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WO2025147775A1 - Polythérapie pour le traitement néoadjuvant pour le cancer - Google Patents

Polythérapie pour le traitement néoadjuvant pour le cancer

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Publication number
WO2025147775A1
WO2025147775A1 PCT/CA2025/050032 CA2025050032W WO2025147775A1 WO 2025147775 A1 WO2025147775 A1 WO 2025147775A1 CA 2025050032 W CA2025050032 W CA 2025050032W WO 2025147775 A1 WO2025147775 A1 WO 2025147775A1
Authority
WO
WIPO (PCT)
Prior art keywords
approximately
antibody
cancer
clusterin
antigen binding
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CA2025/050032
Other languages
English (en)
Inventor
Mario Filion
Julie Laurin
Jacques Jolivet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alethia Biotherapeutics Inc
Original Assignee
Alethia Biotherapeutics Inc
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Filing date
Publication date
Application filed by Alethia Biotherapeutics Inc filed Critical Alethia Biotherapeutics Inc
Publication of WO2025147775A1 publication Critical patent/WO2025147775A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • 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.
  • 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.
  • TLS tertiary lymphoid structures
  • kits for treating cancer in a human in need thereof comprising administering a therapeutically effective amount of an antibody that binds to human clusterin.
  • 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).
  • 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.
  • the chemotherapeutic combination comprises at least three antineoplastic agents selected from 5-fluorouracil, oxaliplatin, leucovorin, or irinotecan.
  • the chemotherapeutic combination comprises oxaliplatin, leucovorin and 5-fluorouracil.
  • the antibody or an antigen binding fragment thereof that binds to clusterin and/or the chemotherapeutic combination are administered as a first-line therapy.
  • the antibody or an antigen binding fragment thereof that binds to clusterin and/or the chemotherapeutic combination are administered as a second-line therapy.
  • 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.
  • the chemotherapeutic combination is suitable for treatment of colorectal cancer.
  • 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.
  • the method of the present disclosure comprises administering an antibody or an antigen binding fragment that binds to secreted clusterin.
  • 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.
  • the anti-clusterin antibody or an antigen binding fragment thereof is generally administered once weekly.
  • 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.
  • the method may comprise administering an adjuvant therapy after tumor or metastasi s(es) ablation.
  • adjuvant therapy may comprise for example, immunotherapy, chemotherapy and/or radiation therapy.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition comprises a fixed dose amount of the anti-clusterin antibody selected between approximately 400 mg to approximately 1000 mg.
  • the combination therapy of the present disclosure may comprise FOLFOX.
  • FOLFOX comprises oxaliplatin for administration at a dose of between approximately 50 mg/m 2 to approximately 85 mg/m 2 , leucovorin for administration at a dose of approximately 400 mg/m 2 and 5-Fluorouracil (5-FU) for administration at a dose of between approximately 200 mg/m 2 to approximately 400 mg/m 2 and for administration at a dose of between approximately 1600 mg/m 2 to approximately 2400 mg/m 2 .
  • 5-FU 5-Fluorouracil
  • the combination therapy is for use in the treatment of colorectal cancer and/or in liver metastasis(es) hepatectomy.
  • 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.
  • the fixed dose amount of the antibody or antigen binding fragment thereof that binds to clusterin is provided as a single unit dose.
  • the article of manufacture may comprise a single unit dose of the anti-clusterin antibody or antigen binding fragment thereof.
  • the article of manufacture may further comprise one or more vial(s) containing one or more antineoplastic agent(s).
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • identity 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 %.
  • the percentage of identity expressed herein such as in the expression “% identical” is with respect to the entire length of the sequence.
  • 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.
  • ortholog with respect to a particular gene or protein refers to a gene or protein of a distinct species.
  • 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.
  • 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).
  • 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.
  • 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).
  • binding 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 ' 6 M (e.g., ⁇ 5x10 ’ 7 M, ⁇ 2x10 - 7 M, ⁇ 10 - 7 M, ⁇ 5x10 ' 8 M, ⁇ 2x10 ' 8 M, ⁇ 10 ' 8 M, ⁇ 5x10 ' 9 M, ⁇ 4x10 ’ 9 M, ⁇ 3x10 ’ 9 M, ⁇ 2x10 ' 9 M, or ⁇ 10 ' 9 M 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).
  • a binding agent e.g., antibody such as single domain antibody
  • clusterin e.g., human clusterin such as human TA-
  • terapéuticaally 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.
