectomy and a follicle stimulating hormone (FSH) value in the postmenopausal range at screening

[0546] Post hysterectomy, oophorectomy, or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure. Participants must understand and be able and willing and likely to fully comply with the trial procedures, including scheduled follow-up, and restrictions.

[0547] Participants must have given written personally signed and dated informed consent to participate in the trial in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines, before completing any trial related procedures. 4.4- TRIAL EXCLUSION CRITERIA

[0548] Participants enrolled in the trial must not meet the following exclusion criteria:

[0549] Participants who have received prior therapy with AB-16B5

[0550] Concurrent administration of anti-VGFR, anti-EGFR, anti-VEGF or other biological or targeted therapy with neoadjuvant FOLFOX

[0551] Participants with MMR-deficient primary colorectal tumor

[0552] Hereditary colorectal cancer (e.g., familial colonic polyposis or Lynch syndrome)

[0553] Participants who have another malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer.

[0554] Participants who are expected to require any other form of systemic or localized antineoplastic therapy while on the trial. This includes maintenance therapy with another agent or radiation therapy.

[0555] Participants who are receiving a dose > 10 mg / day of prednisone (or equivalent) within 7 days prior to the first dose of study treatment or any other form of immunosuppressive medication.

[0556] Participants who are currently participating or have participated in a trial of an investigational agent or using an investigational device within 21 days of the first dose of trial treatment. The 21 -day window should be calculated using the last dose of an investigational agent or last use of an investigational device.

[0557] Participants who have a pre-existing peripheral sensitive neuropathy with functional impairment.

[0558] Participants with clinically significant electrocardiogram (ECG) abnormalities.

[0559] Participants who have received or will receive a live vaccine with 30 days prior to the first dose of trial treatment.

[0560] Participants with a known history of human immunodeficiency (HIV).

[0561] Participants with an active Hepatitis B or C infection. Participants with an active infection requiring antibiotic therapy.

[0562] Participants with a known history of alcohol or other substance abuse within the last year.

[0563] Participants with known hypersensitivity to FOLFOX.

[0564] Participants who have a history or current evidence of any condition, therapy or laboratory abnormalities that may confound the results of the trial, interfere with the participant’s participation for the full duration of the trial or if it is not in the best interest of the participant to participate in the trial.

[0565] Participants with medical, social or psychosocial factors that, in the opinion of the treating Investigator, could impact the safety or compliance with trial procedures.

[0566] Participants who are pregnant or lactating or who are expecting to conceive or father children within the projected duration of the trial through 90 days after the last dose of AB-16B5 or 180 days after the last dose of FOLFOX.

[0567] It is to be understood herein that the inclusion or exclusion criteria listed herein are solely for the purpose of the proof-of-concept phase II trial disclosed herein and is no way a limitation of the population to is sought to be treated.

[0568] 4.5- LIFESTYLE CONSIDERATIONS

[0569] No restrictions are required.

[0570] 4.6- SCREEN FAILURES

[0571] Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently enrolled in the trial. A minimum set of information will be collected from screen failure participants including demography and eligibility criteria not met.

[0572] Rescreening of participants is allowed in certain circumstances. Examples of circumstances when a participant can be rescreened:

[0573] •If a person consents to participate and meets the eligibility criteria but there is a delay in starting trial intervention due to a change in situation

[0574] •If the person previously failed screening due to an acute event that has now resolved / reversed Prescribed medications have stabilised

[0575] •Reversible causes of screen failure have been adequately treated

[0576] In cases of rescreening, a new identification number will be assigned to the participant, and they will be identified as having been rescreened in source documentation and eCRF. Screening Procedures outlined in Table 1 should be repeated as needed.

[0577] 5. TRIAL INTERVENTION AND CONCOMITANT THERAPY

[0578] 5.1- DESCRIPTION OF TRIAL INTERVENTION

[0579] Table 7: Description of trial intervention 5.2- RATIONALE FOR TRIAL INTERVENTION

[0580] AB-16B5 will be administered as a 60-minute intravenous infusion at a dose of 800 mg once weekly on Day 1 and Day 8 of Cycles 1 to 6. AB-16B5 was shown to be safe and well tolerated when administered weekly at doses up to 12 mg / kg in patients with advanced solid malignancy and metastatic non-small cell lung cancer. Because weight was not identified as being predictive of the PK of AB-16B5 during a recently conducted Phase 2 study in metastatic non- small cell lung cancer patients, a fixed dose will be administered. Based on exposure-response analysis from this Phase 2 study, an 800 mg weekly dose of AB-16B5 would be expected to result in area under the curve (AUC) and minimum concentration (Cmin) values comparable to what was seen in responders. The 800 mg weekly dose of AB-16B5 is also expected to be safe and well tolerated since ahigheramountof AB-16B5 was administered when patients weighing more than 67 kg were dosed at 12 mg / kg.

[0581] FOLFOX will be administered as per the standard of care in patients with CRC with resectable liver metastases.

[0582] 5.3- DOSING AND ADMINISTRATION

[0583] Participants enrolled in this trial will receive 4 cycles of FOLFOX (Cycle 1 to Cycle 4) as preoperative neoadjuvant chemotherapy and 6 cycles of AB-16B5 (Cycle 1 to Cycle 6).

[0584] AB-16B5 will be administered by a 60-minute IV infusion at 800 mg once weekly on Day 1 and Day 8 of Cycles 1 to 6. Every effort should be made to target an infusion duration of 60 minutes. An infusion duration window of -5 minutes and +10 minutes is permitted. AB-16B5 will be administered prior to FOLFOX administration.

[0585] Premedication to prevent infusion related reactions (IRR) will be administered to all participants prior to each dose of AB-16B5 and starting on Cycle 1 Dayl. Figure 3 provides details of the premedication to be used and describes the clinical management of infusion related reactions when a participant experiences infusion related reactions despite the premedication.

[0586] The premedication described above or in Figure 3 is a guidance and can be adapted according to the medical judgement of the attending physician and as per local clinical practices.

[0587] Participants who experience infusion-related reactions will be treated with corticosteroids, antihistamines and / or acetaminophen as deemed appropriate and according to the medical judgment of attending physician.

[0588] FOLFOX

[0589] FOLFOX will be administered on Day 1 of Cycles 1 to 4 as follows: oxaliplatin 85 mg / m2IV bolus + leucovorin 400 mg / m2IV bolus + 5-FU 400 mg / m2IV bolus + 5-FU 2400 mg / m2 continuous IV infusion over 46 hours. FOLFOX will be prepared and administered as per approved product labels / monographs and hospital standard practices.

[0590] Anti-emetic medication to prevent FOLFOX-induced nausea and vomiting will be administered to all participants prior to each FOLFOX treatment and starting on Cycle 1 Day 1. Figure 4 provides details of the anti-emetic prophylactic and post-treatment medication.

[0591] Vein extravasation and accidental spillages should be dealt with according to the local clinical practices.

[0592] 5.3.1-Trial Intervention Dose Modification

[0593] AB-16B5 Dose Modification

[0594] Participants who experience any Grade > 3 adverse event that is judged to be related to AB- 16B5 and does not require treatment discontinuation should have a reduction in AB-16B5 dose by one dose level (see table below).

[0595] Table 8: AB-16B5 Dose Modification

[0596] Treatment will be re-initiated at the lower dose only after recovery of the adverse event to Grade < 1. Participants whose original AB-16B5 dose has been reduced for toxicity should not be re- escalated.

[0597] For Grade > 3 infusion-related reaction, participant is discontinued from further treatment with AB-16B5.

[0598] FOLFOX Dose Modification

[0599] FOLFOX regimen can be adjusted for participants presenting toxicities according to the medical judgment of the attending physician and as per local clinical practices. 5.4- TREATMENT OF OVERDOSE

[0600] No information is currently available for the treatment of AB-16B5 overdose.

[0601] Refer to the corresponding approved product monograph of the individual components of the FOLFOX regimen for advice on overdose.

[0602] 5.5 - PREPARATION, HANDLING, STORAGE AND ACCOUNTABILITY

[0603] 5.5.1-Preparation, Handling and Storage of Trial Intervention

[0604] The details of the preparation, handling, and storage of AB-16B5 are detailed in a Pharmacy Manual available as a separate document.

[0605] FOLFOX will be prepared, handled, and stored as per product monograph and / or hospital standard practices.

[0606] 5.5.2- Accountability of Trial Intervention

[0607] Accurate records of all drug shipments reconstituted and dispensed AB-16B5, and a record of all amounts of drug that is returned must be accounted for on AB-16B5 Drug Accountability Form provided to the Investigator by the Sponsor. This inventory record must be available for inspection by the Study Monitor during regular monitoring visits. AB-16B5 drug supplies are to be used only in accordance with this protocol and under the supervision of the Investigator.

[0608] Any trial drug requiring destruction must be destroyed according to the hospital standard practices. At the end of the trial, the final drug accountability reconciliation will take place. The overall number of vials shipped to the center, and the number of vials destroyed or returned will be provided by the pharmacy, and an account given of any discrepancy.

[0609] FOLFOX accountability should be maintained as per the hospital standard practices.

[0610] 5.6- PARTICIPANT ASSIGNMENT, RANDOMIZATION AND BLINDING

[0611] This is a nonrandomized, open-label trial. After confirmation of eligibility, all participants will be assigned to the trial intervention arm: AB-16B5 combined with FOLFOX.

[0612] 5.7- TRIAL INTERVENTION COMPLIANCE The trial intervention will be administered at the clinical site by the clinical staff. Details related to the administration (e.g., dose administered, time of administration) of AB-16B5 and FOLFOX will be recorded in the eCRF.

[0613] 5.8- CONCOMITANT THERAPY

[0614] The Investigator will record all concomitant medications taken by the participants during the trial from start of trial intervention up to 14 days after the last dose of trial intervention. Concomitant medications administered >14 days after the last dose of trial intervention should be recorded only if related to adverse events requiring a follow-up (Section 8.4.5).

[0615] Concomitant medication includes all prescriptions, over the counter (OTC) products, herbal supplements, blood derived products and IV medications and fluids.

[0616] 5.8.1- Prohibited Concomitant Therapy

[0617] The participant must not receive other anti-cancer therapy or investigational drugs while on trial. Cannabis derived products should not be employed while receiving trial intervention.

[0618] The investigator should refer to the approved product monograph of each component of FOLFOX for specific drug interaction information and details concerning any prohibited concomitant medication or drug interactions.

[0619] 5.8.2- Permitted Concomitant Therapy

[0620] Supportive treatments will be given according to label instructions as medically indicated for participants.

[0621] 5.8.3- Rescue Therapy

[0622] Not applicable.

[0623] 5.8.4- Other Therapy

[0624] Not applicable.

[0625] 6. DISCONTINUATION OF TRIAL INTERVENTION

[0626] 6.1- DISCONTINUATION OF TRIAL INTERVENTION

[0627] 6.1.1- Criteria for Permanent Discontinuation of Trial Intervention Participants for which the liver metastases resection surgery is no longer feasible after having received any number of trial treatment cycles will be discontinued from the trial. All applicable activities scheduled for the Safety Follow-Up visit should be performed at the time of discontinuation. The data collected will nonetheless be retained and analyzed as applicable.

[0628] Participants who discontinue AB-16B5 and / or FOLFOX and for whom the liver metastases resection is still indicated will remain in the trial and will undergo all applicable activities scheduled. Participants who underwent the liver metastasis resection should have received at least 3 cycles of treatment to be part of the Clinical Activity Evaluable Analyses Set.

