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WO2025068393A1 - Méthodes de traitement de maladies associées à la fibrotique - Google Patents

Méthodes de traitement de maladies associées à la fibrotique Download PDF

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Publication number
WO2025068393A1
WO2025068393A1 PCT/EP2024/077109 EP2024077109W WO2025068393A1 WO 2025068393 A1 WO2025068393 A1 WO 2025068393A1 EP 2024077109 W EP2024077109 W EP 2024077109W WO 2025068393 A1 WO2025068393 A1 WO 2025068393A1
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Prior art keywords
cancer
cdh1
pathway inhibitor
icafs
antibody
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English (en)
Inventor
Lounes DJERROUDI
Rana MHAIDLY
Hugo CROIZER
Yann Kieffer
Anne VINCENT-SALOMON
Fatima MECHTA-GRIGORIOU
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Institut National de la Sante et de la Recherche Medicale INSERM
Institut Curie
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Institut National de la Sante et de la Recherche Medicale INSERM
Institut Curie
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Publication of WO2025068393A1 publication Critical patent/WO2025068393A1/fr
Pending legal-status Critical Current
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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
    • 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
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2842—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the invention relates to methods and pharmaceutical compositions for the treatment of fibrotic related diseases, particularly cancer and immunotherapy-resistant cancer.
  • Cancer is the second leading cause of death worldwide. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades. Many treatment options exist for cancer, including for example surgery, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, targeted therapy and palliative care. The choice of the best adapted treatment for a patient depends on the type, location and grade of the cancer as well as the patient's health and preferences.
  • CAFs Cancer-Associated Fibroblasts
  • CAFs are abundant components in cancer and play key pro-tumorigenic functions. It is now recognized that CAFs are heterogeneous and that distinct CAFs subsets can be defined based on expression of specific markers. The inventors discovered new subpopulations of CAFs that play crucial roles in the establishment of an immunosuppressive microenvironment at the tumor site. The inventors addressed the heterogeneity of the CAF-S1 immunosuppressive subpopulation and identified different CAF- S1 clusters.
  • iCAF inflammatory
  • myofibroblastic myCAF
  • the inventors described specific clusters (namely ECM-myCAF and TGFb-myCAF) which are involved in resistance to immunotherapy (Kieffer et al., 2020).
  • the invention seeks to meet these needs.
  • ILC Invasive Lobular Carcinoma
  • IBC-NST invasive breast carcinoma of no special type
  • TIL tumor-infiltrating lymphocytes
  • the inventors investigated the role of tumor micro-environment in E- cadherin- cancer (invasive lobular carcinoma) in comparison to E-cadherin+ cancer (invasive breast carcinoma of no special type (IBC-NST) also known as invasive ductal carcinoma (IDC)). Accordingly, the inventors performed an in-depth characterization of the heterogeneity, the function, and the interactions of Cancer Associated Fibroblast (CAF) and immune cells in ILC compared to IBC-NST. To do so, the inventors leveraged a well characterized retrospective series of 251 patients who underwent surgery for a primary ILC (prior to any treatment), for whom frozen tumor samples were available for RNA sequencing.
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive
  • the inventors established tissue microarrays (TMA) for 158 ILC from this cohort and 110 primary IBC-NST (including 77 ER+ IBC-NST). Based on the TMA cohort, the inventors did comparative immunohistochemical analysis of selected CAF and immune cell markers. In addition, the inventors characterized six classical ILC by single cell RNA sequencing after a step of cell sorting (EPCAM+ cells, CD45+ cells and CAF).
  • ILC have more inflammatory CAF and less myofibroblastic CAF than IBC-NST.
  • the inventors demonstrated that the myofibroblastic content is higher in ER+ IDC than in ILC.
  • myCAF-Sl and ECM-myCAF IHC markers are expressed at higher levels in ER+ IDC than in ILC.
  • iCAF enrichment in ILC was confirmed at the single cell level in 6 classical ILC, and by deconvolution of RNAseq data from the whole series of 251 ILC.
  • the inventors performed Ligand-Receptor interaction analysis (CellChat) from scRNAseq data: ATLAS ILC vs IDC. Accordingly, the inventors demonstrated that CAF-S1 are among the cells that most frequently interact with ductal tumor cells via the CDH1 pathway. As expected, lobular tumor cells show almost no interaction with other cells via the CDH1 pathway. The inventors also demonstrated that ductal tumor cells interact with CAF-S1 via CDH1 through ITGB1, EGFR and IGF1R.
  • the inventors also investigated functional impact of ITGB1 silencing on CAF-S1 differentiation and demonstrated that inactivation of ITGB1 in iCAF reduces differentiation into ECM-myCAF, after co-culture with tumor cells.
  • RNAseq deconvolution identifies ILC groups enriched in specific CAF-S1 clusters and with specific TIL infiltration pattern.
  • infiltrating pattern is mainly associated with Detox-iCAF enrichment and margin predominant pattern (with immune exclusion) is mainly associated with ECM-myCAF enrichment, which is validated at the protein level (IHC).
  • iCAFs significantly attract CD8 T cells in vitro in comparison to myCAF and in comparison to siCDHl cancer cells without iCAF phenotype.
  • Co-culture of iCAF with E- cadherin positive cancer cell lines prevents CD8 migration by inducing a myCAF phenotype.
  • Inactivation of CDH1 in tumor cells, while maintaining the iCAF phenotype of fibroblasts, restores CD8 attraction.
  • inactivation of ITGB1 in iCAF restores CD8 attraction upon co-culture with cancer cells.
  • the inventors present data correlating CAF content with E-cadherin expression by tumour cells in non-lobular carcinomas and in gastric carcinomas.
  • E-cadherin low non-lobular breast carcinoma are enriched in iCAF compared to E-cadherin high non-lobular breast carcinoma.
  • Diffuse gastric carcinoma (with CDH1 inactivation) are enriched in iCAF compared to intestinal type gastric carcinoma (without CDH1 inactivation).
  • the inventors therefore believe that the proposed mechanism is generalisable to at least all cancers, particularly E-cadherin positive cancers.
  • fibrosis process is involved in numerous diseases, including liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF), heart failure, and many chronic autoimmune diseases.
  • IPF idiopathic pulmonary fibrosis
  • a feature common to all fibrotic diseases is the activation of ECM-producing myofibroblasts, which are the key mediators of fibrotic tissue remodeling. Inhibiting myofibroblast differentiation by suppressing E-cadherin pathway could therefore have a therapeutic effect on all fibrotic diseases.
  • CDH1 pathway inhibitor in fibrotic related diseases such as cancer and immunotherapy-resistant cancer, and the targeting of CDH1 pathway in the treatment of fibrotic related diseases, particularly cancer and immunotherapyresistant cancer.
  • the invention relates to methods and pharmaceutical compositions for the treatment of fibrotic related diseases, particularly cancer and immunotherapy-resistant cancer.
  • the invention is defined by the claims.
  • the invention concerns a CDH1 pathway inhibitor for use in the treatment of a fibrotic related disease in a subject in need thereof.
  • the fibrotic related disease is a non-cancerous fibrotic related disease such as chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, systemic lupus erythematosus, systemic sclerosis (SSc), sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis.
  • chronic autoimmune diseases including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, systemic lupus erythematosus, systemic sclerosis (SSc), sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibros
  • the fibrotic related disease is cancer, particularly an E-cadherin positive cancer.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer and invasive breast cancer of no-special type.
  • the disease is invasive ductal carcinoma (IDC).
  • the cancer is particularly a gastric cancer, preferably intestinal type gastric carcinoma.
  • the tumoral microstructure comprises inflammatory cancer-associated fibroblasts (iCAFs) and optionally i) myofibroblastic cancer-associated fibroblasts (myCAFs) and/or ii) tumor infiltrating lymphocytes (TILs).
  • the cancer is an immunotherapy-resistant cancer.
  • the CDH1 pathway inhibitor may therefore be used in combination with at least one immunotherapeutic agent in the treatment of immunotherapy-resistant cancer.
  • the CDH1 pathway inhibitor is selected from the group consisting of ITGB1, CDH1, EGFR and IGF1R antagonist or expression inhibitor.
  • the CDH1 pathway inhibitor is an ITGB1 antagonist or expression inhibitor.
  • the CDH1 pathway inhibitor is a CDH1 antagonist or expression inhibitor.
  • the CDH1, ITGB1, EGFR or IGF1R antagonist is particularly selected from the group consisting of small organic molecule, polypeptide, aptamer and antibody.
  • the CDH1 pathway inhibitor is a ITGB1 antagonist selected from the group consisting of Natalizumab, MK-0668, Firategrast, Volociximab and antibody CAS Number 308067-60-9.
  • the invention concerns the use of a CDH1 pathway inhibitor for inhibiting inflammatory cancer-associated fibroblasts (iCAFs) differentiation.
  • the invention relates to a method for inhibiting cancer associated fibroblasts (CAFs) differentiation, wherein said method comprises contacting CAFs, preferably iCAFs, with a CDH1 pathway inhibitor.
  • a method for treating a cancer in a subject in need thereof comprising administering a therapeutic effective amount of a CDH1 pathway inhibitor to said subject, and wherein the cancer is an E-cadherin positive cancer comprising inflammatory cancer-associated fibroblasts (iCAFs).
  • Said cancer can typically be the cancer is an immunotherapy resistant cancer.
  • the invention concerns of a CDH1 pathway inhibitor in the manufacture of a medicament for the treatment of a fibrotic related disease, preferably an E-cadherin positive cancer.
  • CAFs Cancer-Associated Fibroblasts
  • CAF-S1 are among the cells that most frequently interact with ductal tumor cells via the CDH1 pathway through ITGB1, EGFR and IGF1R.
  • the inventors also demonstrated that coculture of iCAF with E-cadherine positive cancer cell lines prevents CD8 migration by inducing a myCAF phenotype and that inactivation of CDH1 or ITGB1 in tumor cells, while maintaining the iCAF phenotype of fibroblasts, restores CD8 attraction.
