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WO2025068157A1 - COMBINAISON D'UN ANTAGONISTE DE βIG-H3 ET D'UN ANTAGONISTE DE PDFG-AA POUR LE TRAITEMENT DU CANCER - Google Patents

COMBINAISON D'UN ANTAGONISTE DE βIG-H3 ET D'UN ANTAGONISTE DE PDFG-AA POUR LE TRAITEMENT DU CANCER Download PDF

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WO2025068157A1
WO2025068157A1 PCT/EP2024/076742 EP2024076742W WO2025068157A1 WO 2025068157 A1 WO2025068157 A1 WO 2025068157A1 EP 2024076742 W EP2024076742 W EP 2024076742W WO 2025068157 A1 WO2025068157 A1 WO 2025068157A1
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pdgf
antagonist
cancer
antibody
cell
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Ana HENNINO
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Stromacare
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Centre Leon Berard
Universite Claude Bernard Lyon 1
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Stromacare
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Centre Leon Berard
Universite Claude Bernard Lyon 1
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    • 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
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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 present invention relates to compositions and methods for preventing or treating cancer disease, such as pancreatic ductal adenocarcinoma (PDAC).
  • cancer disease such as pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • Pancreatic ductal adenocarcinoma is currently the fourth leading cause of cancer-related death in the industrialized world and is predicted to become the second leading cause of cancer-related death by 2030 (Hidalgo 2010).
  • PDAC develops through the preceding formation of acinar-to-duct metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), which are primarily driven by oncogenic Kras activation (Ying 2016).
  • ADM acinar-to-duct metaplasia
  • PanIN pancreatic intraepithelial neoplasia
  • PDAC is associated with an abundant stromal reaction that usually surrounds islands of cancer cells and accounts for 50-80% of the tumor volume (Erkan 2008; Neesse 2011).
  • the purpose of the present invention is therefore to address a medical need by providing a new therapeutical target for treating cancer by restoring beneficial anti-tumor immunity, especially in PDAC.
  • the invention also relates to a combination of (i) a
  • the present invention also relates a combination of (i) a
  • the present invention also relates to the use of a combination of (i) a
  • the present invention also relates to the use of a combination of (i) a
  • the present invention also relates to a method for preventing or treating a patient affected with cancer disease, comprising administering to said patient efficient amounts of both (i) a pig-h3 antagonist, and (ii) a PDGF-AA antagonist.
  • the present invention also relates to a method for activating the anti-tumoral CD8+T cell response of a patient affected with cancer disease, comprising administering to said patient efficient amounts of both (i) a
  • the present invention provides methods and compositions (such as pharmaceutical compositions) combining (i) a
  • the present invention also provides methods and compositions for inhibiting or preventing pancreatic ductal adenocarcinoma.
  • the cancer is a cancer associated with a stroma expressing/secreting PDGF-AA and
  • the cancer may be associated with a solid tumor.
  • cancers that are associated with solid tumor formation include breast cancer, uterine/cervical cancer, oesophageal cancer, pancreatic cancer, colon cancer, colorectal cancer, kidney cancer, ovarian cancer, prostate cancer, head and neck cancer, non-small cell lung cancer stomach cancer, tumors of mesenchymal origin (i.e; fibrosarcoma and rhabdomyoscarcoma), tumors of the central and peripheral nervous system (i.e; including astrocytoma, neuroblastoma, glioma, glioblatoma), thyroid cancer.
  • mesenchymal origin i.e; fibrosarcoma and rhabdomyoscarcoma
  • tumors of the central and peripheral nervous system i.e; including astrocytoma, neuroblastoma, glioma, glioblatoma
  • thyroid cancer i.e; including astrocytoma, neuroblastom
  • the cancer is selected from the group consisting of nonsmall cell lung carcinoma, lung squamous cell carcinoma, lung adeno carcinoma, breast carcinoma, pancreatic cancer, ovarian serous cystadenocarcinoma, uterine carcinosarcoma, gastrointestinal stroma tumors such as stomach adenocarcinoma and cholangiocarcinoma, head and neack squamous carcinoma, oesophageal carcinoma, kidney renal clear cell carcinoma, sarcoma, mesothelioma and colorectal adenocarcinoma such as rectum adenocarcinoma and colon adenocarcinoma.
  • the invention relates to treating one of these cancers, which is associated with a stroma expressing/secreting PDGF-AA and
  • 3ig-h3 antibodies are disclosed in W02023/006919, incorporated herein by reference. Examples in the present description are using humanized antibodies described in W02023/006919.
  • 3ig-h3 antibody and the binding fragment thereof comprise a VH domain comprising the three CDRs of H-330 V1 .2 and a VL domain comprising the three CDRs of L-41 or L-228.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding pig-h3 or PDGF-A can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131 ; 6,365,354; 6,410,323; 6,107,091 ; 6,046,321 ; and 5,981 ,732).
  • Inhibitors of gene expression according to the present invention may be based nuclease therapy (like Talen or Crispr).
  • a “control reference value” can be a “threshold value” or a “cut-off value”. Typically, a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative). Typically, the optimal sensitivity and specificity (and so the threshold value) can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the person skilled in the art may compare the PDGF-AA levels (obtained according to the method of the invention) with a defined threshold value.
  • the threshold value is derived from the PDGF-AA level (or ratio, or score) determined in a blood sample derived from one or more subjects who are responders to pancreatic ductal adenocarcinoma treatment.