[0629] 6.1.2- Temporary Interruption of Trial Intervention

[0630] Interruptions from the protocol-specified treatment plan for > 2 weeks (14 days) require consultation between the Investigator and the Sponsor and written documentation of the collaborative decision on participant management.

[0631] 6.1.3- Rechallenge

[0632] Not applicable.

[0633] 6.2- PARTICIPANT WITHDRAWAL FROM THE TRIAL

[0634] A participant can withdraw their consent to participate in the trial at any time. They will be encouraged to go through the Safety Follow-Up assessments but will retain the right to refuse them. The data collected on the participant up to the point of withdrawal will remain part of the study database and may not be removed.

[0635] 6.3- LOST TO FOLLOW-UP

[0636] A participant who is lost to follow-up will be considered as having ended trial participation on the day of last contact by the site personnel. The data collected data will be retained and analyzed as applicable.

[0637] 6.4- TRIAL STOPPING RULES

[0638] Not applicable.

[0639] 7. TRIAL ASSESSMENTS AND PROCEDURES

[0640] 7.1- SCREENING / BASELINE ASSESSMENTS AND PROCEDURES Visit requirements are outlined herein. Specific procedure-related details are provided below.

[0641] Prior to commencing trial intervention, potential participants will be evaluated to determine that they fulfill the entry requirements as set forth in herein. Screening procedures will be performed within 28 days of first administration.

[0642] Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the participant signing consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame. Screening procedures are to be completed within 28 days prior to the first dose of trial treatment except for the following:

[0643] For women of reproductive potential, a pregnancy test will be performed within 72 hours prior to first dose of trial treatment.

[0644] 7.1.1- Participant Informed Consent

[0645] The Investigator must obtain documented consent from each potential participant or each participant’s legally acceptable representative prior to participating in a clinical trial.

[0646] Informed consent process must be source documented and the consent form must be signed and dated by the participant or by the participant’s legally acceptable representative along with the dated signature of the person conducting the consent discussion. A copy of the signed and dated consent form should be given to the participant before participation in the trial.

[0647] The initial consent form, any subsequent revised written consent form and any written information provided to the participant must receive the Research Ethics Committee (REC) approval / favorable opinion in advance of use. The participant or their legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information will be provided and documented via a revised consent form or addendum to the original consent form that captures the participant’s dated signature or by the participant’s legally acceptable representative’s dated signature.

[0648] The consent form will adhere to REC requirements, applicable laws and regulations and Sponsor requirements. 7.1.2- Inclusion / Exclusion Criteria

[0649] All inclusion and exclusion criteria will be reviewed by the Investigator to ensure that the participant qualifies for the trial.

[0650] 7.1.3- Medical History and Prior Medications

[0651] A medical history will be obtained by the Investigator. Medical history will include all active conditions and any conditions diagnosed within the prior 10 years that are considered to be clinically significant by the Investigator.

[0652] The Investigator will review and record prior medication taken by the subj ect within 1 month prior to start of trial intervention.

[0653] 7.1.4- Colorectal Cancer Medical History

[0654] The Investigator will obtain prior and current details regarding the participant’ s CRC. These details will be recorded separately and not listed as medical history.

[0655] The Investigator will review and record all prior anti-cancer treatments including systemic treatments, radiation, and surgeries, regardless of the time prior to first dose of trial treatment. Prior anti-cancer treatment for CRC will be recorded separately and not listed as a prior medication.

[0656] 7.1.5- Coagulation

[0657] A coagulation test (INR) will be performed at screening and participants receiving anticoagulant therapy must be monitored closely during the study.

[0658] 7.1.6- Electrocardiogram

[0659] 12-lead ECG assessments will be performed at screening after resting for 5 minutes and will include heart rate, PR, QRS, RR, QT, QTc (Bazett). Additional 12-lead ECG assessments may be performed during the study as clinically indicated.

[0660] 7.2- EFFICACY ASSESSMENTS AND PROCEDURES

[0661] 7.2.1- Tumor Tissue Collection

[0662] Specific sample collection and processing instructions will be described in a separate Laboratory Sample Processing Manual. Also refer to the Schedule of Activities herein.

[0663] Liver Biopsy A freshly collected liver metastasis biopsy of ideally the largest lesion or otherwise of the safest lesion to biopsy according to the interventional radiologist will be obtained during the screening phase. The liver segment containing the biopsied metastasis and the approximate size of the biopsied metastasis will be recorded.

[0664] Liver Metastases Resection

[0665] Resection of metastases by hepatectomy will be done as per standard of care. For multiple liver metastases, participants may undergo liver metastases needle-ablation of some metastases combined with surgical resection of others, as long as at least one metastasis is surgically resected.

[0666] Primary Cancer Resection

[0667] The primary tumor will be resected at the time of liver metastases resection or subsequently as per standard of care. The primary cancer resection could also have been performed prior to screening. If the primary cancer resection was performed prior to screening or if it was performed subsequently to the liver metastasis resection but at an external medical institution, formalin-fixed paraffin-imbedded (FFPE) blocks and / or tissue slides will be requested from the external pathology department to perform appropriate analyses.

[0668] 7.2.2- Histopathology Evaluations

[0669] Rubbia-Brandt Score

[0670] The Rubbia-Brandt score will be determined using the tissues derived from the liver metastases resection. The Rubbia-Brandt score distinguishes five TRG according to the presence of residual tumor cells and extent of fibrosis.

[0671] TRG1 : absence of tumor cells and their replacement by abundant fibrosis

[0672] TRG2: residual tumor cells are rare and are scattered throughout abundant fibrosis

[0673] TRG3 : more residual tumor cells throughout a predominantly fibrotic area

[0674] TRG4: tumor cells predominate over the fibrosis

[0675] TRG5: tumor cells are present exclusively (without fibrosis)

[0676] In participants with multiple metastases, all metastases will be evaluated and the worst TRG score will be reported if there is a discordant response. Blazer Score

[0677] The Blazer score will be determined using the tissues derived from the liver metastases resection. The Blazer score distinguishes three TRG according to the % residual cancer cells.

[0678] Complete response: no residual cancer cells

[0679] Major response: 1% to 49% residual cancer cells remaining

[0680] Minor response: 50% residual cancer cells remaining, including no response (100% residual cancer cells)

[0681] In participants with multiple metastases, all metastases will be evaluated and the worst TRG score will be reported if there is a discordant response.

[0682] Modified Ryan Score

[0683] The modified Ryan score will be determined using the tissues derived from the primary cancer resection. The modified Ryan score is a tumor regression grading system comprised of the following grades:

[0684] TRG 0: no viable cancer cells (complete response)

[0685] TRG 1 : single cell or rare small groups of cancer cells (near complete response)

[0686] TRG 2: residual cancer with evident tumor regression but more than single cell or rare small groups of cancer cells (partial response)

[0687] TRG 3 : extensive residual cancer with no evident tumor regression (poor or not response)

[0688] Histopathologic Growth Pattern

[0689] The histopathologic growth pattern (HGP) will be determined using the tissues derived from the liver metastases resection. The HGP is determined as the percentage of desmoplastic pseudocapsule surrounding the liver metastases (% tumor rim with replacement vs desmoplastic features). In participants with multiple metastases, HGP will be determined for each lesion.

[0690] Surgical Margins

[0691] The presence of cancer cells at the surgical margins of resected liver metastases and the primary tumor will be determined by standard of care criteria. Residual Tumor Cell Density

[0692] Tissue detection algorithms will be used to detect the surface area of liver metastases, and tumor cell detection algorithms will identify residual tumor cells within the metastases. The number of residual tumor cells will be divided by the surface area of the liver metastases. In participants with multiple metastases, the residual tumor cell density will be determined for each lesion.

[0693] Intravascular and Microsatellite Lesions adjacent to the Liver Metastases

[0694] The presence of intravascular and microsatellite lesions in the liver tissue adjacent to the colorectal liver metastases will be identified. The result obtained will be categorized as either “absence”, “focal presence” (in < 10% of hepatic portal tracts) or “extensive presence” (in > 10% of hepatic portal tracts).

[0695] Degree of Microscopic Fibrosis-Necrosis

[0696] The percentage of microscopic fibrosis-necrosis within the limits of the tumor area will be estimated for each liver metastasis.

[0697] Tertiary Lymphoid Structures

[0698] The presence and abundance of TLS will be determined in each resected liver metastasis and in the primary cancer. The abundance of TLS will be expressed as the number of TLS divided by the area of tissue sampled.

[0699] 7.2.3- Tumor Imaging and Assessment of Disease

[0700] Tumor imaging of the liver should be acquired by computed tomography (CT) or magnetic resonance imaging (MRI). The same imaging technique regarding modality and use of contrast should be used in a participant throughout the trial to optimize the visualization of existing and new tumor burden.

[0701] Initial tumor imaging at screening must be performed within 28 days prior to the trial treatment start. The site trial team must review screening images to confirm the participant has measurable disease per RECIST 1.1. Scans performed as part of routine clinical management are acceptable for use as screening tumor imaging if they are of diagnostic quality and performed within 28 days prior to the date of trial treatment start. Tumor assessments will be performed at Cycle 5 to assess the Objective Response according to RECIST 1.1. Participants who must discontinue both AB-16B5 and FOLFOX prior to Cycle 5 must have a liver CT or MRI at the time of discontinuation.

[0702] 7.3- SAFETY ASSESSMENTS AND PROCEDURES

[0703] Safety will be assessed by physical examination, measurement of vital signs and clinical laboratory evaluations. Clinically significant changes in these parameters will be captured as adverse events (AEs).

[0704] 7.3.1- Physical Examination

[0705] The Investigator will perform a complete physical exam at Screening. Clinically significant abnormal findings should be recorded as medical history. For treatment cycles, the Investigator will perform a directed physical exam as clinically indicated. A complete physical exam will be performed at Safety Follow-up.

[0706] After the start of the trial intervention, new clinically significant abnormal findings should be recorded as AEs.

[0707] 7.3.2- Vital Signs

[0708] Vitals signs will be measured at Screening, prior to each trial intervention administration (prior to Day 1 and Day 8 of each cycle) and at Safety Follow-Up. Vital signs will include temperature, pulse, respiratory rate, and blood pressure. Body weight will be measured at Screening and prior to Day 1 of each cycle. Height will be measured at Screening only.

[0709] 7.3.3- Clinical Laboratory Assessments

[0710] Clinical laboratory assessments will be performed locally at Screening and prior to trial intervention on Day 1 of each cycle. Results must be known and acceptable prior to trial intervention in each cycle. The following laboratory parameters will be evaluated:

[0711] Hematology: White blood cell count (total and differential), hemoglobin, hematocrit, platelet count, red blood cell count

[0712] Clinical Biochemistry: Albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), calcium, carcinoembryonic Antigen (CEA), chloride, creatinine, creatinine clearance, glucose, potassium, sodium, total bilirubin, total protein, urea, uric acid.

[0713] Urinalysis: Blood, glucose, microscopic exam (if abnormal results are noted), protein, specific gravity.

[0714] A serum pregnancy test will be done within 72 hours prior to the first cycle of treatment (Cycle 1) for all females with an intact uterus, regardless of age, unless amenorrhoeic for the previous 12 months. A serum pregnancy test will also be done at Safety Follow-Up.