  • the present invention highlights the role of CDH1 pathway, particularly CDH1, ITGB1, EGFR and IGF1R inactivation in cancer and the use of CDH1, ITGB1, EGFR and IGF1R inhibitors/antagonists in the treatment of fibrotic related diseases, particularly cancer and immunotherapy-resistant cancer.
  • the invention relates to a CDH1 pathway inhibitor for use in the treatment of fibrotic related disease in a subject in need thereof, particularly cancer and immunotherapyresistant cancer.
  • the invention relates to a CDH1 pathway inhibitor for use in the treatment of fibrotic related disease.
  • the invention relates to a CDH1 pathway inhibitor for use in the treatment of cancer.
  • the invention relates to a CDH1 pathway inhibitor for use in the treatment of non-cancerous fibrotic related disease.
  • CDH1 has its general meaning in the art and refers to Epithelial Cadherin also known as Cadherin 1 or E-Cadherin, a calcium-dependent cell-cell adhesion protein playing a central role in strong intercellular adhesion in epithelial cells (Protein Accession number UniProtKB/Swiss-Prot: P12830).
  • CDH1 pathway has its general meaning in the art and refers to signaling pathways and cross talk, regulated by E-cadherin.
  • CDH1 pathway refers to physiological signaling interactions of E-cadherin and its cascade partners such as CDH1, ITGB1, EGFR and IGF1R (Shenoy etal., 2019).
  • CDH1 pathway inhibitor has its general meaning in the art and refers to any compound selected from the group consisting of but not limited to compounds targeting CDH1 and its partners such as ITGB1 and IGF1R.
  • CDH1 pathway inhibitor refers to compounds such as CDH1 antagonist or CDH1 expression inhibitor, ITGB1 antagonist or ITGB1 expression inhibitor, EGFR antagonist or EGFR expression inhibitor and IGF1R antagonist or IGF1R expression inhibitor.
  • CDH1 pathway inhibitor are well-known in the art as such as described in Lee et al., 2019; Lapteva et al., 2019; Jahangiri et al., 2014.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • the terms “subject”, “individual” or “patient” are interchangeable and refer to a mammal.
  • a subject according to the invention refers to any subject, preferably human.
  • the term “subject” refers to a subject afflicted or at risk to be afflicted with fibrotic related disease.
  • the term “subject” refers to a subject afflicted or at risk to be afflicted with E-cadherin positive cancer.
  • the term “subject” refers to a subject afflicted or at risk to be afflicted with immunosuppressive environment associated cancer.
  • the term “subject” refers to a subject afflicted or at risk to be afflicted with immunotherapy-resistant cancer.
  • the cancer is an immunotherapy resistant cancer, preferably a cancer resistant to immune checkpoint inhibitors such as PD-1, CTLA-4, TIGIT, TIM3 and/or LAG3.
  • the subject suffers of an immunotherapy resistant E-cadherin positive cancer.
  • the cancer is an E-cadherin positive cancer resistant to immunotherapy, preferably an E-cadherin positive cancer resistant to immune checkpoint inhibitors such as PD-1, CTLA-4, TIGIT, TIM3 and/or LAG3.
  • the term “subject” refers to a subject afflicted or at risk to be afflicted with non-cancerous fibrotic related disease such as fibrosing diseases including chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis and systemic lupus erythematosus, systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis.
  • fibrosing diseases including chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis and systemic lupus erythematosus
  • systemic fibrotic diseases such as systemic s
  • the methods and uses according to the invention may comprise a step of characterizing a biological sample from a patient. Therefore, the methods and uses according to the invention may comprise an initial step of providing one or more samples from the patient.
  • the sample can, for example, be obtained from a subject by, but not limited to, venipuncture, excretion, biopsy, needle aspirate, lavage sample, scraping, surgical incision, colonoscopy, fibroscopy, endoscopy, surgery or, any combination thereof, and the like.
  • biological sample preferably refers to a sample obtained from a subject or from components (e.g., cells) of a subject.
  • the sample may be of any biological tissue or fluid.
  • the biological sample may be a "clinical sample” which is a sample derived from a patient.
  • Biological samples may also include sections of tissues such as frozen sections or Formalin- fixed paraffin embedded section (FFPE) section taken for histological purposes.
  • FFPE Formalin- fixed paraffin embedded section
  • fibrotic related disease has its general meaning in the art and refers to a disease with fibrosing or fibrotic condition. Fibrosis has its general meaning in the art and refers to a major pathological feature of fibrotic related disease, fibrosing disease or fibrotic disease.
  • fibrotic related disease refers to cancer or cancerous fibrotic related disease including E-cadherin positive cancer, immunosuppressive environment associated cancer (cancer bearing immunosuppressive environment), immunotherapy-resistant cancer.
  • the term “fibrotic related disease” also refers to non-cancerous fibrotic related disease such as chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis and systemic lupus erythematosus, systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis.
  • the fibrotic related disease comprises E-cadherin positive cells.
  • the organ of origin or site of initiation of the fibrotic related disease comprises E- cadherin positive cells.
  • the fibrotic related disease is cancer.
  • cancer refers to any cancer that may affect any one of the following tissues or organs: breast; liver; kidney; heart, mediastinum, pleura; floor of mouth; lip; salivary glands; tongue; gums; oral cavity; palate; tonsil; larynx; trachea; bronchus, lung; pharynx, hypopharynx, oropharynx, nasopharynx; esophagus; digestive organs such as stomach, intrahepatic bile ducts, biliary tract, pancreas, small intestine, colon; rectum; urinary organs such as bladder, gallbladder, ureter; rectosigmoid junction; anus, anal canal; skin; bone; joints, articular cartilage of limbs; eye and adnexa; brain; peripheral nerves, autonomic nervous system; spinal cord, cranial nerves, meninges;
  • cancer comprises leukemias, seminomas, melanomas, teratomas, lymphomas, non-Hodgkin lymphoma, neuroblastomas, gliomas, adenocarninoma, mesothelioma (including pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and end stage mesothelioma), rectal cancer, endometrial cancer, thyroid cancer (including papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma and paraganglioma), skin cancer (including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sar
  • the fibrotic related disease is cancer, particularly breast cancer, ovarian cancer or invasive breast cancer of no-special type.
  • the fibrotic related disease is a gastric cancer or a breast cancer.
  • the fibrotic related disease is intestinal type gastric carcinoma or invasive ductal carcinoma (IDC).
  • the fibrotic related disease is breast cancer, more preferably invasive ductal carcinoma (IDC).
  • IDC invasive ductal carcinoma
  • filtrating ductal carcinoma or “invasive ductal carcinoma” are used interchangeably and refer to a type of breast cancer wherein the cancer has spread into surrounding breast tissues.
  • the invention relates to a CDH1 pathway inhibitor for use in the treatment of E-cadherin positive cancer or of a cancer that expresses E-cadherin.
  • E- cadherin positive cancer or “cancer expressing E-cadherin” according to the invention comprises E-cadherin+ tumors which include all carcinomas, but also many germ cell tumors, melanomas, Hodgkin lymphomas, and some mesenchymatous or soft tissue tumors and cancers such as described in Burandt et al., 2021.
  • E-cadherin in cancer cells can be performed through various techniques know by the man skilled in the art, that target either the protein itself or its gene expression, such as immunohistochemistry, western blotting, qPCR, FISH, ELISA or flow cytometry.
  • E-cadherin can typically be detected by immunohistochemistry, for example by using antibodies targeting E-cadherin such as monoclonal antibodies NCH-38, EP700Y or 4A2C7.
  • the cancer is E-cadherin positive when the level of E-cadherin in the cancer is comparable to the level of E-cadherin in the surrounding epithelial cells.
  • the cancer is E-cadherin positive when at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the cancer cells are E-cadherin positive.
  • the cancer can be E-cadherin high or low.
  • the cancer is E-cadherin low when the cancer comprises at least 10% of E-cadherin positive cancer cells.
  • the cancer is E- cadherin high when the cancer comprises at least 70%, at least 75%, at least 80% or at least 85% of E-cadherin positive cancer cells.
  • the subject suffering from the fibrotic disease has cancer-associated fibroblasts CAF-S1.
  • the terms “Cancer Associated Fibroblast”, “carcinoma associated fibroblasts” and “CAF” are used interchangeably and refer to fibroblasts present in the stroma of cancers. They are one of the most abundant stromal components with morphology similar to myofibroblasts. CAFs are typically CD45-EpCAM-CD31-CD29+ stromal cells.
  • the term “immunosuppressive Cancer Associated Fibroblast” or “immunosuppressive CAF” refers to CAF that is responsible and/or contribute to immunosuppression or to an immunosuppressive microenvironment in a tumor, i.e., to the partial or complete inhibition or suppression of the immune response of an individual towards cancer cells.
  • the “tumor microenvironment” or “TME” is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signalling molecules and the extracellular matrix (ECM).
  • the CAFs according to the invention particularly belongs to the CAF-S1 subgroup, for example such as described in Costa et al., 2018, Cancer cell Volume 33, Issue 3, Pages 463-479. elO and in WO/2019/020728, the disclosure thereof being incorporated herein by reference.
  • CAF-S1 population particular expresses one or more biomarkers selected from the group consisting of CD29, FAP, aSMA, PDGFRP and FSP1.
  • the CAF-S1 of the invention are FAP+.
  • FAP+ refers to a cell expressing FAP.
  • FAP - refers to a cell that does not express FAP.
  • FAP Fibroblast Activation Protein
  • Prolyl endopeptidase FAP Dipeptidyl peptidase FAP
  • Surface- expressed protease Sepras
  • Serine integral membrane protease SIMP
  • Itegral membrane serine protease Post-proline cleaving enzyme
  • FAP is a cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth.