  • 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.
  • Figure 1 Tumor Volume (Day 22) in a Syngeneic CT26 CRC Mouse Model.
  • Figure 7 Histopathological response scoring scheme.
  • the anti-clusterin antibody or antigen binding fragment thereof of the present disclosure is capable of inhibiting epithelial to mesenchymal transition in carcinoma cells.
  • 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
  • all CDRs are identified using the Kabat definition which is the most commonly used definition (Wu and Kabat, 1970).
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:4, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:5, a CDRH3 having the amino acid sequence set forth in SEQ ID NO:6.
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a 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.
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence having at least 90% identity with the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region having an amino acid sequence at least 90% identity with the amino acid sequence set forth in SEQ ID NO: 11.
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 11.
  • the anti-clusterin antibody or antigen binding fragment thereof 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.
  • 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.
  • 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.
  • 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.
  • the anti-clusterin antibody or antigen binding fragment thereof comprises a light chain having an amino acid sequence identical the amino acid sequence set forth in SEQ ID NO: 14 and a heavy chain having an amino acid sequence identical to the amino acid sequence set forth in SEQ ID NO: 15.
  • the anti-clusterin antibody or antigen binding fragment thereof 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.
  • 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.
  • 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.
  • variants of the sequences disclosed herein are also encompassed by the present disclosure. Such variants include analogs or orthologs.
  • present disclosure therefore encompasses variants of the antibody or antigen binding fragments disclosed herein.
  • 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).
  • the isoelectric point of an antibody is modified via amino acid substitution. See, e.g. US20110076275.
  • modifying the isoelectric point of a polypeptide comprising an antibody results in a change in the antibody’s half-life.
  • 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.
  • 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.
  • mutations in one or more CDR(s), variable region or constant region may be performed by amino acid substitution.
  • substitutions include conservative amino acid substitutions or non-conservative amino acid substitutions. Exemplary substitutions are provided in Table 1.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 900 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 800 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 750 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 650 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 600 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 500 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 450 mg.
  • the one or more fixed dose(s) of the anti-clusterin antibody or an antigen binding fragment thereof is approximately 400 mg.
  • 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.
  • 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.
  • all doses are approximately 800 mg.
  • 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.
  • 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.
  • 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.
  • agent e.g., anti-clusterin antibody or antigen binding fragment thereof, or antineoplastic agent
  • pharmaceutically acceptable diluents e.g., preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
  • 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).
  • buffer content e.g., Tris-HCl., acetate, phosphate
  • pH and ionic strength e.g., arate, phosphate
  • 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.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
  • 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.
  • the pharmaceutical composition is formulated for administration parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially or intratumorally.
  • 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.
  • the article of manufacturing is for singleuse.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the subject is preferably a human subject.
  • 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.
  • the subject has or is selected for having a rectal adenocarcinoma.
  • 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.
  • 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.
  • the subject may have, for example, liver-dominant metastases Accordingly, the subject may have at least one or multiple liver metastases.
  • the subject is a candidate to neoadjuvant FOLFOX followed by partial hepatectomy.
  • the subject may have had resection of their primary colon or rectal adenocarcinoma in the past.
  • the subject may have a partially resectable or resectable primary cancer.
  • 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.
  • the subject may have received prior adjuvant chemotherapy and/or radiotherapy following resection of primary tumor or not.
  • 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)).
  • 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.
  • 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.
  • the subject has or is selected for having adequate organ and/or immune function.
  • the subject has or is selected for having a functional immune system.
  • the subject has or is selected for having one or more lesions that are immunologically cold.
  • the subject is or selected for being immunocompetent.
  • the subject has or is selected for not being immunosuppressed.
  • the subject has or is selected for having one or more lesions with poor infiltration of immune cells.
  • the level of immune cell infiltration may be determined by a trained pathologist.
  • the level of immune cell infiltration may be determined by computer-based quantification of tumor biopsy imaging.
  • the subject in need has a tumor that expresses or secrete clusterin.
  • the subject has or is selected for having one or more lesions having an EMT signature or showing signs of an EMT signature.
  • the EMT signature may be determined by a trained pathologist.
  • the EMT signature may be determined by computer-based quantification of tumor or tumor biopsy imaging.
  • the subject may optionally have not received concurrent administration of anti-VGFR, anti-EGFR, anti-VEGF or other biological or targeted therapy with neoadjuvant FOLFOX.