[0715] CEA will also be measured at the Post-Surgery Follow-Up visit.

[0716] 7.3.4- Eastern Cooperative Oncology Group Performance Scale

[0717] The Investigator will assess the ECOG status at Screening, prior to the trial intervention on Day 1 of each cycle and at Safety Follow-Up.

[0718] 7.4- ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS

[0719] 7.4.1- Definitions of Adverse Event and Serious Adverse Event

[0720] Adverse Event (AE): Any untoward medical occurrence in a patient or clinical trial participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. This includes worsening (e.g., increase in frequency or severity) of pre-existing conditions.

[0721] Serious Adverse Event (SAE): SAEs are a subset of adverse events. An SAE is defined as any untoward medical occurrence that meets any of the following criteria: results in death is life-threatening (The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.) requires inpatient hospitalization or prolongation of existing hospitalization* results in persistent or significant disability / incapacity is a congenital anomaly / birth defect

[0722] In addition, an important medical event that may not result in death, be life threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the participant’s health and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

[0723] *An inpatient hospitalization is defined as an admission for any length of time. A hospitalization for the administration of trial treatment, for routine or planned clinical procedures, or for “social” reasons (not the result of any adverse change in the participant’s condition) should not be considered an adverse event and should not be reported as a serious adverse event. If the participant experiences any adverse change in condition during hospitalization, the condition must be reported as an adverse event or serious adverse event according to the above definitions.

[0724] Unexpected Adverse Event: An AE, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s Brochure for an unapproved trial agent or package insert / summary of product characteristics for an approved product). Expected means that the event has previously been observed with the trial treatment and is identified and / or described in the applicable product information. It does not mean that the event is expected with the underlying disease(s) or concomitant medications.

[0725] 7.4.2- Time Period and Frequency for Collecting Adverse Events and Serious Adverse Events Information

[0726] All AEs from the start of trial treatment administration (Day 1) through 14 days following administration of the last dose of trial treatment will be collected. These AEs will be considered treatment-emergent AEs (TEAEs). In addition, all AEs and SAEs that occur after the participant provides documented informed consent but before the start of trial intervention must be reported if the event is the result of a protocol-specific procedure.

[0727] 7.4.3- Identifying Adverse Events and Serious Adverse Events

[0728] At each visit at the clinical site, participants will be questioned about the occurrence of any new AE or worsening of existing AEs. Open-ended and non-leading verbal questioning of the participant will be used to inquire about the occurrence of adverse events. A laboratory abnormality should be reported as an AE if it is associated with a medical intervention. Medical intervention includes, but is not limited to, discontinuation of trial treatment, dose reduction / delay, or concomitant therapy. In addition, any medically important laboratory abnormality may be reported as an AE at the discretion of the Investigator. This includes laboratory abnormalities for which there is no medical intervention, but the abnormal value(s) suggests a disease or organ toxicity. If clinical sequelae are associated with a laboratory abnormality, the diagnosis or medical condition should be reported (e.g., renal failure, hematuria) not the laboratory abnormality (e.g., elevated creatinine, urine red blood cells increased).

[0729] 7.4.4- Recording of Adverse Events and Serious Adverse Events AEs and SAEs will be recorded on the Adverse Event Electronic Case Report Form (AE eCRF). Toxicities will be characterized in terms regarding seriousness, causality, grading, and action taken regarding trial treatment.

[0730] Severity:

[0731] Severity will be graded using the NCI CTCAE Version 5.0. The CTCAE Version 5.0 may be downloaded from the Cancer Treatment Evaluation Program (CTEP) website (https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / docs / CTCAE_v5_Quick_Re ference_5x7.pdf). If an AE does not have a CTCAE code, the following severity classifications will be used:

[0732] Table 9:

[0733] *Note - a severity assessment of life-threatening is not necessarily the same as the seriousness criterion of life-threatening. The former means that the event is a potential threat to life. The latter means that the event is an immediate threat to life.

[0734] Any AE which changes CTCAE grade over the course of a given episode will have each change of grade recorded on the adverse event case report forms / worksheets. All AEs regardless of CTCAE grade must also be evaluated for seriousness.

[0735] Causality:

[0736] For each AE, the Investigator should determine and document whether there exists a reasonable possibility that any component of the trial treatment caused or contributed to the AE. The Investigator’s assessment should be recorded in the source document. If the Investigator does not know whether the trial treatment is causally related to the event, reporting for trial purposes will be as at least “possibly related” to trial treatment. The initial causality assessment may be revised as new information becomes available (see table below).

[0737] Table 10:

[0738] 7.4.5- Follow-up of Adverse Events and Serious Adverse Events

[0739] AEs that have not resolved by the Safety Follow-Up visit will be recorded as ongoing.

[0740] However, participants with a related AE of Grade 2 will be followed until the resolution of the AE to Grade

[0741] 1, the beginning of a new anti-cancer treatment or the Post Surgery Follow-Up visit, whichever occurs first. SAEs that have not resolved by the Safety Follow-Up visit are followed until final outcome is known. If it is not possible to obtain a final outcome for a SAE (e.g., the participant is lost to follow up), the reason that a final outcome could not be obtained will be documented by the Investigator.

[0742] SAEs that occur beyond 14 days after the last dose of the trial treatment that are assessed by the Investigator to be related to trial intervention must be reported to the Drug Safety designee on the SAE worksheet.

[0743] 7.4.6- Reporting of Serious Adverse Events

[0744] SAEs must be recorded on the SAE Worksheet and sent to the Drug Safety designee within 24 hours of site personnel becoming aware of the SAE. The SAE Worksheet should be completed as much as possible but should not be held until all information is available. Additional information, follow-up information, and corrections should be provided on subsequent updates of the SAE Worksheet that are clearly identified as follow-up (#1, #2, etc.) reports. The SAE Worksheets should be sent to the Sponsor using the Drug Safety contact information and process as provided on the SAE Worksheet.

[0745] Drug Safety personnel will be available to answer questions and assist site personnel in documenting SAEs and completing the SAE worksheet.

[0746] 7.4.7- Regulatory Reporting Requirements for Serious Adverse Events

[0747] All SAEs that are considered unexpected and related to the trial agent will be reported by the Sponsor or designee as expedited (i.e., 15-Day) reports to the appropriate regulatory authorities and to all participating Investigators. In addition, the Sponsor or designee follows all applicable local and national regulatory requirements regarding safety reporting. Each Investigator must also comply with the applicable regulatory requirements related to the reporting of SAEs to the REC responsible for reviewing the trial at their site, as well as the regulatory authority(ies) (if applicable).

[0748] 7.4.8- Serious and Unexpected Adverse Reaction Reporting

[0749] 7.4.9- Adverse Events of Special Interest

[0750] Post-surgical complications will be graded as per the Clavien-Dindo classification which consists of the following 5 grades: Table 11:

[0751] The post-surgical complications will be evaluated only after the liver metastases resection. There will be no post-surgical complications evaluation after the resection of the primary cancer when performed subsequently to the liver metastases resection. 7.4.10- Disease-Related Events or Outcomes Not Qualifying as Adverse Events or Serious

[0752] Adverse Events

[0753] Not applicable 7.5- PREGNANCY AND POSTPARTUM INFORMATION

[0754] 7.5.1- Participants Who Become Pregnant During the Trial

[0755] All pregnancies are reported up to 30 days following the last dose of trial treatment. A pregnancy must be reported to the Drug Safety designee as soon as the site becomes aware of the pregnancy. The Drug Safety designee will send an acknowledgement memorandum to the Investigator along with a Pregnancy Assessment Form. A follow-up Pregnancy Assessment Form will be sent to the site every 3 months. Pregnancy Assessment Forms must be completed by the Investigator until delivery, elective termination of the pregnancy, or miscarriage. The Investigator is responsible for following the participant’s pregnancy through final outcome.

[0756] Pregnancies are not considered AEs unless a negative or consequential outcome occurs in the participant or child / foetus. Complications or medical problems associated with a pregnancy are considered AEs and may be SAEs. If the negative event meets the seriousness criteria, then this is considered an SAE (for example, spontaneous abortion, foetal death, stillbirth, congenital anomalies, ectopic pregnancy, or pre-eclampsia) and reported herein.

[0757] 7.6- MEDICAL DEVICE PRODUCT COMPLAINTS FOR DRUG / DEVICE COMBINATION PRODUCTS

[0758] Not applicable.

[0759] 7.7- PHARMACOKINETICS

[0760] Blood samples will be collected from all participants to define the PK properties of AB- 16B5. Blood samples will be collected throughout the trial at the following time-points:

[0761] Table 12:

[0762] Clinical staff will be asked record the exact time of collection. Blood should not be collected from the same vein used to administer AB-16B5. Specific sample collection and processing instructions will be described in a separate Laboratory Sample Processing Manual.

[0763] 7.8- GENETICS

[0764] Not applicable.

[0765] 7.9- BIOMARKER ANALYSIS

[0766] Specific sample collection and processing instructions will be described in a separate Laboratory Sample Processing Manual.

[0767] 7.9.1- Immune Biomarkers

[0768] Immune cells biomarkers will be investigated by multiplex imaging and machine-learning algorithms deployed on the liver biopsy, the resected liver metastases and the primary cancer. Various panels of antibodies will be assembled to detect the presence of B cells, T cells, macrophages, natural killer cells and myeloid-derived suppressor cells. Other immune biomarkers (e.g., PD-L1, CTLA-4, MHC II, immunosuppressive fibroblasts) might be investigated if deemed necessary.

[0769] 7.9.2- Epithelial to Mesenchymal Transition Biomarkers

[0770] EMT biomarkers will be investigated by multiplex imaging and machine-learning algorithms deployed on the liver biopsy, the resected liver metastases and the primary cancer. The epithelial biomarker E-cadherin, and the mesenchymal biomarker vimentin will be investigated. Other EMT biomarkers might be investigated if deemed necessary.

[0771] 7.9.3- Immunophenotyping

[0772] Immune cells in cell suspensions obtained from the resected liver metastases will be phenotypically characterized using biomarkers of T cell sternness, differentiation, activation, and exhaustion, of regulatory T cells, and of B cell maturation.

[0773] 7.9.4- B and T Cell Receptor Clonotype Diversity The diversity of the B and T cell receptor clonotypes will be investigated in the liver biopsy and the resected liver metastases as well as in the blood. The sampling schedule is detailed in Figure 6.

[0774] 7.9.5- Recognition of Neoantigens by T Cells Expanded from Liver Metastases

[0775] T cells in cell suspensions obtained from the resected liver metastases will be expanded in vitro. The phenotype and percentage of expanded T cells that recognize tumor neoantigens predicted from the liver biopsy and the resected colorectal liver metastases sequencing will be determined. Expanded T cells could be cryopreserved for further characterization.

[0776] 7.9.6- Minimal Residual Disease Detection Rate by Circulating Tumor DNA Analysis

[0777] Blood samples will be collected to determine the minimal residual disease detection rate by circulating tumor DNA (ctDNA) analysis. The sampling schedule is detailed in Figure 6.

[0778] 7.9.7- Cytokines

[0779] Cytokines will be evaluated using the blood samples collected for the PK evaluations.

[0780] 7.10- IMMUNOGENICITY ASSESSMENTS

[0781] Blood samples will be collected from all participants to determine the presence of anti- AB- 16B5 antibodies (ADA) and to determine if they are neutralizing.