  • FAP+ CAF or “FAP+ Cancer Associated Fibroblast” refers to a subpopulation of CAFs that express FAP. Not all CAFs express FAP. Therefore, in a preferred embodiment, the detection of FAP+ CAFs relies on the detection of CAFs expressing FAP, preferably the detection of FAP mRNA and/or protein. However, other markers specific of FAP+ CAFs can also be used to detect them.
  • CAF-S1 is a subpopulation of inflammatory CAF, also called “iCAF” subgroup.
  • iCAFs have been previously described in pancreatic cancer (Ohlund D, et al. J Exp Med 2017;214(3):579-96) and in immunotherapy resistant cancer (Kieffer et al., Cancer Discovery 2020), the content thereof being incorporated herein by reference.
  • iCAFs show high expression of chemokines and pro-inflammatory molecules such as CXCL12 (CXC motif chemokine ligand 12) and SOD2 (Superoxide dismutase 2), but also high levels of CD74, encoding Major Histocompatibility Class (MHC) II invariant chain.
  • CXCL12 CXC motif chemokine ligand 12
  • SOD2 Superoxide dismutase 2
  • iCAFs are ANTXR1 negative.
  • the terms “Anthrax Toxin Receptor 1”, “ANTXR Cell Adhesion Molecule 1”,” ANTXR”, “ANTXR1”, “Tumor Endothelial Marker 8”, “TEM8”, “ATR” or “GAPO” are equivalent and refer to the product of the human ANTXR1 gene, for example such as described under Gene ID: 84168 and UniProt Q9H6X2 references.
  • ANTXR1 protein plays a role in cell attachment and migration.
  • iCAFs are FAP+ANTXR1-.
  • the term iCAFs encompasses detox-iCAFs, IL-iCAF and IFNy-iCAF, preferably detox-iCAFs and IL-iCAF, more preferably are detox-iCAFs.
  • the subject suffering from the fibrotic disease has cancer-associated fibroblasts CAF-S1, preferably iCAFs, even more preferably detox-iCAFs.
  • the fibrotic associated disease comprises or is associated with CAF-S1, preferably iCAFs, even more preferably detox-iCAFs.
  • the subject suffering from a fibrotic disease has detox-iCAF and/or IL- iCAFs.
  • the fibrotic disease preferably cancer, comprises or is associated with detox-iCAF and/or IL-iCAFs.
  • Detox-iCAF are typically FAP + ANTXRF GPC3 + DLK1 +/ '.
  • IL- iCAFs are typically FAP + ANTXRF GPC3 + DLK1 + .
  • the iCAF is a detox- iCAF.
  • Glypican-3 » and « GPC3 » are used interchangeably and refer to the product of the human GPC3 gene, for example such as described under Gene ID: 2719 and UniProt P51654 references.
  • delta like non-canonical Notch ligand 1 » and « DLK1 » are used interchangeably and refer to the product of the human DLK1 gene, for example such as described under Gene ID: 8788 and UniProt P80370 references.
  • the presence of iCAFs is detected by protein expression level assessment by FACS or by immunohistochemistry.
  • Fluorescence-activated cell sorting is a specialized type of flow cytometry. It provides a method for sorting a heterogeneous mixture of biological cells into two or more containers, one cell at a time, based upon the specific light scattering and fluorescent characteristics of each cell.
  • Immunohistochemistry refers to the process of selectively imaging antigens (e.g., proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. Visualizing the antibodyantigen interaction can be accomplished in a number of ways, well known by the man skilled in the art. In the most common instance, an antibody is conjugated to an enzyme, such as peroxidase, that can catalyze a color-producing reaction or is tagged by a fluorophore, such as fluorescein or rhodamine.
  • an enzyme such as peroxidase
  • antibodies that can be used to measure FAP expression level in a CAF by FACS or immunohistochemistry are for example: the anti-human FAP antibody of reference #MAB3715 (from R&D systems), ab53066 (abeam), ABIN560844, Vitatex-MABSIOOI.
  • Antibodies that can be used to measure ANTXR1 expression level in a CAF by FACS or immunohistochemistry are for example: the anti- ANTXR1-AF405 antibody of reference #NB- 100-56585 (from Novus Biological), Human TEM8/ANTXR1 Antibody MAB3886 (R&Dsystem), ABIN252539, ANTXR1 Antibody (15091-1-AP, Thermo Fischer), NB-100- 56585 (Novus), MAI-91702 (Thermo Fischer), ab21270 (Abeam), LS-B13896 (Life span bioscience), rbl58588 (Biorbyt), bs-5210R (Bioss) or any of these antibody with an alternative label, in particular fluorescent label.
  • Antibodies that can be used to measure GPC3 expression level in a CAF by FACS or immunohistochemistry are for example: GPC3-AF594 (RnD), Anti- Glypican 3/GPC3 Antibody PicobandTM, Anti-GPC3 antibody(DMC371), GPC3 recombinant monoclonal antibody clone GPC3/1534R, and Anti -Gly pi can-3 antibody [SPM595],
  • Antibodies that can be used to measure DLK1 expression level in a CAF by FACS or immunohistochemistry are for example: anti-DLKl-AF488 (RnD) Human Pref-1/DLK1/FA1 Antibody Catalog #: MAB1144, DLK1 Monoclonal Antibody (3A10), DLK1 Antibody [PF13- 3] and DLK1 Antibody [PF299-1],
  • the subject suffering from a fibrotic related disease such as cancer has a level of detox-iCAFs and/or IL-iCAFs, higher
  • the subject biological sample comprises a level of detox-iCAFs and/or IL-iCAFs, higher than a reference level.
  • the fibrotic related disease preferably cancer, comprises or is associated with a level of iCAFs, preferably detox-iCAFs, higher than a reference level.
  • the subject biological sample comprises a level of iCAFs, preferably detox- iCAFs, higher than a reference level.
  • the subject or the cancer preferably the TME, comprises a level of detox-iCAFs and/or IL-iCAFs, higher than a reference level.
  • the uses or methods of the invention may comprise a step of detecting iCAFs and/or determining the level of iCAFs, preferably of detox-iCAFs.
  • percentage is used interchangeably herein and may refer to an absolute quantification of a molecule or a cell in a sample, or to a relative quantification of a molecule or a cell in a sample, i.e., relative to another value such as relative to a reference value as taught herein.
  • the term “percentage of iCAFs” may refer to any ratio having the number of iCAFs as nominator, and a number of reference cells as a denominator.
  • the term “percentage of iCAFs” may refer to any ratio having the number of iCAFs cells as nominator, and a number of reference cells as a denominator.
  • reference cells can particularly be selected from the group consisting of: all the cells of the cancer sample, cancer cells, stromal cells, CAFs cells and CAF-S1 cells.
  • the percentage of iCAF is the ratio of the number of iCAF as nominator and of CAFs or CAF-S1 as denominator.
  • the cancer or biological sample is considered has comprising iCAFs when the cancer or biological sample comprises at least 1%, 2%, 5%, 10%, 15% 20%, 25%, 30%, 35%, 40%, 45% or 50%of iCAFs in the total population of CAFs or CAFs-Sl.
  • the reference level(s) are determined by measuring the percentage of iCAFs in biological sample from cohorts of patients from who a fibroblasts associated disease stage and/or progression is known or who are healthy individual or group of healthy individuals (i.e., that do not suffer from a fibroblasts associated disease).
  • the reference level of iCAFs preferably detox-iCAFs
  • the reference level of iCAFs can typically be a level of iCAFs, preferably detox-iCAFs, of at least 1%, 2%, 5%, 10%, 15% 20%, 25%, 30%, 35%, 40%, 45% or 50%, typically of about 1%, 2%, 5%, 10%, 15% 20%, 25%, 30%, 35%, 40%, 45% or 50%.
  • the subject comprises CAF-S1, preferably iCAFs and/or myCAFs, even more preferably detox-iCAFs and/or ECM-myCAFs.
  • the fibrotic associated disease comprises or is associated with CAF-S1, preferably iCAFs and/or myCAFs, even more preferably detox-iCAFs and/or ECM-myCAFs.
  • the biological sample of the subject particularly the cancer sample, comprises CAF-S1, preferably iCAFs, even more preferably detox-iCAFs and optionally myCAFs such as ECM-myCAFs.
  • the tumoral microenvironment may comprise cancer-associated fibroblasts CAF-S1, preferably iCAFs, even more preferably detox- iCAFs, and optionally i) my-CAFs such as ecm-myCAFs and/or ii) tumor infiltrating lymphocytes (TILs).
  • ecm-myCAF and “CAF-S1 cluster 0”, are used interchangeably and refer to a subpopulation of CAFs, especially a cluster of CAF subpopulation CAF-S1.
  • Ecm-myCAF expresses FAP, ANTXR1 and SDC1 but does not express LAMP5. They are typically FAP + ANTXR1 + SDC1 + LAMPS'
  • antibodies that can be used to measure LAMPS expression level in CAFs by FACS or immunohistochemistry are for example: the anti-LAMP5-PE antibody of reference #130-109-156 (from Miltenyi Biotech).
  • antibodies that can be used to measure SDC1 expression level in CAFs by FACS or immunohistochemistry are for example: the anti-SDCl-BUV737 antibody of reference #BD-564393 (from BD Biosciences), ABIN5680139.
  • CAF IHC can been performed with antibodies directed against SMA (pH6, 15’, 1 :200, clone 1A4, DAKO #20079184), FAP (pH9, 60’, 1 :500, clone EPR20021, Abeam #ab207178), ANTXR1 (pH9, 90’, 1 :50, clone EPNCI-R173-37, Abeam #241067) and SDC1 (pH6, 30’, 1 : 100, clone MI15, DAKO #M7228).
  • the above embodiments described for iCAFs apply mutatis mutandis to inflammatory fibroblasts of said non-cancerous fibrotic disease.
  • iCAFs and inflammatory fibroblasts share similar cell markers, including CXCL12 and SFRP1 for instance.