  • the subject may optionally be selected for not having a defective DNA mismatch repair (MMR-deficient) primary colorectal tumor.
  • MMR-deficient DNA mismatch repair
  • 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.
  • 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.
  • the subject may optionally be selected for not having an active Hepatitis B or C infection.
  • the subject may optionally be selected for not having a known history of alcohol or other substance abuse within the last year.
  • the subject may optionally be selected for not having a known hypersensitivity to FOLFOX.
  • 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.
  • anti- hormonal agents that act to regulate or inhibit hormone action on tumors
  • 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.
  • the chemotherapeutic combination comprises oxaliplatin, leucovorin and 5-fluorouracil.
  • the dose of capecitabine is approximately 500 mg/m 2 , approximately 600 mg/m 2 , approximately 700 mg/m 2 , approximately 800 mg/m 2 , approximately 900 mg/m 2 , approximately 1000 mg/m 2 , approximately 1100 mg/m 2 , approximately 1200 mg/m 2 , approximately 1300 mg/m 2 , approximately 1400 mg/m 2 , approximately 1500 mg/m 2 , approximately 1600 mg/m 2 , approximately 1700 mg/m 2 , approximately 1800 mg/m 2 , approximately 1900 mg/m 2 , approximately 2000 mg/m 2 , approximately 2100 mg/m 2 , approximately 2200 mg/m 2 , approximately 2300 mg/m 2 , approximately 2400 mg/m 2 , or approximately 2500 mg/m 2 .
  • 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.
  • the dose of 5-Fluorouracil (5-FU) is initially between approximately 200 mg/m 2 to approximately 500 mg/m 2 .
  • the dose of 5-FU is approximately 100 mg/m 2 , approximately 150 mg/m 2 , approximately 200 mg/m 2 , approximately 250 mg/m 2 , approximately 300 mg/m 2 , approximately 350 mg/m 2 , approximately 400 mg/m 2 , approximately 450 mg/m 2 , approximately 500 mg/m 2 or approximately 550 mg/m 2 .
  • the subsequent dose of 5-FU is approximately 1000 mg/m 2 , approximately 1100 mg/m 2 , approximately 1200 mg/m 2 , approximately 1300 mg/m 2 , approximately 1400 mg/m 2 , approximately 1500 mg/m 2 , approximately 1600 mg/m 2 , approximately 1700 mg/m 2 , approximately 1800 mg/m 2 approximately 1900 mg/m 2 , approximately 2000 mg/m 2 , approximately 2100 mg/m 2 approximately 2200 mg/m 2 , approximately 2300 mg/m 2 , approximately 2400 mg/m 2 approximately 2500 mg/m 2 , approximately 2600 mg/m 2 , approximately 2700 mg/m 2 approximately 2800 mg/m 2 , approximately 2900 mg/m 2 , approximately 3000 mg/m 2 approximately 3100 mg/m 2 , approximately 3200 mg/m 2 , approximately 3300 mg/m 2 approximately 3400 mg/m 2 , or approximately 3500 mg/m 2 .
  • 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.
  • 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.
  • the dose of oxaliplatin is between approximately 50 mg/m 2 to approximately 130 mg/m 2 .
  • oxaliplatin is administered intravenously (IV) at a dose of approximately 85 mg/m once per cycle of 14 days.
  • oxaliplatin is administered at a dose of 85 mg/m 2 IV in 250-500 mL D5W over 120 minutes.
  • the dose of oxaliplatin may be decreased for example to 75 mg/m 2 , 65 mg/m 2 or 50 mg/m 2 .
  • oxaliplatin may be discontinued.
  • the dose of oxaliplatin is approximately 20 mg/m 2 , approximately 30 mg/m 2 , approximately 40 mg/m 2 , approximately 50 mg/m 2 , approximately 60 mg/m 2 , approximately 70 mg/m 2 , approximately 80 mg/m 2 , approximately 90 mg/m 2 , approximately 100 mg/m 2 , approximately 110 mg/m 2 , approximately 120 mg/m 2 , approximately 130 mg/m 2 , approximately 140 mg/m 2 , approximately 150 mg/m 2 .
  • Oxaliplatin may be administered, for example, as IV bolus or as intravenous infusion (IVI).
  • 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.
  • the dose of leucovorin is between approximately 200 mg/m 2 to approximately 500 mg/m 2 .