[0782] Blood samples will be collected throughout the trial at the following time-points:

[0783] Table 13:

[0784] 7.11- MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS

[0785] Not applicable. 7.12- FUTURE RESEARCH AND BIOBANKING

[0786] Biospecimens collected during the trial could be preserved and used for future analyses in relation to the objectives of this clinical trial.

[0787] 8. STATISTICAL CONSIDERATIONS

[0788] Statistical analyses will be performed after all participants have completed the study and the database has been locked.

[0789] A Statistical Analysis Plan (SAP) will be developed and finalised before the study database lock.

[0790] Data will be summarized based on observed data as there is no plan to estimate missing data and no statistical inferences will be performed. Continuous endpoints will be summarized using descriptive statistics (number of participants with available data [‘n’], mean, standard deviation, median, minimum, and maximum values) while categorical endpoints will be summarized using number and percentage of participants among participants with available data.

[0791] Listing of all data will be prepared.

[0792] 8.1- ANALYSIS SETS

[0793] Analysis sets to support each analysis are specified in the following sections and will be described in detail in the SAP.

[0794] 8.1.1- Clinical Activity Evaluable Analyses Set

[0795] The Clinical Activity Evaluable (CAE) analysis set will include all enrolled participants who received both study treatments (AB-16B5 and FOLFOX) for at least 3 cycles and had a liver metastases resection surgery.

[0796] This analysis set will be used to summarize the efficacy and biomarker endpoints.

[0797] 8.1.2- Full Analysis Set

[0798] The full analysis set (FAS) will include all enrolled participants who received at least one dose of each study treatment drug (AB-16B5 and FOLFOX) and had a liver metastases resection surgery.

[0799] This analysis set will be used as a supportive analysis set for efficacy endpoints’ analyses. 8.1.3- Safety Analysis Set

[0800] The safety analysis set will include all participants who received at least one dose of any study treatment drug (AB-16B5 or FOLFOX).

[0801] This analysis set will be used for all safety analyses.

[0802] 8.1.4- Pharmacokinetic Analysis Set

[0803] The PK analysis will include all participants who received at least one dose of AB-16B5 and have at least one adequately documented and measurable PK sample for concentration.

[0804] This analysis set will be used to evaluate the pharmacokinetics of AB-16B5.

[0805] 8.1.5- Immunogenicity Analysis Set

[0806] The ADA analysis set will include all participants who received at least one dose of AB- 16B5. This analysis set will be used to evaluate ADA data.

[0807] 8.2- PRIMARY EFFICACY ENDPOINT

[0808] Unless otherwise indicated, all efficacy endpoints will be summarized based on the CAE.

[0809] 8.2.1- Statistical Model, Hypothesis, and Method of Analysis

[0810] Number and percentage of participants in each category of the Rubbia-Brandt score will be presented.

[0811] The analysis will be performed on the CAE analysis set as well as the FAS, as supportive analyses.

[0812] 8.2.2- Handling of Missing Data

[0813] Missing data will not be imputed.

[0814] 8.2.3- Sensitivity Analysis

[0815] Subgroup analyses may be performed, if deemed necessary and details will be included in the SAP.

[0816] 8.2.4- Supportive Analysis

[0817] As a supportive analysis, the Rubbia-Brandt score will be summarized as described herein but based on the FAS. Additional supportive analyses might be defined in the SAP.

[0818] 8.3- SECONDARY ENDPOINTS

[0819] 8.3.1- Objective Response Rate

[0820] The objective disease response will be categorized in accordance with RECIST 1.1.

[0821] Number and percentage of participants with objective disease response, defined as the percentage of patients with a complete response (CR) or partial response (PR) will be provided along with two-sided 95% exact Clopper-Pearson confidence internal (CI).

[0822] Number and percentage of participants in each category of best overall response (CR, PR, stable disease [SD], and progressive disease [PD]) will also be provided.

[0823] 8.3.2- Minimal Residual Detection Rate

[0824] The minimal residual disease detection rate, assessed by quantitating ctDNA in blood, will be presented for each participant.

[0825] The analysis will be performed on the CAE analysis set as well as the FAS, as supportive analyses.

[0826] 8.3.3- Pharmacokinetic Analysis

[0827] Population PK (PPK) modeling of PK concentration data will be conducted using standard approaches which will be defined in a separate analysis plan. If feasible, the peak concentration (Cmax), AUC, clearance (CL), volumes of distribution (V) and half-life (Thalf) will be derived and reported.

[0828] 8.3.4- Anti- AB-16B5 Antibodies

[0829] Number and percentage of participants with ADA will be provided by visit.

[0830] 8.4- ANALYSIS OF EXPLORATORY OBJECTIVE(S)

[0831] Possible relationships between histopathology or biomarker data and response data may be examined, if appropriate.

[0832] 8.4.1- Histopathology Analysis Number and percentage of participants in each category of the Blazer and modified Ryan scores will be presented.

[0833] Number and percentage of participants having TLS will be presented. In addition, the number of TLS per liver metastasis and in the primary cancer will be presented.

[0834] The surgical margins, histopathologic growth pattern, residual tumor cell density, presence of microscopic dissemination, degree of microscopic fibrosis-necrosis will be presented.

[0835] The analysis will be performed on the CAE analysis set as well as the FAS, as supportive analyses.

[0836] 8.4.2- Biomarker Analysis

[0837] Immune biomarkers, EMT biomarkers, immunophenotyping, B and T receptor clonotype diversity, recognition of neoantigens by T cells, inflammatory cytokines, and CEA will be presented.

[0838] 8.5- SAFETY ANALYSES

[0839] Unless otherwise indicated, all safety endpoints will be summarized based on the safety analysis set.

[0840] 8.5.1- Adverse Events

[0841] AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).

[0842] TEAEs will be defined as any AE that occurred on or after the first dose of any study treatment or that worsened in severity after exposure to any study treatment.

[0843] Number and percentage of participants with at least one TEAE will be summarized by system organ class and preferred term. TEAEs summaries will also be presented for TEAEs with a relationship to study treatment and by worst reported CTCAE grade, separately.

[0844] Number and percentage of participants with at least one AE with an outcome of death, treatment emergent SAE, TEAE leading to discontinuation from study treatment, TEAE leading to withdrawal from study will be summarized.

[0845] Postoperative complications will be summarized by grade per Clavien-Dindo classification. Separate listings will be provided for all AEs, all AEs with an outcome of death, all SAEs, all TEAEs leading to discontinuation from study treatment, all TEAEs leading to withdrawal from study, and all postoperative complications.

[0846] 8.5.2- Other Assessments

[0847] Observed value and change from baseline in each clinical safety laboratory test (hematology, biochemistry, and urinalysis) and each vital sign will be summarized using descriptive statistics by visit.

[0848] Laboratory observed values outside of the normal ranges will be identified (low [below the lower limit of normal] or high [above the upper limit of normal]) and presented.

[0849] Number and percentage of participants in each ECOG category will be summarized by visit.

[0850] 8.6- OTHER ANALYSES

[0851] 8.6.1- Participant Disposition, Demographics, and Other Baseline Characteristics

[0852] Participant disposition, demographic, other baseline disease characteristics, medical history, primary disease history, and prior CRC therapies / surgeries will be summarized.

[0853] 8.6.2- Protocol Deviations

[0854] The number of events and the number and percentage of participants with at least one important protocol deviation will be summarized by deviation category.

[0855] 8.6.3- Prior and Concomitant Medication

[0856] Prior and concomitant medications will be coded using the World Health Organization (WHO) medical dictionary and summarized separately by ATC Class and preferred drug name.

[0857] 8.6.4- Analysis of Study Treatment Dosing

[0858] Duration of exposure, total number of cycles administered, compliance, cumulative dose, and relative dose will be summarized by study treatment.

[0859] 8.7- INTERIM ANALYSES

[0860] There is no interim analysis planned for this study.

[0861] 8.8- SAMPLE SIZE DETERMINATION The study is descriptive in nature and the number of participants is not based on a formal sample size calculation. A total of 17 participants will be enrolled in order to obtain 15 evaluable participants as per the CAE definition. This number is considered appropriate to gather enough information to fulfill the primary, secondary, and exploratory objectives. Table 14-APPENDIX: GLOSSARY OF TERMS LIST OF ABBREVIATIONS

[0862]

[0863] Ill

[0864] EXAMPLE 4-PRELIMINARY CLINICAL DATA

[0865] Patients 001, and 004 received 4 cycles of FOLFOX (Cycle 1 to Cycle 4) and 6 cycles of the anti-clusterin antibody AB-16B5 (Cycle 1 to Cycle 6). One cycle of treatment consisted of 14 days (2 weeks). AB-16B5 was administered by intravenous (IV) infusion at 800 mg on Day 1 and Day 8 of each cycle. FOLFOX was administered on Day 1 of Cycle 1 to Cycle 4 as follows: oxaliplatin 85 mg / m2IV infusion + leucovorin 400 mg / m2IV infusion + 5 -Fluorouracil (5-FU) 400 mg / m2IV bolus + 5-FU 2400 mg / m2continuous IV infusion over 46 hours. Patient 001 As exemplified in Figure 8A, the level of CEA increased after the first two cycles of treatment, followed by a sharp reduction (below baseline) observed starting from cycle 3, which may be indicative of the efficacy of treatment.

[0866] Target lesions were removed 79 days after the last cycle of treatment. One hepatic target lesion was assessed (nodular liver hypodensity segment VII). At screening, the size of the lesion was determined to be 33.0 mm. After treatment, the size of the target lesion (assessed by scan after 5 cycles of treatment) was 31.0 mm, i.e., -6.1% reduction from base line ((33.0 mm -31.0 mm) / 33.0 mm).

[0867] The target lesions were characterized by pathologist, and the following macroscopic and histopathological observations were made.

[0868] A significant regression of the liver lesions was observed; the target lesions are characterized by 90% necrosis with an average histological response scoring of TRG3 (Rubbia- Brandt score).

[0869] Presence of large necrotic center with residual cancer cells in the periphery.

[0870] The stroma is highly cellular (rare for colon metastases to the liver), is rich in mononuclear immune cells overlaid onto activated fibroblasts (inflammatory cancer associated fibroblast (iCAF)) and is mostly composed of lymphocytes, macrophages, and plasma cells, with a few eosinophils.

[0871] Some areas of the lesion are characterized by the presence of immune-poor fibroblasts and extracellular matrix.

[0872] Presence of immune aggregates, strong presence of tertiary lymphoid structures (TLS+++), on the periphery at the interface between tumor and adjacent liver.

[0873] Lack of the immuno-exclusionary zones from the interface to the tumor which is atypical of liver metastasis. The immune cells, mostly T cells, penetrate into the stroma and appear to be in contact with the tumor (as revealed by the lack of an exclusionary area generated by fibroblasts).

[0874] Presence of lymphoid aggregates in nearby portal tracts, while portal tracts at distance from the tumor are normal.

[0875] Some areas of residual tumor are replaced by a dense, non-tumoral, myofibroblastic reaction, reminiscent of a myofibroblastic inflammatory tumor. This myofibroblastic reaction is composed of very plump myofibroblasts and is immuno-permissive. It does not contain tumor cells with extensive immunohistochemistry staining (CDX2 staining). It is characterized by the presence of CD20 expressing cells (B-cells) and the presence of TLS. The myofibroblastic reaction is rich in CD3 expressing cells (T-cells), characterized by the presence of CD8 expressing T-cells and is highly enriched in cytotoxic T-cells.