  • the above embodiments described for myCAFs apply mutatis mutandis to myofibroblasts of said non-cancerous fibrotic disease.
  • myCAFs and myofibroblasts share similar cell markers, including FAP, ANTXR1, COL1 Al and SMA/ACTA2 for instance.
  • the invention relates to a CDH1 pathway inhibitor for use in combination with at least one immunotherapeutic agent in the treatment of immunotherapyresistant cancer.
  • the invention relates to a CDH1 pathway inhibitor for use in the treatment of immunotherapy-resistant cancer.
  • Immunotherapy -resistant cancer has its general meaning in the art such as described in Bai et al., 2020; Said and (2004), 2023; Wang et al., 2021.
  • Immunotherapy-resistant cancer comprises but is not limited to breast cancer, invasive breast cancer of no-special type (invasive ductal carcinomas), triple-negative breast cancer (TNBC), ovarian cancer, uterine (endometrial) cancer, cervical cancer, brain cancer such as astrocytoma, ependymoma, glioma, meningioma, medulloblastoma and neuroblastoma; lung cancer such as small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), adenocarcinoma, squamous cell (epidermoid) carcinoma, large cell (undifferentiated) carcinoma and mesothelioma; liver cancer such as hepatocellular carcinoma (HCC), cholangiocarcinoma (bile duct cancer) and hepatoblastoma; bladder cancer, kidney cancer, colorectal cancer, esophageal cancer such as squamous cell carcinoma and aden
  • the CDH1 pathway inhibitor is preferably selected from the group consisting of ITGB1, CDH1, EGFR and IGF1R inhibitor.
  • the CDH1 pathway inhibitor is selected from the group consisting of ITGB1, CDH1, EGFR and IGF1R antagonist or expression inhibitor.
  • IGB 1 has its general meaning in the art and refers to Integrin Subunit Beta 1, an integrin that is a member of integrin family members, a membrane receptor involved in cell adhesion and recognition in a variety of biological and pathological processes (Protein Accession number UniProtKB/Swiss-Prot: P05556).
  • EGFR has its general meaning in the art and refers to Epidermal Growth Factor Receptor, a transmembrane glycoprotein that is a member of the protein kinase superfamily, a receptor for members of the epidermal growth factor family (Protein Accession number UniProtKB/Swiss-Prot: P00533).
  • IGF1R has its general meaning in the art and refers to Insulin Like Growth Factor 1 Receptor, a receptor which binds insulin-like growth factor with a high affinity.
  • IGF 1R refers to a receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1) (Protein Accession number UniProtKB/Swiss-Prot: P08069).
  • the CDH1 pathway inhibitor is CDH1 antagonist, preferably an ITGB 1, CDH1, EGFR or IGF1R antagonist.
  • the term “antagonist” has its general meaning in the art and refers to a compound that selectively inactivates the target and any compound targeting a member of CDH1 pathway.
  • the term “antagonist” refers to compounds that bind to the target and function as potent antagonists of the target.
  • the term “antagonist” refers to any compound that can directly or indirectly inhibit the signal transduction cascade related to target and inhibits target ligand binding.
  • the term “selectively inactivates” refers to a compound that preferentially inactivates the target with a greater affinity and potency, respectively, than its interaction with the other sub-types or isoforms of the target signaling family.
  • an antagonist is a small organic molecule, a polypeptide, an aptamer, an oligonucleotide (antisense oligonucleotides, siRNA, shRNA, DNA and RNA aptamers), or an antibody.
  • Tests and assays for determining whether a compound is an antagonist are well known by the skilled person in the art such as described in Lee et al., 2019; Lapteva et al., 2019; Jahangiri et al., 2014. Determining whether a compound is an antagonist may also be performed by using recombinant target proteins, competitive binding assays and measuring the binding affinities, or assays such as described in the examples.
  • CDH1 antagonist refers to any compound selected from but not limited to CDH1 antagonist OS2966 a first-in-class humanized antagonizing monoclonal antibody against pi integrin, shRNA-targeting pi integrin (shBETAl).
  • the CDH1 pathway inhibitor is monoclonal humanized antibody OS2966. This antibody is for example described under DrugBank Accession Number DB 17207.
  • the CDH1 pathway inhibitor is an ITGB1 antagonist.
  • ITGB1 antagonist refers to any compound selected from but not limited to ITGB1 antagonist Natalizumab, MK-0668, Firategrast, Volociximab and the antibody CAS Number 308067-60- 9.
  • the CDH1 pathway inhibitor is an EGFR antagonist.
  • EGFR antagonist refers to any compound selected from but not limited to EGFR antagonist Brigatinib, Erlotinib, Gefitinib, Icotinib, Lapatinib, Simotinib, Vandetanib, Afatinib, Neratinib, Pyrotinib, Almonertinib, Olmutinib, Osimertinib, Dacomitinib.
  • the CDH1 pathway inhibitor is an IGF1R antagonist.
  • IGF1R antagonist refers to any compound selected from but not limited to IGF1R antagonist Ganitumab, Figitumumab, Cixutumumab, MK-0646, Xentuzumab, Linsitinib (OSI-906), AXL1717.
  • the CDH1 pathway inhibitor preferably the CDH1 inhibitor is an aptamer.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990.
  • the random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence.
  • Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996). Then after raising aptamers directed against the target of the invention as above described, the skilled man in the art can easily select those blocking or inactivating the target.
  • a platform protein such as E. coli Thioredoxin A
  • the CDH1 pathway inhibitor preferably the CDH1 inhibitor is an antibody (the term including “antibody portion”) directed against the target.
  • the antibody is a monoclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a polyclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a humanized antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a chimeric antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a light chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a heavy chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fab portion of the antibody.
  • the portion of the antibody comprises a F(ab')2 portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fc portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fv portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a variable domain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises one or more CDR domains of the antibody.
  • antibody includes both naturally occurring and non-naturally occurring antibodies. Specifically, “antibody” includes polyclonal and monoclonal antibodies, and monovalent and divalent fragments thereof. Furthermore, “antibody” includes chimeric antibodies, wholly synthetic antibodies, single chain antibodies, and fragments thereof. The antibody may be a human or nonhuman antibody. A nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in man.
  • Antibodies are prepared according to conventional methodology. Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the invention, a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with antigenic forms of the target. The animal may be administered a final "boost" of antigen within one week of sacrifice. It is often desirable to use an immunologic adjuvant during immunization.
  • Suitable immunologic adjuvants include Freund's complete adjuvant, Freund's incomplete adjuvant, alum, Ribi adjuvant, Hunter's Titermax, saponin adjuvants such as QS21 or Quil A, or CpG-containing immunostimulatory oligonucleotides.
  • Other suitable adjuvants are well-known in the field.
  • the animals may be immunized by subcutaneous, intraperitoneal, intramuscular, intravenous, intranasal or other routes. A given animal may be immunized with multiple forms of the antigen by multiple routes.
  • the antigen may be provided as synthetic peptides corresponding to antigenic regions of interest in the target.
  • lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hybridoma.
  • cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods, as described (Coding, Monoclonal Antibodies: Principles and Practice: Production and Application of Monoclonal Antibodies in Cell Biology, Biochemistry and Immunology, 3rd edition, Academic Press, New York, 1996).
  • cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen.
  • Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non-denaturing ELISA, flow cytometry, and immunoprecipitation.
  • an antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody.
  • an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region designated an Fab fragment, retains one of the antigen binding sites of an intact antibody molecule.
  • Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd.
  • the Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation.
  • CDRs complementarity determining regions
  • FRs framework regions
  • CDR1 through CDRS complementarity determining regions
  • compositions and methods that include humanized forms of antibodies.
  • humanized describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules.
  • Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference.
  • the above U.S. Pat. Nos. 5,585,089 and 5,693,761, and WO 90/07861 also propose four possible criteria, which may be used in designing the humanized antibodies.
  • the first proposal was that for an acceptor, use a framework from a particular human immunoglobulin that is unusually homologous to the donor immunoglobulin to be humanized, or use a consensus framework from many human antibodies.
  • the second proposal was that if an amino acid in the framework of the human immunoglobulin is unusual and the donor amino acid at that position is typical for human sequences, then the donor amino acid rather than the acceptor may be selected.
  • the third proposal was that in the positions immediately adjacent to the 3 CDRs in the humanized immunoglobulin chain, the donor amino acid rather than the acceptor amino acid may be selected.
  • the fourth proposal was to use the donor amino acid reside at the framework positions at which the amino acid is predicted to have a side chain atom within 3 A of the CDRs in a three dimensional model of the antibody and is predicted to be capable of interacting with the CDRs.
  • the above methods are merely illustrative of some of the methods that one skilled in the art could employ to make humanized antibodies.
  • One of ordinary skill in the art will be familiar with other methods for antibody humanization.
  • humanized forms of the antibodies some, most or all of the amino acids outside the CDR regions have been replaced with amino acids from human immunoglobulin molecules but where some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they would not abrogate the ability of the antibody to bind a given antigen.
  • Suitable human immunoglobulin molecules would include IgGl, IgG2, IgG3, IgG4, IgA and IgM molecules.
  • a "humanized" antibody retains a similar antigenic specificity as the original antibody.
  • the affinity and/or specificity of binding of the antibody may be increased using methods of "directed evolution", as described by Wu et al., /. Mol. Biol. 294: 151, 1999, the contents of which are incorporated herein by reference.
  • Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest.
  • monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans.
  • KAMA human anti-mouse antibody
  • the present invention also provides for F(ab') 2 Fab, Fv and Fd fragments; chimeric antibodies in which the Fc and/or FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric F(ab')2 fragment antibodies in which the FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric Fab fragment antibodies in which the FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; and chimeric Fd fragment antibodies in which the FR and/or CDR1 and/or CDR2 regions have been replaced by homologous human or non-human sequences.
  • the present invention also includes so-called single chain antibodies.
  • the various antibody molecules and fragments may derive from any of the commonly known immunoglobulin classes, including but not limited to IgA, secretory IgA, IgE, IgG and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4.