  • leucovorin is administered intravenously (IV) at a dose of approximately 400 mg/m 2 once per cycle of 14 days.
  • leucovorin is administered at a dose of 400 mg/m 2 IV 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).
  • the dose of leucovorin is approximately 100 mg/m 2 , approximately 150 mg/m 2 , approximately 200 mg/m 2 , approximately 250 mg/m 2 , approximately 300 mg/m 2 , approximately 350 mg/m 2 , approximately 400 mg/m 2 , approximately 450 mg/m 2 , approximately 500 mg/m 2 , approximately 550 mg/m 2 , approximately 600 mg/m 2 .
  • the chemotherapeutic combination is selected from 5-FU/leucovorin, FOLFOX, XELOX, FOLFIRI or FOLFIRINOX.
  • the chemotherapeutic combination is FOLFOX.
  • the FOLFOX regimen comprises administration of oxaliplatin at a dose of between approximately 50 mg/m 2 to approximately 85 mg/m 2 , leucovorin at a dose of approximately 400 mg/m 2 and 5 -Fluorouracil (5-FU) at a dose of between approximately 200 mg/m 2 to approximately 400 mg/m 2 followed by at a dose of between approximately 1600 mg/m 2 to approximately 2400 mg/m 2 .
  • the FOLFOX treatment regimen may comprise for example, FOLFOX4.
  • the FOLFOX treatment regimen may comprise for example, FOLFOX 6.
  • the FOLFOX treatment regimen may comprise for example, FOLFOX 7.
  • the FOLFOX treatment regimen may comprise for example, modified FOLFOX 6.
  • the FOLFOX treatment regimen may comprise for example, modified FOLFOX 7.
  • the FOLFOX regimen comprises oxaliplatin at a dose of approximately 85 mg/m 2 , leucovorin at a dose of approximately 400 mg/m 2 and 5 -Fluorouracil (5- FU) at a dose of approximately 400 mg/m 2 followed by at a dose of approximately 2400 mg/m 2 .
  • the present application therefore provides a combination therapy comprising an anticlusterin antibody and FOLFOX.
  • the FOLFIRI regimen comprises leucovorin, 5 -fluorouracil and irinotecan.
  • the FOLFIRI regimen comprises administration of leucovorin at a dose of approximately 200 mg/m 2 , irinotecan at a dose of approximately 180 mg/m 2 and fluorouracil at a dose of approximately 400 mg/m 2 followed by a dose of approximately 2400 to 3000 mg/m 2 (Solimando, D. A. et al., Hospital Pharmacy, Vol. 40 (5): 393-398).
  • the FOLFIRINOX regimen comprises leucovorin, irinotecan, oxaliplatin and 5 -fluorouracil.
  • the FOLFIRINOX regimen comprises administration of oxaliplatin at a dose of approximately 85 mg/m 2 , leucovorin at a dose of approximately 400 mg/m 2 , irinotecan at a dose of approximately 180 mg/m 2 and fluorouracil at a dose of approximately 400 mg/m 2 followed by a dose of approximately 2400 mg/m 2 (Jao, M.E. et al., JHOP, 2022, vol 12(6), pp. 334-339).
  • the XELOX regimen comprises oxaliplatin at a dose of 130 mg/m 2 (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.
  • 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.
  • 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).
  • the method of the present disclosure may also involve administration of an antineoplastic agent or a chemotherapeutic combination of antineoplastic agents.
  • 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).
  • 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).
  • the method is used for inhibiting recurrence of tumor(s).
  • the method is used for reducing recurrence or reducing the risk of recurrence of tumor(s).
  • the method is used for inhibiting growth of tumor(s).
  • the method is used for delaying growth of tumor(s).
  • the method is used for preventing persistence of tumor(s).
  • the method is used for reducing persistence of tumor(s).
  • the method is used for inhibiting recurrence of metastasis(es).
  • the method is used for reducing growth of metastasis(es).
  • 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.
  • 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.
  • the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and FOLFOX.
  • the anti-clusterin 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.
  • 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).
  • the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and FOLFIRINOX.
  • the method may comprise administering an antibody or an antigen binding fragment thereof that binds to clusterin and XELOX.
  • the method comprises administering at least one cycle of treatment wherein one cycle of treatment consists of approximately 7 days.
  • the initial cycle(s) of treatment and subsequent cycle(s) of treatment may also vary in length from one another.