[0876] Patient 004

[0877] As exemplified in Figure 8B, the level of CEA increased after the first two cycles of treatment, followed by a sharp reduction (below baseline) observed starting from cycle 3, which may be indicative of the efficacy of treatment.

[0878] Target lesions were removed 33 days after last cycle of treatment. Two hepatic target lesions were assessed (hepatic meta junction segment VIII and IVa and meta hepatic segment VIII). At screening, the size of each of these lesions was determined to be 66.0 mm and 20,0 mm respectively. The size of the target lesions (assessed by scan after 5 cycles of treatment) was 31.0 mm and 10.0 mm respectively, i.e., -52.3% reduction from base line ((86.0 mm -41.0 mm) / 86.0 mm).

[0879] The target lesions were characterized by pathologist, and the following macroscopic and histopathological observations were made.

[0880] A very significant regression of the liver lesions was observed (near total); the target lesions are characterized by 90% necrosis with an average histological response scoring of TRG1-2 (Rubbia-Brandt score).

[0881] One of the hepatic target lesions is characterized by a TRG2 scoring with presence of immune infiltration and TLS.

[0882] Residual cancer cells show an immune-exclusion barrier and high-grade morphology (single-cells). Otherwise, there is abundant TLS within and at proximity of the tumor bed.

[0883] The other hepatic target lesion is characterized by a TRG1 scoring with complete tumor regression, residual immune-permissive stroma and the presence of TLS.

[0884] In addition to the embodiments described and provided in this disclosure, the following non-limiting embodiments are contemplated. 1. A method of treating a subject having metastatic colorectal cancer, the method comprising administering an antibody or antigen binding fragment thereof that binds to clusterin in combination with FOLFOX.

[0885] 2. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and FOLFOX are administered prior to resection of one or more metastases or of one or more tumors.

[0886] 3. The method of any one of the preceding embodiments, wherein the method results in regression of at least one of the one or more metastases and / or of at least one of the one or more tumors.

[0887] 4. The method of any one of the preceding embodiments, wherein the one or more metastases comprise one or more liver metastases.

[0888] 5. A method of treating one or more liver metastases in a subject in need thereof, the method comprising administering an antibody or an antigen binding fragment thereof that binds to clusterin.

[0889] 6. The method of any one of the preceding embodiments, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is administered at least prior to ablation of the one or more liver metastases.

[0890] 7. The method of any one of the preceding embodiments, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is administered after ablation of the one or more metastases or of the one or more liver metastases.

[0891] 8. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as a single therapy.

[0892] 9. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as a combination therapy with one or more antineoplastic agents (e.g., chemotherapeutic combination).

[0893] 10. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in combination with radiation therapy. 11. The method of any one of the preceding embodiments, wherein the one or more metastases originates from, or is caused by, an invasive adenocarcinoma.

[0894] 12. The method of any one of the preceding embodiments, wherein the one or more metastases originates from, or is caused by, colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0895] 13. The method of any one of the preceding embodiments, wherein the one or more metastases comprises one or more liver metastases originating from, or caused by, colorectal cancer.

[0896] 14. The method of any one of the preceding embodiments, wherein the one or more antineoplastic agent is selected from an alkylating agent, an anti-metabolite, an alkaloid, an antitumor antibiotic or combination thereof.

[0897] 15. The method of any one of the preceding embodiments, wherein the one or more antineoplastic agents is selected from altretamine, busulfan, carboplatin, oxaliplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5 -fluorouracil, 6-mercaptopurine, azacytidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, vincristine, vinblastine, vinorelbine, taxanes (e.g., paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel), etoposide, teniposide, irinotecan, topotecan, daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, valrubicin, capecitabine, leucovorin or a chemotherapeutic combination thereof comprising two or more antineoplastic agents.

[0898] 16. The method of any one of the preceding embodiments, wherein the method comprises ablation of at least one of the one or more tumors and / or of at least one of the one or more metastases.

[0899] 17. A method for inhibiting, delaying, or reducing recurrence and / or growth of tumor(s) and / or metastases subsequent to ablation of the tumors and / or metastases or for preventing or reducing persistence of tumor(s) or metastasi s(es) in a subject having cancer, the method comprising administering at least prior to ablation an antibody or an antigen binding fragment thereof that binds to clusterin.

[0900] 18. A method of treating a subject having one or more tumors and / or one or more metastases, the method comprising administering an antibody or an antigen binding fragment thereof that binds to clusterin at least prior to ablation of the one or more tumors and / or one or more metastases.

[0901] 19. The method of any one of the preceding embodiments, wherein the method further comprises administering one or more antineoplastic agent at least prior to ablation.

[0902] 20. The method of any one of the preceding embodiments, wherein the method further comprises administering one or more antineoplastic agent after ablation.

[0903] 21. The method of any one of the preceding embodiments, wherein the method comprises administering a chemotherapeutic combination comprising one or more antineoplastic agents and wherein at least one of the antineoplastic agents is selected from 5 -fluorouracil, oxaliplatin, leucovorin, capecitabine or irinotecan.

[0904] 22. A method of treating a subject having cancer, the method comprising administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising one or more antineoplastic agents and wherein at least one of the antineoplastic agents is selected from 5 -fluorouracil, oxaliplatin, leucovorin, capecitabine or irinotecan.

[0905] 23. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as a first line therapy.

[0906] 24. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as a second line therapy.

[0907] 25. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as neoadjuvant therapy. 26. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as adjuvant therapy.

[0908] 27. The method of any one of the preceding embodiments, wherein the chemotherapeutic combination is 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX.

[0909] 28. The method of any one of the preceding embodiments, wherein the chemotherapeutic combination is FOLFOX.

[0910] 29. The method of any one of the preceding embodiments, wherein the antibody or an antigen binding fragment thereof that binds to clusterin and / or FOLFOX is administered at least prior to ablation of the one or more liver metastases.

[0911] 30. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as a single therapy or in combination with FOLFOX.

[0912] 31. The method of any one of the preceding embodiments, wherein the one or more liver metastases originates from or is caused by an invasive adenocarcinoma or metastatic cancer.

[0913] 32. The method of any one of the preceding embodiments, wherein the one or more liver metastases originates from, or is caused by colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0914] 33. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or FOLFOX are administered as a first line therapy.

[0915] 34. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or FOLFOX are administered as a second line therapy. 35. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or FOLFOX are administered as a neoadjuvant therapy.

[0916] 36. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or FOLFOX are administered as an adjuvant therapy.

[0917] 37. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0918] 38. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13.

[0919] 39. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15.

[0920] 40. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin 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. 41. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of between approximately 3 mg / kg to approximately 20 mg / kg.

[0921] 42. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of approximately 6 mg / kg.

[0922] 43. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of approximately 9 mg / kg.

[0923] 44. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of approximately 12 mg / kg.

[0924] 45. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) selected between approximately 400 mg to approximately 1000 mg.

[0925] 46. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) selected from approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0926] 47. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of between approximately 800 mg to approximately 400 mg.

[0927] 48. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of approximately 600 mg and / or of approximately 450 mg.

[0928] 49. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered once weekly.

[0929] 50. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered for a period of at least 12 weeks. 51. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as an intravenous infusion.

[0930] 52. The method of any one of the preceding embodiments, wherein FOLFOX comprises administration of oxaliplatin at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) at a dose of between approximately 200 mg / m2to approximately 400 mg / m2followed by at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m2.

[0931] 53. The method of any one of the preceding embodiments, wherein FOLFOX comprises administration of oxaliplatin at a dose of approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5-Fluorouracil (5-FU) at a dose of approximately 400 mg / m2followed by at a dose of approximately 2400 mg / m2.

[0932] 54. The method of any one of the preceding embodiments, wherein FOLFOX is administered once every two weeks.

[0933] 55. The method of any one of the preceding embodiments, wherein FOLFOX is administered for a period of at least 12 weeks.

[0934] 56. The method of any one of the preceding embodiments, wherein the subject is treated for at least 1, at least 2, at least 3, or at least 4 cycles of FOLFOX and for at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 cycles of the antibody or antigen binding fragment thereof that binds to clusterin, wherein each cycle is approximately 14 days.

[0935] 57. The method of any one of the preceding embodiments, wherein the subject is treated for 4 cycles of FOLFOX and for 6 cycles of the antibody or antigen binding fragment thereof that binds to clusterin, wherein each cycle is approximately 14 days.

[0936] 58. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered intravenously at approximately 800 mg on Day 1 and Day 8 of each cycle and wherein FOLFOX is administered on Day 1 of Cycle 1 to Cycle 4 as follows: oxaliplatin at approximately 85 mg / m2IV bolus + leucovorin at approximately 400 mg / m2IV bolus + 5 -Fluorouracil (5-FU) at approximately 400 mg / m2IV bolus + 5-FU at approximately 2400 mg / m2continuous IV infusion over 46 hours. 59. The method of any one of the preceding embodiments, wherein the one or more metastasi s(es) comprises one or more liver metastasis(es).

[0937] 60. The method of any one of the preceding embodiments, wherein the method comprises ablation (resecting or thermo-ablation) of one or more tumors and / or one or more metastases after treatment.

[0938] 61. The method of any one of the preceding embodiments, wherein the method comprises ablation of one or more liver metastases at approximately 4 to at least 6 weeks after Cycle 4 of treatment or at approximately 2 to at least 4 weeks following the last dose of the antibody or antigen binding fragment thereof that binds to clusterin.

[0939] 62. The method of any one of the preceding embodiments, wherein the method comprises administering an adjuvant therapy after tumor and / or metastases ablation.

[0940] 63. The method of any one of the preceding embodiments, wherein the adjuvant therapy is immunotherapy, chemotherapy and / or radiation therapy.

[0941] 64. The method of any one of the preceding embodiments, wherein the subject is treated with immunotherapy, chemotherapy and / or radiation therapy.

[0942] 65. The method of any one of the preceding embodiments, wherein the immunotherapy comprises an antibody or an antigen binding fragment thereof that binds to clusterin.

[0943] 66. The method of any one of the preceding embodiments, wherein the immunotherapy comprises cetuximab, bevacizumab, panitumumab.

[0944] 67. The method of any one of the preceding embodiments, wherein the immunotherapy comprises an immune checkpoint inhibitor.

[0945] 68. The method of any one of the preceding embodiments, for use in the treatment of a solid tumor.

[0946] 69. The method of any one of the preceding embodiments, wherein the subject has a cancer selected from, or one or more tumors caused by, and / or one or more metastases originating from, or caused by, colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0947] 70. The method of any one of the preceding embodiments, wherein the one or more liver metastases is from, or caused by, colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

[0948] 71. The method of any one of the preceding embodiments, wherein the cancer is a metastatic cancer.

[0949] 72. The method of any one of the preceding embodiments, wherein the method is for treating a subject having colorectal carcinoma.

[0950] 73. The method of any one of the preceding embodiments, wherein the method is for treating a subject having one or more liver metastases from colorectal carcinoma.

[0951] 74. The method of any one of the preceding embodiments, wherein the subject has stage III or stage IV colon adenocarcinoma or rectal adenocarcinoma.

[0952] 75. The method of any one of the preceding embodiments, wherein the one or more tumors, one or more metastases or one or more liver metastases are at least partially resectable.