  • the compound of the invention is a Human IgG4.
  • the antibody according to the invention is a single domain antibody.
  • the term “single domain antibody” (sdAb) or “VHH” refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals, which are naturally devoid of light chains. Such VHH are also called “nanobody®”. According to the invention, sdAb can particularly be llama sdAb.
  • VHH refers to the single heavy chain having 3 complementarity determining regions (CDRs): CDR1, CDR2 and CDR3.
  • CDRs complementarity determining region
  • CDR complementarity determining region
  • VHH according to the invention can readily be prepared by an ordinarily skilled artisan using routine experimentation.
  • VHH variants and modified form thereof may be produced under any known technique in the art such as in-vitro maturation.
  • VHHs or sdAbs are usually generated by PCR cloning of the V-domain repertoire from blood, lymph node, or spleen cDNA obtained from immunized animals into a phage display vector, such as pHEN2.
  • Antigen-specific VHHs are commonly selected by panning phage libraries on immobilized antigen, e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells.
  • immobilized antigen e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells.
  • VHHs often show lower affinities for their antigen than VHHs derived from animals that have received several immunizations.
  • VHHs from immune libraries are attributed to the natural selection of variant VHHs during clonal expansion of B-cells in the lymphoid organs of immunized animals.
  • the affinity of VHHs from non-immune libraries can often be improved by mimicking this strategy in vitro, i.e., by site directed mutagenesis of the CDR regions and further rounds of panning on immobilized antigen under conditions of increased stringency (higher temperature, high or low salt concentration, high or low pH, and low antigen concentrations).
  • VHHs derived from camelid are readily expressed in and purified from the E. coli periplasm at much higher levels than the corresponding domains of conventional antibodies.
  • VHHs generally display high solubility and stability and can also be readily produced in yeast, plant, and mammalian cells.
  • the “Hamers patents” describe methods and techniques for generating VHH against any desired target (see for example US 5,800,988; US 5,874, 541 and US 6,015,695).
  • the “Hamers patents” more particularly describe production of VHHs in bacterial hosts such as E. coli (see for example US 6,765,087) and in lower eukaryotic hosts such as moulds (for example Aspergillus or Trichoderma) or in yeast (for example Saccharomyces, Kluyveromyces, Hansenula or Pichia) (see for example US 6,838,254).
  • the invention provides an antibody that competes for binding to the target with the antibody of the invention.
  • the invention concerns an antibody that binds to a molecule of the CDH1 pathway, preferably to ITGB1, CDH1, EGFR or IGF1R.
  • the CDH1 pathway inhibitor is an antagonist antibody of ITGB1, CDH1, EGFR or IGF1R.
  • binding in the context of the binding of an antibody to a predetermined antigen or epitope typically is a binding with an affinity corresponding to a KD of about 10-7 M or less, such as about 10-8 M or less, such as about 10-9 M or less, about 10- 10 M or less, or about 10-11 M or even less when determined by for instance surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using a soluble form of the antigen as the ligand and the antibody as the analyte.
  • SPR surface plasmon resonance
  • BIACORE® GE Healthcare, Piscaataway, NJ
  • BIACORE® is one of a variety of surface plasmon resonance assay formats that are routinely used to epitope bin panels of monoclonal antibodies.
  • an antibody binds to the predetermined antigen with an affinity corresponding to a KD that is at least ten-fold lower, such as at least 100-fold lower, for instance at least 1,000-fold lower, such as at least 10,000-fold lower, for instance at least 100,000-fold lower than its KD for binding to a non-specific antigen (e.g., BSA, casein), which is not identical or closely related to the predetermined antigen.
  • a non-specific antigen e.g., BSA, casein
  • An antibody is said to essentially not bind an antigen or epitope if such binding is either not detectable (using, for example, plasmon resonance (SPR) technology in a BIAcore 3000 instrument using a soluble form of the antigen as the ligand and the antibody as the analyte), or is 100 fold, 500 fold, 1000 fold or more than 1000 fold less than the binding detected by that antibody and an antigen or epitope having a different chemical structure or amino acid sequence.
  • SPR plasmon resonance
  • Additional antibodies can be identified based on their ability to cross-compete (e.g., to competitively inhibit the binding of, in a statistically significant manner) with other antibodies of the invention in standard antigen binding assays.
  • the ability of a test antibody to inhibit the binding of antibodies of the present invention to the target demonstrates that the test antibody can compete with that antibody for binding to the target; such an antibody may, according to non-limiting theory, bind to the same or a related (e.g., a structurally similar or spatially proximal) epitope on the target as the antibody with which it competes.
  • another aspect of the invention provides antibodies that bind to the same antigen as, and compete with, the antibodies disclosed herein.
  • an antibody “competes” for binding when the competing antibody inhibits the target binding of an antibody or antigen binding fragment of the invention by more than 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% in the presence of an equimolar concentration of competing antibody.
  • the antibodies or antigen binding fragments of the invention bind to one or more epitopes of the target.
  • the epitopes to which the present antibodies or antigen binding fragments bind are linear epitopes. In other embodiments, the epitopes to which the present antibodies or antigen binding fragments bind are non-linear, conformational epitopes.
  • the CDH1 pathway inhibitor of the invention is a CDH1, ITGB1, EGFR or IGF1R expression inhibitor.
  • a gene product can be the direct transcriptional product of a gene (e.g., mRNA, tRNA, rRNA, antisense RNA, ribozyme, structural RNA or any other type of RNA) or a protein produced by translation of a mRNA.
  • Gene products also include messenger RNAs, which are modified, by processes such as capping, polyadenylation, methylation, and editing, and proteins modified by, for example, methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, ADP- ribosylation, myristilation, and glycosylation.
  • an “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • An “inhibitor of expression” refers to any compound that has a biological effect to inhibit the expression of a target gene and/or the expression of target protein.
  • said inhibitor of expression is a short hairpin RNA (shRNA), a small inhibitory RNA (siRNA), or an antisense oligonucleotide.
  • the inhibitor of expression is a siRNA or a shRNA.
  • the target expression inhibitors for use in the present invention may be based on antisense oligonucleotide constructs.
  • Anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of the target mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of the target proteins, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding the target can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Small inhibitory RNAs can also function as a target expression inhibitors for use in the present invention.
  • the target gene expression can be reduced by contacting the subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that the target expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschl, T. et al. (1999); Elbashir, S. M. et al. (2001); Hannon, GJ. (2002); McManus, MT. et al.
  • the CDH1 pathway inhibitor is a siRNA targeting ITGB1, CDH1, EGFR and/or IGF1R. In some aspects, the siRNA targets CDH1 or ITGB1.
  • the CDH1 pathway inhibitor is a siRNA targeting ITGB 1.
  • said siRNA has a sequence comprising or consisting of nucleotide sequence as set forth in SEQ ID NO: 1 or 2 or a variant thereof having at least 85%, 90%, 95%, 97% or 99% sequence identity thereto.
  • the siRNA variant comprises one, two or three nucleic acid modification selected from the group consisting of addition, deletion or substitution, preferably substitution.
  • said variant is still capable of interfering with the expression of ITGB 1.
  • the CDH1 pathway inhibitor is made of two siRNAs targeting ITGB1, in particular two siRNAs of SEQ ID NO: 1 and 2, respectively, or a variant thereof having at least 85%, 90%, 95%, 97% or 99% sequence identity thereto or comprising one, two or three nucleic acid modification selected from the group consisting of addition, deletion or substitution, preferably substitution.
  • the CDH1 pathway inhibitor is a siRNA targeting CDH1.
  • said siRNA has a sequence comprising or consisting of nucleotide sequence as set forth in SEQ ID NO: 3 or 4 or a variant thereof having at least 85%, 90%, 95%, 97% or 99% sequence identity thereto.
  • the siRNA variant comprises one, two or three nucleic acid modification selected from the group consisting of addition, deletion or substitution, preferably substitution.
  • said variant is still capable of interfering with the expression of CDH1.
  • the CDH1 pathway inhibitor is made of two siRNAs targeting CDH1, in particular two siRNAs of SEQ ID NO: 3 and 4, respectively, or a variant thereof having at least 85%, 90%, 95%, 97% or 99% sequence identity thereto or comprising one, two or three nucleic acid modification selected from the group consisting of addition, deletion or substitution, preferably substitution.
  • the invention concerns an ITGB1 inhibitor, preferably such as disclosed herein, for use in the treatment of a cancer comprising iCAFs, preferably of detox- iCAFs and optionally myCAFs such as ECM-myCAFs.
  • a cancer comprising iCAFs, preferably of detox- iCAFs and optionally myCAFs such as ECM-myCAFs.
  • the cancer is an E-cadherin positive cancer.
  • the cancer is an immunotherapy resistant cancer.
  • the cancer is an E-cadherin positive cancer resistant to immunotherapy, typically resistant to immune checkpoint inhibitors.
  • Short hairpin RNA shRNA
  • siRNAs Small inhibitory RNAs
  • Gene expression can be reduced with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Ribozymes can also function as target expression inhibitors for use in the present invention.
  • Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
  • Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of the target mRNA sequences are thereby useful within the scope of the present invention.
  • ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • Both antisense oligonucleotides (ODNs) and ribozymes useful as target inhibitors can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis.
  • anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life.
  • Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2'-O-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
  • Antisense oligonucleotides, siRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide siRNA or ribozyme nucleic acid to the cells and preferably cells expressing the target.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide siRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40- type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • adenovirus adeno-associated virus
  • SV40- type viruses polyoma viruses
  • Epstein-Barr viruses Epstein-Barr viruses
  • papilloma viruses herpes virus
  • Non-cytopathic viral vectors are based on non-cytopathic eukaryotic viruses in which non- essential genes have been replaced with the gene of interest.
  • Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA.
  • Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle).
  • retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
  • Standard protocols for producing replication-deficient retroviruses including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles
  • KRIEGLER A Laboratory Manual
  • MURRY Method of Recombinant retroviruses by the packaging cell line
  • Methods in Molecular Biology vol.7, Humana Press, Inc., Cliffton, N.J., 1991.
  • adeno-viruses and adeno-associated viruses are double-stranded DNA viruses that have already been approved for human use in gene therapy.
  • the adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hemopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions.
  • the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection.
  • wildtype adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event.
  • the adeno-associated virus can also function in an extrachromosomal fashion.
  • Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et al., "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989.
  • plasmid vectors have been used as DNA vaccines for delivering antigenencoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors.
  • These plasmids however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid.
  • Plasmids may be delivered by a variety of parenteral, mucosal and topical routes.
  • the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally.
  • the plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation.
  • the invention relates to a method of treating fibrotic related disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 pathway inhibitor.
  • the invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 pathway inhibitor.
  • the invention relates to a method of treating E-cadherin positive cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 pathway inhibitor.
  • the invention relates to a method of treating immunosuppressive environment associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 pathway inhibitor.
  • the invention relates to a method of treating immunotherapyresistant cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 inhibitor.
  • the invention relates to a method of treating immunotherapyresistant cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 inhibitor.
  • the invention relates to a method of treating non-cancerous fibrotic related disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDH1 pathway inhibitor.
  • the invention also concerns a method for selecting a patient affected with a fibrotic associated disease as suitable for a treatment with a CDH1 pathway inhibitor wherein the method comprises:
  • the invention also concerns a method for selecting a patient affected with a fibrotic associated disease as suitable for a treatment with a CDH1 pathway inhibitor wherein the method comprises:
  • the reference level is typically as described above.
  • the invention also concerns a method for selecting a patient suffering from cancer, preferably a E-cadherin positive cancer resistant to immunotherapy, as suitable for a treatment with a CDH1 pathway inhibitor wherein the method comprises:
  • the invention also concerns a method for treating a fibrotic associated disease in a subject in need thereof, wherein the method comprises: a) detecting inflammatory cancer-associated fibroblasts (iCAFs), preferably detox- iCAFs, in a biological sample from said subject; b) administering a therapeutic effective amount of a CDH1 pathway inhibitor to said subject if iCAFs, preferably detox-iCAFs, are detected in the biological sample.
  • iCAFs cancer-associated fibroblasts
  • the invention also relates to a method for treating a cancer in a subject in need thereof, wherein the method comprises administering a therapeutic effective amount of a CDH1 pathway inhibitor to said subject, and wherein the cancer is an E-cadherin positive cancer comprising inflammatory cancer-associated fibroblasts (iCAFs).
  • a CDH1 pathway inhibitor to said subject
  • the cancer is an E-cadherin positive cancer comprising inflammatory cancer-associated fibroblasts (iCAFs).
  • the invention also concerns a method for treating a cancer in a subject in need thereof, wherein the method comprises: a) detecting inflammatory cancer-associated fibroblasts (iCAFs), preferably detox- iCAFs, in a cancer sample from said subject; b) Administering a therapeutic effective amount of a CDH1 pathway inhibitor to said subject if iCAFs, preferably detox-iCAFs, are detected in the cancer sample.
  • iCAFs cancer-associated fibroblasts
  • the invention also refers to a method of treatment of a patient suffering from a non- cancerous fibroblast associated disease, comprising:
  • the invention also refers to a method of treatment of a patient suffering from a fibroblast associated disease, comprising:
  • the fibroblast associated disease is preferably cancer, more preferably an E-cadherin positive cancer, even more preferably an E-cadherin positive cancer resistant to immunotherapy.
  • the invention also refers to a method for treating a subject suffering from cancer, more preferably an E-cadherin positive and/or immunotherapy resistant cancer, comprising:
  • the treatment methods may comprise an initial step of providing a biological sample from the subject, such as a cancer sample. Additionally or alternatively, the method may comprise a step of detecting iCAFs.
  • the invention concerns the use of a CDH1 pathway inhibitor, preferably an ITGB1 inhibitor, in the manufacture of a medicament for the treatment of a fibrotic related disease, preferably cancer, more preferably a E-cadherin positive and/or immunotherapy resistant cancer.
  • a CDH1 pathway inhibitor preferably an ITGB1 inhibitor
  • the compounds of the invention may be used or prepared in a pharmaceutical composition. Any one of the CDH1 pathway inhibitors described herein may be used or prepared in a pharmaceutical composition.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention and a pharmaceutical acceptable carrier for use in the treatment of fibrotic related disease in a subject of need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention and a pharmaceutical acceptable carrier for use in the treatment of cancer in a subject in need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention and a pharmaceutical acceptable carrier for use in the treatment of E-cadherin positive cancer in a subject in need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention and a pharmaceutical acceptable carrier for use in the treatment of immunosuppressive environment associated cancer in a subject in need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention and a pharmaceutical acceptable carrier for use in the treatment of immunotherapy-resistant cancer in a subject in need thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention in combination with at least one immunotherapeutic agent and a pharmaceutical acceptable carrier for use in the treatment of immunotherapy-resistant cancer in a subject in need thereof.
  • the invention relates to a pharmaceutical composition comprising the compound of the invention and a pharmaceutical acceptable carrier for use in the treatment of non-cancerous fibrotic related disease in a subject in need thereof.
  • the compound of the invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • the compounds according to the invention as described above are administered to the subject in a therapeutically effective amount.
  • a “therapeutically effective amount” of the compound, preferably of the CDH1 pathway inhibitor, preferably the CDH1 inhibitor of the present invention as above described is meant a sufficient amount of the compound at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the compound of the present invention for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the compound of the present invention, preferably from 1 mg to about 100 mg of the compound of the present invention.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the man skilled in the art is perfectly able to select a suitable treatment depending of the fibrotic disease or organ to treat.
  • the amount of treatment according to the invention or of the pharmaceutical composition according to the invention administered or to be administered can be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient.
  • the compound according to the invention may be used in a concentration between 0.01 pM and 20 pM, particularly, the compound of the invention may be used in a concentration of 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0 pM.
  • the compound of the present invention is administered to the subject in the form of a pharmaceutical composition.
  • the compound of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • pharmaceutically acceptable excipients or “pharmaceutically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compound of the present invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized agents of the present inventions into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the typical methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the compound of the present invention plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the CDH1 pathway inhibitor or the pharmaceutical composition comprising said CDH1 pathway inhibitor is used in combination with an additional treatment or agent against the fibrotic disease, preferably an anti-cancer treatment.
  • an additional treatment or agent against the fibrotic disease preferably an anti-cancer treatment.
  • said agent or treatment enhances CD8+ T-cell functionality/activation.
  • the invention therefore also concerns a combination therapy comprising i) the CDH1 pathway inhibitor or the pharmaceutical composition comprising said CDH1 pathway inhibitor and ii) an additional therapeutic agent.
  • the CDH1 pathway inhibitor or the pharmaceutical composition comprising said CDH1 pathway inhibitor can be administered simultaneously, sequentially or separately with another fibrotic disease treatment.
  • the CDH1 inhibitor or the pharmaceutical composition comprising said CDH1 inhibitor is used in combination with an additional treatment or agent against the fibrotic disease, preferably an anti -cancer treatment.
  • an additional treatment or agent against the fibrotic disease preferably an anti -cancer treatment.
  • said agent or treatment enhances CD8+ T-cell functionality/activation.
  • the invention therefore also concerns a combination therapy comprising i) the CDH1 inhibitor or the pharmaceutical composition comprising said CDH1 inhibitor and ii) an additional therapeutic agent.
  • a combination therapy comprising i) the CDH1 inhibitor or the pharmaceutical composition comprising said CDH1 inhibitor and ii) an additional therapeutic agent.
  • the CDH1 inhibitor or the pharmaceutical composition comprising said CDH1 inhibitor can be administered simultaneously, sequentially or separately with another fibrotic disease treatment.
  • the term “simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e. at the same time.
  • the term “sequential” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e. one after the other.
  • the active ingredients are used or administered sequentially, i.e. one after the other.
  • all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.
  • the term “separate” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered at distinct time of the day.
  • the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours.
  • the treatment i.e., the CDH1 pathway inhibitor, preferably the CDH1 inhibitor, the pharmaceutical composition or the combination therapy
  • the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, even more preferably between every day and every week.
  • the duration of treatment is preferably comprised between 1 day and 24 weeks, more preferably between 1 day and 10 weeks, even more preferably between 1 day and 4 weeks.
  • the treatment i.e., the CDH1 pathway inhibitor, preferably the CDH1 inhibitor, the pharmaceutical composition or the combination therapy
  • the treatment last as long as the fibroblast associated disease persists.
  • the CDH1 pathway inhibitor and/or pharmaceutical composition according to the invention is used in combination with cancer therapies.
  • compound and/or pharmaceutical composition of the invention may be administered in combination with targeted therapy, immunotherapy such as immune checkpoint therapy and immune checkpoint inhibitor, co-stimulatory antibodies, chemotherapy and/or radiotherapy.
  • the CDH1 pathway inhibitor and/or pharmaceutical composition according to the invention is used in combination with immunotherapy.
  • immunotherapy refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells.
  • the CDH1 pathway inhibitor and/or pharmaceutical composition according to the invention is used in combination with an immune checkpoint inhibitor.
  • Immune checkpoint therapy such as checkpoint inhibitors include, but are not limited to programmed death- 1 (PD-1) inhibitors, programmed death ligand- 1 (PD-L1) inhibitors, programmed death ligand-2 (PD-L2) inhibitors, lymphocyte-activation gene 3 (LAG3) inhibitors, T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, B- and T-lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors, Indoleamine 2,3- dioxygenase (IDO) inhibitors, killer immunoglobulin-like receptors (KIR) inhibitors, KIR2L3 inhibitors, KIR
  • checkpoint inhibitors include antibodies anti-PDl, anti- PD-L1, anti-CTLA-4, anti-TIM-3, anti-LAG3.