  • the initial cycle(s) of treatment may be 14 days and the subsequent cycle(s) of treatment may be more than 14 days.
  • 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.
  • 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.
  • one cycle of treatment consists in 14 days. In another particular exemplary embodiment, each cycle of treatment consists in 14 days.
  • the anti-clusterin antibody or an antigen binding fragment thereof is administered once weekly, once every two weeks, once every three weeks, once monthly.
  • the anti-clusterin antibody or antigen binding fragment thereof is administered once per week.
  • the frequency of treatment i.e., once per week, every two weeks, every three weeks, every four weeks and the like
  • a physician may decide to administer a dose ahead of the schedule or delay the dose by a few days or longer.
  • one or more doses be skipped without affecting treatment.
  • the anti-clusterin antibody or an antigen binding fragment thereof is generally administered once weekly.
  • 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.
  • the antibody or an antigen binding fragment thereof that binds to clusterin is administered as neoadjuvant therapy.
  • the anti-clusterin antibody or an antigen binding fragment thereof is administered before ablation of the tumor(s) or metastasis(es).
  • the CD3+ PD1+ T cells selected by fluorescence- activated cell sorting 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).
  • FACS fluorescence- activated cell sorting
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • IgG2 humanized type 2 immunoglobulin
  • 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/m 2 IV bolus + leucovorin 400 mg/m 2 IV bolus + 5 -Fluorouracil (5-FU) 400 mg/m 2 IV bolus + 5-FU 2400 mg/m 2 continuous IV infusion over 46 hours. Participants will undergo liver metastasis resection with or without primary cancer resection following recovery from preoperative neoadjuvant systemic chemotherapy.
  • 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.
  • Rescreening of participants is allowed in certain circumstances. Examples of circumstances when a participant can be rescreened:
  • 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.
  • AUC area under the curve
  • Cmin
  • 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.
  • 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.
  • 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
  • FOLFOX will be prepared, handled, and stored as per product monograph and/or hospital standard practices.
  • Concomitant medication includes all prescriptions, over the counter (OTC) products, herbal supplements, blood derived products and IV medications and fluids.
  • Cannabis derived products should not be employed while receiving trial intervention.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Resection of metastases by hepatectomy will be done as per standard of care.
  • 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.
  • 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.
  • FFPE formalin-fixed paraffin-imbedded
  • 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.
  • TRG1 absence of tumor cells and their replacement by abundant fibrosis
  • TRG2 residual tumor cells are rare and are scattered throughout abundant fibrosis
  • TRG3 more residual tumor cells throughout a predominantly fibrotic area
  • TRG4 tumor cells predominate over the fibrosis
  • TRG5 tumor cells are present exclusively (without fibrosis)
  • 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.
  • TRG 0 no viable cancer cells (complete response)
  • TRG 1 single cell or rare small groups of cancer cells (near complete response)
  • TRG 2 residual cancer with evident tumor regression but more than single cell or rare small groups of cancer cells (partial response)
  • TRG 3 extensive residual cancer with no evident tumor regression (poor or not response)
  • 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.
  • 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).
  • the percentage of microscopic fibrosis-necrosis within the limits of the tumor area will be estimated for each liver metastasis.
  • TLS TLS tetrachloro-2 TLS .
  • the abundance of TLS will be expressed as the number of TLS divided by the area of tissue sampled.
  • Tumor imaging of the liver should be acquired by computed tomography (CT) or magnetic resonance imaging (MRI).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • 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.
  • 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.
  • AEs adverse events
  • 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.
  • 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.
  • Drug Safety personnel will be available to answer questions and assist site personnel in documenting SAEs and completing the SAE worksheet.
  • 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:
  • 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.
  • PD-L1, CTLA-4, MHC II, immunosuppressive fibroblasts might be investigated if deemed necessary.
  • 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.
  • SAP Statistical Analysis Plan
  • 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.
  • the full analysis set 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.
  • the safety analysis set will include all participants who received at least one dose of any study treatment drug (AB-16B5 or FOLFOX).
  • 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.
  • 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.
  • Subgroup analyses may be performed, if deemed necessary and details will be included in the SAP.
  • the minimal residual disease detection rate assessed by quantitating ctDNA in blood, will be presented for each participant.
  • 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.
  • Target lesions were removed 79 days after the last cycle of treatment.
  • One hepatic target lesion was assessed (nodular liver hypodensity segment VII).
  • the size of the lesion was determined to be 33.0 mm.