[0953] 76. The method of any one of the preceding embodiments, wherein the subject is candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

[0954] 77. The method of any one of the preceding embodiments, further comprising administering a preparation of tumor infiltrating lymphocytes (TILS) to the subject subsequent to ablation of the one or more tumors and / or metastases, wherein the preparation of tumor infiltrating lymphocytes is obtained (e.g., by isolating and expanding tumor infiltrating lymphocytes) from the subject’s one or more tumors and / or one or more metastases.

[0955] 78. The method of any one of the preceding embodiments, wherein the subject is lymphodepleted prior to administration of the preparation of tumor infiltrating lymphocytes. 79. The method of any one of the preceding embodiments, wherein the tumor infiltrating lymphocytes comprise CD3+PD1+T cells.

[0956] 80. The method of any one of the preceding embodiments, wherein the method comprises administering IL-2 to the subject.

[0957] 81. A method for treating cancer in a subject in need thereof, the method comprising administering one or more fixed dose(s) of an antibody or an antigen binding fragment thereof that binds to clusterin, wherein the fixed dose amount is selected between approximately 400 mg to approximately 1000 mg and wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0958] 82. A method for treating cancer in a subject in need thereof, the method comprising administering one or more fixed dose(s) of an antibody or an antigen binding fragment thereof that binds to clusterin, wherein the fixed dose amount is selected between approximately 400 mg to approximately 1000 mg and wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical 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%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13.

[0959] 83. A method for treating cancer in a subject in need thereof, the method comprising administering one or more fixed dose(s) of an antibody or an antigen binding fragment thereof that binds to clusterin, wherein the fixed dose amount is selected between approximately 400 mg to approximately 1000 mg and wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15. 84. A method for treating cancer in a subject in need thereof, the method comprising administering one or more fixed dose(s) of an antibody or an antigen binding fragment thereof that binds to clusterin, wherein the fixed dose amount is selected between approximately 400 mg to approximately 1000 mg and wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0960] 85. The method of any one of the preceding embodiments, wherein the fixed dose amount is approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0961] 86. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as a single therapy or as a combination therapy with one or more antineoplastic agent(s), chemotherapeutic combinations or with radiation therapy.

[0962] 87. The method of any one of the preceding embodiments, wherein the taxane is paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel.

[0963] 88. The method of any one of the preceding embodiments, wherein the method results in an improved prognostic and / or in a clinical benefit for the subject.

[0964] 89. The method of any one of the preceding embodiments, wherein the method comprises administering an antibody that binds to secreted clusterin.

[0965] 90. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin binds to a polypeptide comprising an amino acid sequence comprising amino acid residues 228 to 449 of SEQ ID NO:42 or a portion thereof.

[0966] 91. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin binds to a polypeptide comprising an amino acid sequence comprising amino acid residues 375 to 449 of SEQ ID NO:42 or a portion thereof.

[0967] 92. The method of any one of the preceding embodiments, wherein the antibody or antigen binding fragment thereof that binds to clusterin binds to a polypeptide comprising an amino acid sequence comprising amino acid residues 421 to 443 of SEQ ID NO:42 or a portion thereof. 93. The method of any one of the preceding embodiments, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is provided as a single unit dose.

[0968] 94. The method of any one of the preceding embodiments, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is provided in a vial(s) or container(s) for singleuse.

[0969] 95. The method of any one of the preceding embodiments, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is provided as a single unit dose and for single-use at each treatment cycle.

[0970] 96. A combination therapy comprising a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX, wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0971] 97. A combination therapy comprising a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX, wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical 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%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13.

[0972] 98. A combination therapy comprising a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX, wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15.

[0973] 99. A combination therapy comprising a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX, wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0974] 100. The combination therapy of any one of the preceding embodiments, wherein the combination therapy comprises the antibody or antigen binding fragment thereof that binds to clusterin and FOLFOX.

[0975] 101. The combination therapy of any one of the preceding embodiments, wherein the pharmaceutical composition comprises a fixed dose amount of the antibody selected between approximately 400 mg to approximately 1000 mg.

[0976] 102. The combination therapy of any one of the preceding embodiments, wherein the pharmaceutical composition comprises a fixed dose amount of the antibody of approximately approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0977] 103. The combination therapy of any one of the preceding embodiments, wherein FOLFOX comprises oxaliplatin for administration at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin for administration at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) for administration at a dose of between approximately 200 mg / m2to approximately 400 mg / m2and for administration at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m2

[0978] 104. The combination therapy of any one of the preceding embodiments, wherein FOLFOX comprises oxaliplatin for administration at a dose of approximately 85 mg / m2, leucovorin for administration at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) for administration at a dose of approximately 400 mg / m2and for administration at a dose of approximately 2400 mg / m2. 105. The combination therapy of any one of the preceding embodiments for use in the treatment of colorectal cancer and / or in liver metastases hepatectomy.

[0979] 106. An article of manufacture comprising one or more vial(s) containing a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin formulated for administration by intra-venous infusion at a fixed dose amount selected between approximately 400 mg to approximately 1000 mg.

[0980] 107. The article of manufacturing of any one of the preceding embodiments, wherein the fixed dose amount is approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

[0981] 108. The article of manufacturing of any one of the preceding embodiments, further comprising one or more vial(s) containing one or more antineoplastic agent(s).

[0982] 109. The article of manufacturing of any one of the preceding embodiments, wherein the fixed dose amount of the antibody or antigen binding fragment thereof that binds to clusterin is provided as a single unit dose.

[0983] 110. The article of manufacturing of any one of the preceding embodiments, wherein the article of manufacturing is a kit.

[0984] 111. A unit dose form comprising an antibody or an antigen binding fragment thereof that binds to clusterin provided as a single unit dose, wherein the single unit dose comprises a fixed dose amount selected from between approximately 400 mg to approximately 1000 mg of the antibody or an antigen binding fragment thereof that binds to clusterin and wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0985] 112. A unit dose form comprising an antibody or an antigen binding fragment thereof that binds to clusterin provided as a single unit dose, wherein the single unit dose comprises a fixed dose amount selected from between approximately 400 mg to approximately 1000 mg of the antibody or an antigen binding fragment thereof that binds to clusterin and wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical 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%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13.

[0986] 113. A unit dose form comprising an antibody or an antigen binding fragment thereof that binds to clusterin provided as a single unit dose, wherein the single unit dose comprises a fixed dose amount selected from between approximately 400 mg to approximately 1000 mg of the antibody or an antigen binding fragment thereof that binds to clusterin and wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15.

[0987] 114. A unit dose form comprising an antibody or an antigen binding fragment thereof that binds to clusterin provided as a single unit dose, wherein the single unit dose comprises a fixed dose amount selected from between approximately 400 mg to approximately 1000 mg of the antibody or an antigen binding fragment thereof that binds to clusterin and wherein the antibody or antigen binding fragment thereof that binds to clusterin 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.

[0988] 115. The unit dose form of any one of the preceding embodiments, wherein the unit dose form is a unit package comprising one or more single unit doses of the antibody or antigen binding fragment thereof that binds to clusterin.

[0989] 116. The unit dose form of any one of the preceding embodiments, wherein the one or more single unit doses comprise a fixed dose amount of approximately 800 mg, approximately 600 mg or approximately 450 mg.

[0990] 117. The unit dose form of any one of the preceding embodiments, wherein the single unit doses is for single-use. 118. The unit dose form of any one of the preceding embodiments, further comprising an antineoplastic agent or chemotherapeutics combination.

[0991] 119. A method for promoting / inducing (formation, enrichment, apparition of) tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases for the treatment of cancer in a subject in need thereof, the method comprising administering an antibody or an antigen binding fragment thereof that binds to clusterin to the subject.

[0992] 120. The method of embodiment 119, wherein the method is as set forth in any one of the preceding embodiments.

[0993] 121. A method for the prognosis of cancer comprising detecting tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases of a subject treated with an antibody or an antigen binding fragment thereof that binds to clusterin.

[0994] 122. The method of any one of the preceding embodiments, wherein the presence and / or abundance of tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases is indicative of favorable prognosis (e.g., clinical response, clinical benefit, remission, disease-free survival, overall survival).

[0995] 123. A method for monitoring a response to a treatment that comprises an antibody or an antigen binding fragment thereof that binds to clusterin to a subject in need thereof, the method comprising quantifying the level(s) of carcinoembryonic Antigen (CEA) (expression) in a sample obtained from the subject.

[0996] 124. The method of any one of the preceding embodiments, wherein a reduction in the level of CEA (expression) compared to base-line (e.g., level at screening, before treatment) is indicative of at least partial efficacy.

[0997] 125. The method of any one of the preceding embodiments, wherein a reduction in the level(s) of CEA (expression) compared to base-line (e.g., level at screening, before treatment) is indicative of at least partial regression of one or more tumors and / or of one or more metastases.

[0998] 126. The method of any one of embodiments 123 to 125, wherein the sample is a blood sample or a serum sample.

[0999] 127. A method for monitoring a response to a treatment that comprises an antibody or an antigen binding fragment thereof that binds to clusterin to a subject in need thereof, the method comprising detecting tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases of the subject.

[1000] 128. The method of embodiment 127, wherein the detection is performed on a biopsy and / or on resected tumor and / or on resected metastasis (e.g., obtained during the course or after treatment).

[1001] 129. The method of embodiment 121 or 128, wherein the treatment comprises a method as set forth in any one of the preceding embodiments.

[1002] All publications, patents, and Accession numbers mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[1003] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[1004] REFERENCES

[1005] All patents, patent applications and publications referred to throughout the application are incorporated herein by reference.

[1006] Alethia Biotherapeutics Inc. Clinical Trial Protocol entitled “AB-16B5 Combined With Docetaxel in Subjects With Metastatic Non-Small Cell Lung Cancer” identifier number: NTC043634620 published on clinicaltrials.gov on April 28, 2020.

[1007] Al-Lazikani et al., Standard conformations for the canonical structures of immunoglobulins. J Mol Biol 273:927-948, 1997.

[1008] Ammar H, Closset JL. Clusterin activates survival through the phosphatidylinositol 3-kinase / Akt pathway. J Biol Chem. 283: 12851-61 (2008).

[1009] Andrew C.R. Martin, Antibody Engineering Vol. 2, Chapter 3: Protein Sequence and Structure Analysis of Antibody Variable Domains. R. Kontermann and S. Dubel (eds.), DOI 10.1007 / 978-3-642-01147-4_3, # Springer- Verlag Berlin Heidelberg 2010. Brochet et al. IMGT / V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucl Acids Res 36:W503-W508, 2008.

[1010] Chi, K. N., et al., Randomized Phase II Study of Docetaxel and Prednisone With or Without OGX-011 in Patients With Metastatic Castration-Resistant Prostate Cancer, J Clin Oncol. 28 :4247-4254, 2010.

[1011] Engstrand J, Nilsson H, Stromberg C, Jonas E, Freedman J. Colorectal cancer liver metastases - a population-based study on incidence, management and survival. BMC Cancer. 18: 78 (2018).

[1012] Eisenhauer, E.A., P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij; New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1); Eur J Cancer, 45 (2009) 228 -247.

[1013] Hodge, J.W. Garnett, C.T., Farsaci, B., et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int. J. Cancer. 133: 624-636 (2013).

[1014] Jiang X, Dudzinski S, Beckermann KE, et al. MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy. Journal for ImmunoTherapy of Cancer 2020;8:e000328. doi : 10.1136 / j itc-2019-000328.