  • Immune checkpoint therapy also include costimulatory antibodies delivering positive signals through immune-regulatory receptors including but not limited to ICOS, CD137, CD27, OX-40 and GITR.
  • Example of anti-PDl antibodies include, but are not limited to, nivolumab, cemiplimab (REGN2810 orREGN-2810), tislelizumab (BGB-A317), tislelizumab, spartalizumab (PDR001 or PDR-001), ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034, pidilizumab, nivolumab (ONO-4538, BMS-936558, MDX1106, GTPL7335 or Opdivo), pembrolizumab (MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda) and antibodies described in International patent applications W02004004771, W02004056875, W02006121168, WO2008156712, W02009014708, W02009114335, WO2013043569 and W02014047350.
  • Example of anti-PD-Ll antibodies include, but are not limited to, LY3300054, atezolizumab, durvalumab and avelumab.
  • Example of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab (see, e.g., US patents US6,984,720 and US8,017,114), tremelimumab (see, e.g., US patents US7, 109,003 and US8, 143,379), single chain anti-CTLA4 antibodies (see, e.g., International patent applications WO1997020574 and WO2007123737) and antibodies described in US patent US8,491,895.
  • Example of anti-VISTA antibodies are described in US patent application US20130177557.
  • Example of inhibitors of the LAG3 receptor are described in US patent US5,773,578.
  • Example of KIR inhibitor is IPH4102 targeting KIR3DL2.
  • the compound and/or pharmaceutical composition of the invention may be used in combination with targeted therapy.
  • targeted therapy refers to targeted therapy agents, drugs designed to interfere with specific molecules necessary for tumor growth and progression.
  • targeted therapy agents such as therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors.
  • Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the target protein such as for example proteasome inhibitor, tyrosine kinase or cyclin-dependent kinase inhibitor, histone deacetylase inhibitor.
  • Targeted therapy may also use cytokines.
  • Examples of such targeted therapy include with no limitations: Ado-trastuzumab emtansine (HER2), Afatinib (EGFR (HER1/ERBB1), HER2), Aldesleukin (Proleukin), alectinib (ALK), Alemtuzumab (CD52), axitinib (kit, PDGFRbeta, VEGFR1/2/3), Belimumab (BAFF), Belinostat (HDAC), Bevacizumab (VEGF ligand), Blinatumomab (CD19/CD3), bortezomib (proteasome), Brentuximab vedotin (CD30), bosutinib (ABL), brigatinib (ALK), cabozantinib (FLT3, KIT, MET, RET, VEGFR2), Canakinumab (IL-1 beta), carfilzomib (proteasome), ceritinib (ALK
  • the compound and/or pharmaceutical composition of the invention may be used in combination with chemotherapy.
  • chemotherapy or “chemotherapy” has its general meaning in the art and refers to a cancer therapeutic treatment using chemical or biochemical substances, in particular using one or several antineoplastic agents or chemotherapeutic agents.
  • Chemotherapeutic agents include, but are not limited to 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, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; du
  • calicheamicin especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin
  • the compound and/or pharmaceutical composition of the invention is administered to the subject in combination with radiotherapy.
  • radiation therapies include, but are not limited to external beam radiotherapy (such as superficial X-rays therapy, orthovoltage X-rays therapy, megavoltage X-rays therapy, radiosurgery, stereotactic radiation therapy, Fractionated stereotactic radiation therapy, cobalt therapy, electron therapy, fast neutron therapy, neutron-capture therapy, proton therapy, intensity modulated radiation therapy (IMRT), 3 -dimensional conformal radiation therapy (3D- CRT) and the like); brachytherapy; unsealed source radiotherapy; tomotherapy; and the like.
  • Gamma rays are another form of photons used in radiotherapy.
  • Radiotherapy may be proton radiotherapy or proton minibeam radiation therapy.
  • Proton radiotherapy is an ultra-precise form of radiotherapy that uses proton beams (Prezado Y, Jouvion G, Guardiola C, Gonzalez W, Juchaux M, Bergs J, Nauraye C, Labiod D, De Marzi L, Pouzoulet F, Patriarca A, Dendale R. Tumor Control in RG2 Glioma-Bearing Rats: A Comparison Between Proton Minibeam Therapy and Standard Proton Therapy.
  • Radiotherapy may also be FLASH radiotherapy (FLASH-RT) or FLASH proton irradiation.
  • FLASH radiotherapy involves the ultra-fast delivery of radiation treatment at dose rates several orders of magnitude greater than those currently in routine clinical practice (ultra-high dose rate) (Favaudon V, Fouillade C, Vozenin MC. The radiotherapy FLASH to save healthy tissues. Med Sci (Paris) 2015; 31 : 121-123. DOI: 10.105 l/medsci/20153102002); Patriarca A., Fouillade C. M., Martin F., Pouzoulet F., Nauraye C., et al. Experimental set-up for FLASH proton irradiation of small animals using a clinical system. Int J Radiat Oncol Biol Phys, 102 (2018), pp. 619-626. doi: 10.1016/j ijrobp.2018.06.403. Epub 2018 Jul 11).
  • compositions of the invention may include any further compound which is used in the treatment of cancer such as described above.
  • said additional active compounds may be contained in the same composition or administrated separately.
  • the pharmaceutical composition of the invention relates to combined preparation for simultaneous, separate or sequential use in the treatment of fibrotic related disease in a subject in need thereof.
  • the pharmaceutical composition of the invention relates to combined preparation for simultaneous, separate or sequential use in the treatment of cancer, E-cadherin positive cancer, immunosuppressive environment associated cancer, immunotherapy-resistant cancer or non-cancerous fibrotic related disease.
  • the invention finally relates to methods and uses for i) inhibiting inflammatory cancer associated fibroblasts (iCAFs) differentiation or ii) inhibiting myCAFs accumulation.
  • iCAFs inflammatory cancer associated fibroblasts
  • myCAFs myofibroblastic CAFs
  • Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response. Without wishing to be bound by any theory, it is believed that such differentiation inhibition will help treating fibrotic associated diseases such as cancer, in particular E-cadherin positive cancer.
  • the invention relates to the use of a CDH1 pathway inhibitor to inhibit inflammatory cancer-associated fibroblasts (iCAFs) differentiation.
  • iCAFs cancer-associated fibroblasts
  • the invention also refers to a method for inhibiting inflammatory cancer associated fibroblasts (iCAFs) differentiation, wherein said method comprises contacting iCAFs, preferably detox- iCAF, with a CDH1 pathway inhibitor.
  • iCAFs inflammatory cancer associated fibroblasts
  • Such method is particularly an in vitro method.
  • iCAFs inflammatory ancer associated fibroblasts
  • myCAFs myofibroblastic
  • iCAFs are ANTXRF whereas myCAFs are ANTXR1 + .
  • iCAFs differentiation to myCAFs can be therefore monitored by assessing the expression of ANTXR1, for example by FACS or immunohistochemistry, such as explained hereabove.
  • the CDH1 pathway inhibitor inhibits the differentiation of detox -iCAFs into ecm-myCAFs.
  • the invention also concerns the use of a CDH1 pathway inhibitor to inhibit or prevent the accumulation or increase of myCAFs, preferably ecm-myCAFs, particularly in a tumoral microenvironment.
  • the invention also refers to a method for preventing or inhibiting the accumulation or increase of myCAFs, preferably ecm-myCAFs, wherein said method comprises contacting CAFs-Sl with a CDH1 pathway inhibitor.
  • a method for preventing or inhibiting the accumulation or increase of myCAFs preferably ecm-myCAFs
  • Such method comprises contacting CAFs-Sl with a CDH1 pathway inhibitor.
  • Such method is particularly an in vitro method.
  • the invention also refers to a method for preventing or inhibiting the accumulation or increase of myCAFs, preferably ecm-myCAFs, in a tumoral microenvironment, wherein said method comprises contacting CAFs-Sl with a CDH1 pathway inhibitor.
  • inhibiting the accumulation of myCAFs it is meant that the number of myCAFs is stabilized (i.e., remains substantially the same) or is reduced, typically in the subject, cancer, biological sample or tumoral microenvironment. It preferably means that the number or percentage of myCAFs does not increase, typically over time.
  • kits comprising the compound of the invention. Kits containing the compound of the invention find use in therapeutic methods.
  • the disclosure relates to a CDH1 pathway inhibitor for use in the treatment of a fibrotic related disease in a subject in need thereof.
  • the fibrotic related disease is typically cancer, particularly breast cancer, ovarian cancer, invasive breast cancer of no-special type.
  • the fibrotic related disease is immunosuppressive environment associated cancer.
  • the fibrotic related disease is immunotherapy-resistant cancer.
  • the CDH1 pathway inhibitor can be for use in combination with at least one immunotherapeutic agent in the treatment of immunotherapy-resistant cancer.
  • the fibrotic related disease is a non-cancerous fibrotic related disease such as chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, systemic lupus erythematosus, systemic sclerosis (SSc), sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis.
  • chronic autoimmune diseases including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, systemic lupus erythematosus, systemic sclerosis (SSc), sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibros
  • the CDH1 pathway inhibitor is particularly selected from the group consisting of CDH1, ITGB1, EGFR and IGF1R antagonist or expression inhibitor.
  • the CDH1, ITGB1, EGFR or IGF1R antagonist is particularly selected from the group consisting of small organic molecule, polypeptide, aptamer and antibody.
  • the CDH1, ITGB1, EGFR or IGF1R expression inhibitor is selected from the group consisting of antisense oligonucleotide, shRNA, siRNA, RNAi and ribozyme.
  • the CDH1 antagonist is OS2966.
  • FIG. 1 Functional impact of CDH1 silencing in cancer cells on CAF-S1 differentiation.
  • CDH1 inactivation in ER+ cancer cells prevents detox-iCAF differentiation into ECM-myCAF after co-culture.