  • 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).
  • 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.
  • liver metastases originates from or is caused by an invasive adenocarcinoma or metastatic cancer.
  • 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.
  • CDRs complementarity determining regions
  • 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.
  • the immunotherapy comprises an antibody or an antigen binding fragment thereof that binds to clusterin.
  • the immunotherapy comprises cetuximab, bevacizumab, panitumumab.
  • 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.
  • 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.
  • TILS tumor infiltrating lymphocytes
  • a method for treating cancer in a subject in need thereof 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 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.
  • taxane is paclitaxel, docetaxel, Abraxane®, cabazitaxel, larotaxel, milataxel, ortataxel, tesetaxel.
  • 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.
  • 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 comprising detecting tertiary lymphoid structures in the microenvironment of one or more tumors and/or of one or more metastases of the subject.

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Abstract

La présente divulgation concerne le dosage fixe d'anticorps anti-clustérine, ou de fragments de liaison à l'antigène de ceux-ci pour le traitement du cancer. Des méthodes de traitement du cancer avec une polythérapie comprenant un anticorps anti-clustérine ou un fragment de liaison à l'antigène de celui-ci et une combinaison chimiothérapeutique comprenant au moins deux agents antinéoplasiques sont également divulguées. La présente divulgation concerne également le traitement du cancer colorectal métastatique avec des anticorps anti-clustérine ou des fragments de liaison à l'antigène de ceux-ci en monothérapie ou en combinaison avec FOLFOX pour la résection de métastases.
PCT/CA2025/050032 2024-01-10 2025-01-10 Polythérapie pour le traitement néoadjuvant pour le cancer Pending WO2025147775A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011063523A1 (fr) * 2009-11-24 2011-06-03 Alethia Biotherapeutics Inc. Anticorps anti-clustérine et fragments de liaison de l'antigène et leur utilisation dans la réduction du volume d'une tumeur

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011063523A1 (fr) * 2009-11-24 2011-06-03 Alethia Biotherapeutics Inc. Anticorps anti-clustérine et fragments de liaison de l'antigène et leur utilisation dans la réduction du volume d'une tumeur

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Title
FERRARIO, C. ET AL.: "Abstract CT098: Phase I first-in-human study of anti-clusterin antibody AB-16B5 in patients with advanced solid malignancies", CANCER RESEARCH, vol. 77, no. 13, 1 July 2017 (2017-07-01), pages CT098, ISSN: 1538-7445, Retrieved from the Internet <URL:https://doi.org/10.1158/1538-7445.AM2017-CT(98> [retrieved on 20250325] *
KEVANS DAVID, FOLEY JANE, TENNISWOOD MARTIN, SHEAHAN KIERAN, HYLAND JOHN, O'DONOGHUE DIARMUID, MULCAHY HUGH, O'SULLIVAN JACINTHA: "High Clusterin Expression Correlates with a Poor Outcome in Stage II Colorectal Cancers", CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION, AMERICAN ASSOCIATION FOR CANCER RESEARCH, vol. 18, no. 2, 1 February 2009 (2009-02-01), pages 393 - 399, XP093337575, ISSN: 1055-9965, DOI: 10.1158/1055-9965.EPI-08-0302 *
PASETTO LARA MARIA, ANTONIO, JIRILLO GIROLAMA, IADICICCO ELENA, ROSSI MYRIAM KATJA, PARIS SILVIO, MONFARDINI: "FOLFOX Versus FOLFIRI: A Comparison of Regimens in the Treatment of Colorectal Cancer Metastases", ANTICANCER RESEARCH 25: 563-576 (2005), 28 December 2004 (2004-12-28), pages 563 - 576, XP093337577, Retrieved from the Internet <URL:https://ar.iiarjournals.org/content/anticanres/25/1B/563.full.pdf> *
TREMBLAY GILLES; MALOUIN MIREILLE; GROTHE SUZANNE; KALBAKJI AIDA; ROY SOPHIE; PAGE MARTINE; PAUL-ROC BEATRICE; SULEA TRAIAN; LENFE: "AB-16B5, a therapeutic monoclonal antibody against human clusterin that blocks the epithelial-to-mesenchymal transition.", AMERICAN ASSOCIATION FOR CANCER RESEARCH. PROCEEDINGS OF THE ANNUAL MEETING, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 51, 21 April 2010 (2010-04-21), US , XP009172047, ISSN: 0197-016X *

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