[1015] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 119: 1420-8 (2009).

[1016] Lenferink AE, Cantin C, Nantel A, Wang E, Durocher Y, Banville M, Paul-Roc B, Marcil A, Wilson MR, O'Connor-McCourt MD. Transcriptome profiling of a TGF -beta-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies. Oncogene 29: 831-44 (2009).

[1017] Ferrario, C., Laurin, J., Van Kempen, L., Lambert, C., Spatz, A., Markova, O., Batist, G., Adrian Langleben, A., Filion, M., Jolivet, J. Phase 1 first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies. Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl): Abstract nr CT098. doi: 10.1158 / 1538-7445.AM2017- CT098.

[1018] MacCallum, R. M., Martin, A. C. R. and Thornton, J. T. 'Antibody-antigen interactions: Contact analysis and binding site topography' J. Mol. Biol. 262:732-745, 1996.

[1019] Munoz-Erazo, L. et al., Tertiary lymphoid structures in cancer- consideration for patient prognosis, Cellular and Molecular Immunology, 12:570-575, 2020.

[1020] Ojima I., Brendan, L., Siyeon, L., Wang, C. and Wang, X., Taxane anticancer agents: a patent perspective, Expert Opin Ther Pat. 2016: 26(1): 1-20.

[1021] Peng, M. et al., The Role of Clusterin in Canacer Metastasis, Cancer Management and Research 11 :2405-2414, 2019.

[1022] Radvanyl, L.G., Tumor-Infiltrating lymphocyte therapy: addressing prevailing questions, The Cancer Journal 21(6):450-464, 2015.

[1023] Romeo, E. et al., The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System, Cells: 8(5):460, 2019.

[1024] Sautes-Fridman, C. et al., Tertiary lymphoid structures in the era of cancer immunotherapy, Nature Review, Cancer, Vol. 19:307-325, 2019.

[1025] Seymour, L. et al., iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics, Lancet Oncol. 18(3)el43-el52, 2017.

[1026] Shibue, T., Weinberg, R. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14: 611-629 (2017).

[1027] Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 73: 233-254 (2023).

[1028] Taki, M. et al., Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition, Clin Can Res., 27:4669-4679, 2021.

[1029] Terry, S., Savagner, P., Ortiz-Cuaran, S., Mahjoubi, L., Saintigny, P., Thiery, J.-P. and Chouaib, S., New insights into the role of EMT in tumor immune escape. Mol Oncol, 11: 824-846 (2017). Tremblay, G., Malouin, M., Grothe, S., Kalbakji, A., Roy, S., Page, M., Paul-Roc, B., & Sulea, T., Lenferink, A., O'Connor-Mccourt, M., & Filion, M. (2011). AB-16B5, a therapeutic monoclonal antibody against human clusterin that blocks the epithelial -to-mesenchymal transition. Cancer Research. 70: 1467- 1467 (2010).

[1030] Tremblay, G., Viau, E., Malouin, M., Turcotte, E. Fortin, A., & Filion, M.: Pre-clinical evaluation of AB- 16B5, a monoclonal antibody specific for tumor-associated sCLU, demonstrates therapeutic potential as an inhibitor of EMT in prostate, pancreatic and lung cancer. Cancer Research. 71 : LB-33 (2011).

[1031] Tremblay, G., Viau, E., Filion, M. The EMT inhibitor AB-16B5 interacts with specific isoforms of secreted clusterin. Cancer Research. 72: LB-297 (2012).

[1032] Waldner MJ, Neurath MF. TGFP and the Tumor Microenvironment in Colorectal Cancer. Cells 12: 1139 (2023).

[1033] Wu and Kabat, An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J Exp Med 132:211-250, 1993.

[1034] Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, Rizvi SM, Qin A, Waninger JJ, Lang X, Chopra Z, El Naqa I, Zhou J, Bian Y, Jiang L, Tezel A, Skvarce J, Achar RK, Sitto M, Rosen BS, Su F, Narayanan SP, Cao X, Wei S, Szeliga W, Vatan L, Mayo C, Morgan MA, Schonewolf CA, Cuneo K, Kryczek I, Ma VT, Lao CD, Lawrence TS, Ramnath N, Wen F, Chinnaiyan AM, Cieslik M, Alva A, Zou W. Liver metastasis restrains immunotherapy efficacy via macrophage- mediated T cell elimination. Nat Med. 27: 152-164 (2021).

[1035] Zarour LR, Anand S, Billingsley KG, Bisson WH, Cercek A, Clarke MF, Coussens LM, Gast CE, Geltzeiler CB, Hansen L, Kelley KA, Lopez CD, Rana SR, Ruhl R, Tsikitis VL, Vaccaro GM, Wong MH, Mayo SC. Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions. Cell Mol Gastroenterol Hepatol. 3: 163-173 (2017).

[1036] Zhou, J. et al., Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin, Scientific Reports, 6:29521, 2016. International application No. PCT / CA2006 / 001505 filed on September 13, 2006, in the name of National Research Council of Canada and published March 22, 2007, under No. W02007 / 030930 Al.

[1037] International application No. PCT / CA2010 / 001882 filed on November 24, 2010, in the name of Alethia Biotherapeutics Inc. and published on June 3, 2011, under number WO201 1 / 063523 Al.

[1038] International application No. PCT / CA2021 / 050572 filed on April 27, 2021, in the name of Alethia Biotherapeutics Inc. and published on November 3, 2022, under No. WO2022 / 226623 Al.

[1039] International application No. PCT / CA2022 / 050632 filed on April 26, 2022, in the name of Alethia Biotherapeutics Inc. and published on November 3, 2022, under No. WO2022 / 226637 Al.

[1040] International application No. PCT / CA2022 / 050636 filed on April 27, 2022, in the name of Alethia Biotherapeutics Inc. and published on November 3, 2022, under No. WO2022 / 226641A1.

[1041] International application No. PCT / CA2023 / 050151 filed on February 6, 2023, in the name of Alethia Biotherapeutics Inc. and published on August 10, 2023, under No. WO2023 / 147673 Al.

[1042] Table 15- SEQUENCE TABLE

[1043]

[1044]

Claims

WE CLAIM:

1. A method of treating a subject having metastatic colorectal cancer, the method comprising administering an antibody or antigen binding fragment thereof that binds to clusterin in combination with FOLFOX.

2. The method of claim 1 , wherein the antibody or antigen binding fragment thereof that binds to clusterin and FOLFOX are administered prior to resection of one or more metastases.

3. The method of claim 1 or 2, wherein the method results in regression of at least one of the one or more metastases.

4. The method of claim 2 or 3, wherein the one or more metastases comprise one or more liver metastases.

5. A method of treating one or more liver metastases in a subject in need thereof, the method comprising administering an antibody or an antigen binding fragment thereof that binds to clusterin.

6. The method of claim 5, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as a single therapy or in combination with FOLFOX.

7. The method of claim 5 or 6, wherein the antibody or an antigen binding fragment thereof that binds to clusterin and / or FOLFOX is administered at least prior to ablation of the one or more liver metastases.

8. The method of any one of claims 5 to 7, wherein the one or more liver metastases originates from or is caused by an invasive adenocarcinoma or metastatic cancer.

9. The method of any one of claims 5 to 8, wherein the one or more liver metastases originates from or is caused by colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

10. The method of any one of claims 5 to 9, wherein the one or more liver metastases originates from, or is caused by colorectal cancer.

11. The method of any one of the preceding claims, wherein the method comprises ablation of one or more tumors and / or of one or more metastases.

12. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or FOLFOX are administered as a first-line therapy.

13. A method for inhibiting, delaying, or reducing recurrence and / or growth of tumor(s) and / or metastases subsequent to ablation of the tumors and / or metastases or for preventing or reducing persistence of tumor(s) or metastasi s(es) in a subject having cancer, the method comprising administering at least prior to ablation an antibody or an antigen binding fragment thereof that binds to clusterin.

14. A method of treating a subject having one or more tumors and / or one or more metastases, the method comprising administering an antibody or an antigen binding fragment thereof that binds to clusterin at least prior to ablation of the one or more tumors and / or one or more metastases.

15. The method of claim 13 or 14, wherein the method further comprises administering one or more antineoplastic agent at least prior to ablation.

16. The method of claim 15, wherein the method comprises administering a chemotherapeutic combination comprising two or more antineoplastic agents and wherein at least one of the antineoplastic agents is selected from 5-fluorouracil, oxaliplatin, leucovorin, capecitabine or irinotecan.

17. A method of treating a subject having cancer, the method comprising administering a combination therapy comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination comprising two or more antineoplastic agents and wherein at least one of the antineoplastic agents is selected from 5-fluorouracil, oxaliplatin, leucovorin, capecitabine or irinotecan.

18. The method of any one of claims 13 to 17, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as a first line therapy.

19. The method of any one of claimsl3 to 18, wherein the antibody or antigen binding fragment thereof that binds to clusterin and / or the chemotherapeutic combination are administered as neoadjuvant therapy.

20. The method of any one of claims 13 to 19, wherein the chemotherapeutic combination is 5- FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX.

21. The method of any one of claims 13 to 20, wherein the chemotherapeutic combination is FOLFOX.

22. The method of claim 20 or 21 wherein the antibody or antigen binding fragment thereof that binds to clusterin and FOLFOX are administered as a first line therapy.

23. The method of any one of claims 1 to 12, or 20 to 22, wherein the antibody or antigen binding fragment thereof that binds to clusterin and FOLFOX are administered as a neoadjuvant therapy.

24. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises: a. a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13; b. a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 12 and a heavy chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13; c. a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15 or; d. 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.

25. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of between approximately 3 mg / kg to approximately 20 mg / kg.

26. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of approximately 6 mg / kg.

27. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of approximately 9 mg / kg.

28. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered at a dose of approximately 12 mg / kg.

29. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) selected between approximately 400 mg to approximately 1000 mg.

30. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) selected from approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

31. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of between approximately 800 mg to approximately 400 mg.

32. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered in one or more fixed dose(s) of approximately 800 mg followed by one or more fixed dose(s) of approximately 600 mg and / or of approximately 450 mg.

33. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered once weekly.

34. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered for a period of at least 12 weeks.

35. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as an intravenous infusion.

36. The method of any one of claims 1 to 12, or 20 to 35, wherein FOLFOX comprises administration of oxaliplatin at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) at a dose of between approximately 200 mg / m2to approximately 400 mg / m2followed by at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m2.

37. The method of any one of claims 1 to 12, or 20 to 36, wherein FOLFOX comprises administration of oxaliplatin at a dose of approximately 85 mg / m2, leucovorin at a dose of approximately 400 mg / m2and 5-Fluorouracil (5-FU) at a dose of approximately 400 mg / m2followed by at a dose of approximately 2400 mg / m2.

38. The method of any one of the claims 1 to 12, or 20 to 37, wherein FOLFOX is administered once every two weeks.

39. The method of any one of the claims 1 to 12, or 20 to 38, wherein FOLFOX is administered for a period of at least 12 weeks.

40. The method of any one of claims 1 to 12, or 20 to 39, wherein the subject is treated for at least 1, at least 2, at least 3, or at least 4 cycles of FOLFOX and for at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 cycles of the antibody or antigen binding fragment thereof that binds to clusterin, wherein each cycle is approximately 14 days.