  • siCDHl refers to a siRNA targeting CDH1.
  • MCF7 and T47D correspond to cell lines of invasive ductal carcinoma (TDC).
  • Figure 2 Functional impact of ITGB1 silencing on CAF-S1 differentiation. Inactivation of ITGB1 in iCAF reduces differentiation into ECM-myCAF, after co-culture with tumor cells.
  • silTGBl refers to a siRNA targeting silTGBl.
  • FIG. 3 Functional experiments validate the differential ability of iCAF vs myCAF to attract lymphocytes.
  • iCAFs significantly attract CD8 T cells in vitro in comparison to myCAF and in comparison to siCDHl cancer cells (Breast cancer cell lines (MCF7 and T47D) whitout iCAF phenotype.
  • Co-culture of iCAF with E-cadherin positive cancer cell lines prevents CD8 migration by inducing a myCAF phenotype.
  • FIG. 4 Functional impact of CDH1 silencing in cancer cells on subpopulations of CAF-S1.
  • siCDHl refers to a siRNA targeting CDH1.
  • MCF7 and T47D correspond to cell lines of invasive ductal carcinoma (IDC).
  • FIG. 5 Functional impact of ITGB1 silencing on subpopulations of CAF-S1.
  • silTGBl refers to a siRNA targeting silTGBl.
  • FIG. 6 E-cadherin low non-lobular breast carcinoma are enriched in iCAF compared to E-cadherin high non-lobular breast carcinoma. Bar plots showing the proportion of CAF-S1 clusters among CAF-S1, estimated by scRNAseq.
  • Figure 7 Diffuse gastric carcinoma (with CDH1 inactivation) are enriched in iCAF compared to intestinal type gastric carcinoma. Bar plots showing the proportion of iCAF and myCAF, estimated by scRNAseq.
  • E-cadherin inactivation shapes tumor microenvironment specificities in Invasive Lobular Carcinoma
  • ILC Invasive Lobular Carcinoma
  • IBC-NST invasive breast carcinoma of no special type
  • TIL tumor-infiltrating lymphocytes
  • the inventors investigated the role of tumor micro-environment in E- cadherin- cancer (invasive lobular carcinoma) in comparison to E-cadherin+ cancer (invasive breast carcinoma of no special type (IBC-NST) also known as invasive ductal carcinoma (IDC)). Accordingly, the inventors performed an in-depth characterization of the heterogeneity, the function, and the interactions of Cancer Associated Fibroblast (CAF) and immune cells in ILC compared to IBC-NST. To do so, the inventors leveraged a well characterized retrospective series of 251 patients who underwent surgery for a primary ILC (prior to any treatment), for whom frozen tumor samples were available for RNA sequencing.
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive breast carcinoma of no special type
  • IBC-NST invasive
  • the inventors established tissue microarrays (TMA) for 158 ILC from this cohort and 110 primary IBC-NST (including 77 ER+ IBC-NST). Based on the TMA cohort, the inventors did comparative immunohistochemical analysis of selected CAF and immune cell markers. In addition, the inventors characterized six classical ILC by single cell RNA sequencing after a step of cell sorting (EPCAM+ cells, CD45+ cells and CAF).
  • ILC have more inflammatory CAF and less myofibroblastic CAF than IBC-NST.
  • the inventors demonstrated that the myofibroblastic content is higher in ER+ IDC than in ILC.
  • myCAF-Sl and ECM-myCAF IHC markers are expressed at higher levels in ER+ IDC than in ILC.
  • the inventors identified that classical ILCs are enriched in iCAF-Sl, ER+ IDC are enriched in myCAF-Sl, in particular ECM-myCAF and the composition in CAF-S1 clusters is highly heterogeneous across ILC cases. Distinct groups of ILCs can be distinguished based on CAF- S1 cluster content, in relation with some clinico-pathological features.
  • the inventors performed Ligand-Receptor interaction analysis (CellChat) from scRNAseq data: ATLAS ILC vs IDC. Accordingly, the inventors demonstrated that CAF-S1 are among the cells that most frequently interact with ductal tumor cells via the CDH1 pathway. As expected, lobular tumor cells show almost no interaction with other cells via the CDH1 pathway. The inventors also demonstrated that Ductal tumor cells interact with CAF-S1 via CDH1 through ITGB1, EGFR and IGF1R.
  • CAF markers were evaluated by histological score (H-score; 0 to 300), which corresponds to the sum of intensities (1 to 3) multiplied by the percentage of stained cells (0 to 100) for each intensity. The percentage of stained cells was defined as the ratio of labeled fibroblast surface area to stromal surface area.
  • H-score histological score
  • the inventors performed an analysis combining H-score results for several single IHC markers. The inventors first excluded cases without significant FAP expression (H-score ⁇ 1 st quartile), to eliminate CAFS1 devoid cases.
  • the iCAF-Sl enriched cases were then defined as tumors with low ANTXR1 H-score, the ECM-myCAF enriched as cases with ANTXR1- High/SDCl-High H-scores and the other myCAF enriched as cases with ANTXR1- High/SDCl-low H-scores, on the basis of previous publications (Bonneau et al., 2020; Costa et al., 2018b; Givel et al., 2018b; Kieffer et al., 2020b; Pelon et al., 2020). Gaussian mixture models were use to determine the threshold between low versus high H-score for these CAFS1 cluster markers.
  • ITGB1 silencing in primary fibroblasts was performed with two distinct siRNAs targeting ITGB1 (GUGCAGAGCCUUCAAUAAA (SEQ ID NO: 1) and GGUAGAAAGUCGGGACAAA (SEQ ID NO: 2), Horizon Discovery, #LQ-004506-00- 0005).
  • CDH1 silencing in MCF7 and T47D breast cancer cells was achieved using two different siRNA targeting CDH1 (GAGAACGCAUUGCCACAUA (SEQ ID NO: 3) and GGGACAACGUUUAUUACUA (SEQ ID NO: 4), Horizon Discovery, #LQ-003877-00- 0005).
  • the Co-culture of Detox-iCAF with ER+ IDC cancer cells induces fibroblast differentiation into ECM-myCAF.
  • the inventors demonstrated that CDH1 inactivation in ER+ cancer cells prevents detox-iCAF differentiation into ECM-myCAF after co-culture ( Figures 1 and 4).
  • the inventors also investigated functional impact of ITGB1 silencing on CAF-S1 differentiation and demonstrated that inactivation of ITGB1 in iCAF reduces differentiation into ECM-myCAF, after co-culture with tumor cells ( Figures 2 and 5).
  • RNAseq deconvolution identifies ILC groups enriched in specific CAF-S1 clusters and with specific TIL infiltration pattern.
  • infiltrating pattern is mainly associated with Detox-iCAF enrichment and margin predominant pattern is mainly associated with ECM-myCAF enrichment, which is validated at the protein level (IHC).
  • the inventors also investigated CAF content in non-lobular breast carcinoma expressing E-cadherin, in single cell RNAseq dataset.
  • the E-cadherin low non-lobular breast carcinoma are enriched in iCAF compared to E-cadherin high non-lobular breast carcinoma ( Figure 6).
  • Diffuse gastric carcinoma (with CDH1 inactivation) are enriched in iCAF compared to intestinal type gastric carcinoma ( Figure 7).
  • Intestinal type gastric carcinoma expresses E-cadherin.
  • Bai R Chen N, Li L, Du N, Bai L, Lv Z, Tian H, Cui J. Mechanisms of Cancer Resistance to Immunotherapy. Front Oncol. 2020 Aug 6; 10: 1290. doi: 10.3389/fonc.2020.01290.
  • Kieffer Y Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, Lameiras S, Albergante L, Bonneau C, Guyard A, Tarte K, Zinovyev A, Bauisme S, Zalcman G, Vincent- Salomon A, Mechta-Grigoriou F. Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer. Cancer Discov. 2020 Sep; 10(9): 1330-1351. doi: 10.1158/2159-8290. CD-19-1384.

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Abstract

La divulgation concerne des méthodes et des compositions pharmaceutiques pour le traitement de maladies associées à la fibrotique, en particulier le cancer et le cancer résistant à l'immunothérapie. Les inventeurs ont étudié le rôle de nouveaux mécanismes et voies de facteurs clés de microenvironnement immunosuppresseurs et l'interaction entre les cellules cancéreuses avec les fibroblastes associés au cancer (CAF) et les cellules immunitaires pour trouver des options curatives alternatives pour le cancer comprenant un cancer résistant à l'immunothérapie. Les inventeurs ont identifié que le carcinome lobulaire infiltrant (ILC) a plus de CAF inflammatoires et moins de CAF myofibroblastiques que le carcinome mammaire infiltrant d'aucun type spécial (IBC-NST). Les inventeurs ont démontré que les CAF-S1 sont parmi les cellules qui interagissent le plus fréquemment avec des cellules tumorales canalaires par l'intermédiaire de la voie CDH1 par ITGB1, EGFR et IGF1R. Les inventeurs ont démontré que l'inactivation de CDH1 ainsi que l'extinction d'ITGB 1 empêche et réduit la différenciation de iCAF en ECM-myCAF après co-culture avec des cellules tumorales et restaure l'attraction de CD8. Dans l'ensemble, la présente divulgation met en évidence le rôle de la voie CDH1 dans le cancer et l'utilisation d'antagonistes de CDH1, ITGB1, EGFR et IGFIR dans le traitement de maladies associées à la fibrotique, en particulier le cancer et le cancer résistant à l'immunothérapie. Ainsi, la présente divulgation concerne un inhibiteur de la voie CDH1 destiné à être utilisé dans le traitement d'une maladie liée à la fibrotique, en particulier le cancer et le cancer résistant à l'immunothérapie.
PCT/EP2024/077109 2023-09-27 2024-09-26 Méthodes de traitement de maladies associées à la fibrotique Pending WO2025068393A1 (fr)

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