41. The method of any one of claims 1 to 12, or 20 to 40, wherein the subject is treated for 4 cycles of FOLFOX and for 6 cycles of the antibody or antigen binding fragment thereof that binds to clusterin, wherein each cycle is approximately 14 days.

42. The method of any one claims 1 to 12, or 20 to 41, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered intravenously at approximately 800 mg on Day 1 and Day 8 of each cycle and wherein FOLFOX is administered on Day 1 of Cycle 1 to Cycle 4 as follows: oxaliplatin at approximately 85 mg / m2IV bolus + leucovorin at approximately 400 mg / m2IV bolus + 5 -Fluorouracil (5-FU) at approximately 400 mg / m2IV bolus + 5-FU at approximately 2400 mg / m2continuous IV infusion over 46 hours.

43. The method of any one claims 13 to 42, wherein the one or more metastasi s(es) comprises one or more liver metastasis(es).

44. The method of any one of the preceding claims, wherein the method comprises ablation of one or more tumors or one or more metastases after treatment.

45. The method of any one of the preceding claims, wherein the method comprises ablation of one or more liver metastases.

46. The method of any one of the preceding claims, wherein the method comprises administering an adjuvant therapy after ablation of one or more tumors or one or more metastases.

47. The method of claim 46, wherein the adjuvant therapy is immunotherapy, chemotherapy and / or radiation therapy.

48. The method of claim 47, wherein the immunotherapy comprises an antibody or an antigen binding fragment thereof that binds to clusterin.

49. The method of claim 47, wherein the immunotherapy comprises cetuximab, bevacizumab, panitumumab.

50. The method of claim 47, wherein the immunotherapy comprises an immune checkpoint inhibitor.

51. The method of any one of the preceding claims, for use in the treatment of a solid tumor.

52. The method of any one of claims 5 to 51, wherein the subject has a cancer selected from, or one or more tumors caused by, colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

53. The method of any one of claims 5 to 52, wherein the one or more liver metastases is from, or caused by colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

54. The method of any one of claims 5 to 53, wherein the method is for treating a subject having colorectal carcinoma.

55. The method of any one of claims 5 to 54, wherein the method is for treating a subject having one or more liver metastases from colorectal carcinoma.

56. The method of any one of any one of the preceding claims, wherein the subject has stage III or stage IV colon adenocarcinoma or rectal adenocarcinoma.

57. The method of any one of the preceding claims, wherein the subject has one or more tumors, one or more metastases or one or more liver metastases that are at least partially resectable.

58. The method of any one of the preceding claims, wherein the subject is candidate to neoadjuvant FOLFOX followed by partial hepatectomy.

59. The method of any one of the preceding claims, further comprising administering a preparation of tumor infiltrating lymphocytes (TILS) to the subject subsequent to ablation of the one or more tumors and / or metastases, wherein the preparation of tumor infiltrating lymphocytes is obtained (by isolating and expanding tumor infiltrating lymphocytes) from the subject’s one or more metastases and / or one or more tumors.

60. The method of claim 59, wherein the subject is lymphodepleted prior to administration of the preparation of tumor infiltrating lymphocytes.

61. The method of any one of claims 59 or 60, wherein the tumor infiltrating lymphocytes comprises CD3+PD1+T cells.

62. The method of any one of the preceding claims, wherein the method comprises administering IL-2 to the subject.

63. A method for treating cancer in a subject in need thereof, the method comprising administering one or more fixed dose(s) of an antibody or an antigen binding fragment thereof that binds to clusterin, wherein the fixed dose amount is selected between approximately 400 mg to approximately 1000 mg and wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises: a. a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chainvariable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13; b. a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical 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%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13 or; c. a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15.

64. The method of claim 63, wherein the fixed dose amount is approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

65. The method of claim 63 or 64, wherein the antibody or antigen binding fragment thereof that binds to clusterin is administered as a single therapy or as a combination therapy with one or more antineoplastic agent(s), chemotherapeutic combinations or with radiation therapy.

66. The method of claim 65, wherein antineoplastic agents is selected from an alkylating agent, an anti-metabolite, an alkaloid, an anti-tumor antibiotic or combination thereof.

67. The method of claim 15 or 66, wherein the one or more antineoplastic agent is selected from altretamine, busulfan, carboplatin, oxaliplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5-fluorouracil, 6- mercaptopurine, azacytidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, vincristine, vinblastine, vinorelbine, taxanes, etoposide, teniposide, irinotecan, topotecan, daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, valrubicin, capecitabine or leucovorin or chemotherapeutic combination thereof comprising two or more antineoplastic agents.

68. The method of claim 67, wherein the taxane is paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, milataxel, ortataxel, te setaxel.

69. The method of any one of claims 63 to 68, wherein the cancer is colorectal cancer, endometrial cancer, breast cancer, liver cancer, prostate cancer, renal cancer, bladder cancer, cervical cancer, ovarian cancer, rectal cancer, pancreatic cancer, lung cancer (non-small cell lung cancer), gastric cancer, head and neck cancer, thyroid cancer, cholangiocarcinoma, mesothelioma, kidney cancer, esophageal cancer or melanoma.

70. The method of any one of the preceding claims, wherein the method results in an improved prognostic and / or in a clinical benefit for the subject.

71. The method of any one of the preceding claims, wherein the method comprises administering an antibody that binds to secreted clusterin.

72. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin binds to a polypeptide comprising an amino acid sequence comprising amino acid residues 228 to 449 of SEQ ID NO:42 or a portion thereof.

73. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin binds to a polypeptide comprising an amino acid sequence comprising amino acid residues 375 to 449 of SEQ ID NO:42 or a portion thereof.

74. The method of any one of the preceding claims, wherein the antibody or antigen binding fragment thereof that binds to clusterin binds to a polypeptide comprising an amino acid sequence comprising amino acid residues 421 to 443 of SEQ ID NO:42 or a portion thereof.

75. The method of any one of the preceding claims, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is provided as a single unit dose.

76. The method of any one of the preceding claims, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is provided in a vial(s) or container(s) for single-use.

77. The method of any one of the preceding claims, wherein the antibody or an antigen binding fragment thereof that binds to clusterin is provided as a single unit dose and for single-use at each treatment cycle.

78. A combination therapy comprising a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin and a chemotherapeutic combination selected from 5-FU / leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX, wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises:a. a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13; b. a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical 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%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13 or; c. a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15.

79. The combination therapy of claim 78, wherein the combination therapy comprises the antibody or antigen binding fragment thereof that binds to clusterin and FOLFOX.

80. The combination therapy of claim 78 or 79, wherein the pharmaceutical composition comprises a fixed dose amount of the antibody selected between approximately 400 mg to approximately 1000 mg.

81. The combination therapy of any one of claims 78 to 80, wherein the pharmaceutical composition comprises a fixed dose amount of the antibody of approximately approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

82. The combination therapy of any one of claims 78 to 81, wherein FOLFOX comprises oxaliplatin for administration at a dose of between approximately 50 mg / m2to approximately 85 mg / m2, leucovorin for administration at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5- FU) for administration at a dose of between approximately 200 mg / m2to approximately 400 mg / m2and for administration at a dose of between approximately 1600 mg / m2to approximately 2400 mg / m283. The combination therapy of any one of claims 78 to 82, wherein FOLFOX comprises oxaliplatin for administration at a dose of approximately 85 mg / m2, leucovorin for administration at a dose of approximately 400 mg / m2and 5 -Fluorouracil (5-FU) for administration at a dose of approximately 400 mg / m2and for administration at a dose of approximately 2400 mg / m2.

84. The combination therapy of any one of claims 78 to 83 for use in the treatment of colorectal cancer and / or in liver metastases hepatectomy.

85. An article of manufacture comprising one or more vial(s) containing a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that binds to clusterin formulated for administration by intra-venous infusion at a fixed dose amount selected between approximately 400 mg to approximately 1000 mg.

86. The article of manufacturing of claim 85, wherein the fixed dose amount is approximately 800 mg, approximately 600 mg and / or approximately 450 mg.

87. The article of manufacturing of claim 85 or 86, further comprising one or more vial(s) containing one or more antineoplastic agent(s).

88. The article of manufacturing of any one of claims 85 to 87, wherein the fixed dose amount of the antibody or antigen binding fragment thereof that binds to clusterin is provided as a single unit dose.

89. The article of manufacturing of any one of claims 85 to 88, wherein the article of manufacturing is a kit.

90. A unit dose form comprising an antibody or an antigen binding fragment thereof that binds to clusterin provided as a single unit dose, wherein the single unit dose comprises a fixed dose amount selected from between approximately 400 mg to approximately 1000 mg of the antibody or an antigen binding fragment thereof that binds to clusterin and wherein the antibody or antigen binding fragment thereof that binds to clusterin comprises: a. a light chain variable region comprising the complementarity determining regions (CDRs) of the light chain variable region set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the CDRs of the heavy chain variable region set forth in SEQ ID NO: 13;b. a light chain variable region having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical 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%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 13 or; c. a light chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical with the amino acid sequence set forth in SEQ ID NO: 15.

91. The unit dose form of claim 90, wherein the unit dose form is a unit package comprising one or more single unit doses of the antibody or antigen binding fragment thereof that binds to clusterin.

92. The unit dose form of claim 90 or 91, wherein the one or more single unit doses comprise a fixed dose amount of approximately 800 mg, approximately 600 mg or approximately 450 mg.

93. The unit dose form of any one of claims 90 to 92, wherein the single unit doses is for singleuse.

94. The unit dose form of any one of claims 90 to 93, further comprising an antineoplastic agent or chemotherapeutics combination.

95. A method for promoting and / or inducing formation, enrichment, or apparition of tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases for the treatment of cancer in a subject in need thereof, the method comprising administering an antibody or an antigen binding fragment thereof that binds to clusterin to the subject.

96. The method of claim 95, wherein the method is as set forth in any one of claims 1 to 77.

97. A method for the prognosis of cancer comprising detecting tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases of a subject treated with an antibody or an antigen binding fragment thereof that binds to clusterin.

98. The method of claim 97, wherein the treatment comprises the method set forth in any one of claims 1 to 77.

99. The method of claim 97 or 98, wherein the presence of tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases is indicative of favorable prognosis.

100. A method for monitoring the response to a treatment that comprises administering an antibody or an antigen binding fragment thereof that binds to clusterin to a subject in need thereof, the method comprising quantifying the levels of CEA in a sample obtained from the subject.

101. The method of claim 100, wherein a reduction of the levels of CEA compared to base-line is indicative of at least partial efficacy.

102. The method of claim 100 or 101, wherein a reduction of the levels of CEA compared to base-line is indicative of at least partial regression of one or more tumors and / or of one or more metastases.

103. The method of any one of claims 100 to 102, wherein the treatment comprises the method as set forth in any one of claims 1 to 77.

104. The method of any one of claims 100 to 103, wherein the sample is a blood sample or a serum sample.

105. A method for monitoring the response to a treatment that comprises administering an antibody or an antigen binding fragment thereof that binds to clusterin to a subject in need thereof, the method comprising detecting tertiary lymphoid structures in the microenvironment of one or more tumors and / or of one or more metastases of the subject.

106. The method of claim 105, wherein the sample is a biopsy or a resected metastasis.

107. The method of claim 105 or 106, wherein the treatment comprises the method as set forth in any one of claims 1 to 77.