  • the threshold value may also be derived from PDGF-AA level (or ratio, or score) determined in a blood sample derived from one or more subjects who are not affected with pancreatic ductal adenocarcinoma.
  • retrospective measurement of the PDGF-AA levels (or ratio, or scores) in properly banked historical subject samples may be used in establishing these threshold values.
  • a body fluid sample is obtained from the subject and the level of PDGF-AA is measured in this sample. Indeed, statistical analyses revealed that decreasing PDGF-AA levels would be particularly beneficial in those patients displaying high levels of PDGF-AA.
  • the present invention also relates to a pharmaceutical composition for use in the prevention or treatment of cancer comprising a PDGF-AA antagonist according to the invention, a
  • the invention relates to treating one of these cancers, which is associated with a stroma expressing/secreting PDGF-AA and
  • “Pharmaceutically” or “pharmaceutically acceptable” refers 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 choice of the formulation ultimately depends on the intended way of administration, such as e.g. an intravenous, intraperitoneal, subcutaneous or oral way of administration, or a local administration via tumor injection.
  • the pharmaceutical composition according to the invention may be a solution or suspension, e.g. an injectable solution or suspension. It may for example be packaged in dosage unit form.
  • 3ig-h3 antagonist and the PDGF-AA antagonist of the invention, and the pharmaceutical composition of the invention are administered by the intravenous route.
  • compositions of the present invention may be suited to oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration. They 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 appropriate unit forms of administration include forms for oral administration, such as tablets, gelatine capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administration, aerosols, implants, forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms for rectal administration.
  • each one active principle is generally formulated as dosage units containing from 0.5 to 1000 mg, preferably from 1 to 500 mg, more preferably from 2 to 200 mg of said active principle per dosage unit for daily administrations.
  • a wetting agent such as sodium laurylsulfate can be added to the active principles optionally micronized, which is then mixed with a pharmaceutical vehicle such as silica, gelatine, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as silica, gelatine, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, with various polymers or other appropriate substances or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
  • a preparation in the form of gelatin capsules is obtained by mixing the active principles with a diluent such as a glycol or a glycerol ester and pouring the mixture obtained into soft or hard gelatine capsules.
  • a diluent such as a glycol or a glycerol ester
  • a preparation in the form of a syrup or elixir can contain the active principles together with a sweetener, which is preferably calorie-free, methyl-paraben and propylparaben as an antiseptic, a flavoring and an appropriate color.
  • a sweetener which is preferably calorie-free, methyl-paraben and propylparaben as an antiseptic, a flavoring and an appropriate color.
  • the water-dispersible powders or granules can contain the active principles mixed with dispersants or wetting agents, or suspending agents such as polyvinyl-pyrrolidone, and also with sweeteners or taste correctors.
  • Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example cacao butter or polyethylene glycols.
  • Parenteral, intranasal or intraocular administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol, butylene glycol, or polyethylene glycol.
  • pharmacologically compatible dispersants and/or wetting agents for example propylene glycol, butylene glycol, or polyethylene glycol.
  • a cosolvent for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween. RTM. 80, can be used to prepare an aqueous solution injectable by intravenous route.
  • the active principle can be solubilized by a triglyceride or a glycerol ester to prepare an oily solution injectable by intramuscular route.
  • Transdermal administration is effected using multilaminated patches or reservoirs into which the active principle is in the form of an alcoholic solution.
  • Administration by inhalation is effected using an aerosol containing for example sorbitan trioleate or oleic acid together with trichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas.
  • the active principle can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives.
  • implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
  • the active principle can also be presented in the form of a complex with a cyclodextrin, for example .alpha.-, .beta.- or .gamma. -cyclodextrin, 2-hydroxypropyl-. beta. -cyclodextrin or methyl-. beta. -cyclodextrin.
  • a cyclodextrin for example .alpha.-, .beta.- or .gamma. -cyclodextrin, 2-hydroxypropyl-. beta. -cyclodextrin or methyl-. beta. -cyclodextrin.
  • Figure 1 Identification of PDGF signaling signature associated with tissue stiffness.
  • A Violin plots displaying the gene expression scores for the PDGF signaling pathway calculated from the WikiPathways (WP) or the Reactome databases.
  • B Violin plots displaying the gene expression of PDGRFA, PDGFRB, PDGFA, PDGFB and ITB3 by CAFs and ducts obtained from six-week-old KC and 4KC mice determined by scRNAseq (C-G). ***p ⁇ 0.001 ;****p ⁇ 0.0001 ; ns not significant.
  • Figure 2 Increased tissue stiffness favors the accumulation of siCAFs.
  • A Representative FACS dot plots showing the surface expression of PDGFRa and CD61 on PDGFRa + CAFs and siCAFs (PDGFRa-) in pancreata from six-week-old KC (top) and 4KC (bottom) mice. Cells were gated on viable CD45-CD31- Lectin PNA-EpCAM- CAFs.
  • B Frequencies of PDGFRa + CAFs and siCAFs among CD45-CD31-Lectin PNA- EpCAM' CAFs in pancreata from six-week-old KC (squares) and 4KC mice (triangles).
  • FIG. 3 Neoplastic cells instruct the emergence of siCAFs at early tumor stages.
  • A-B Frequencies of (A) PDGFRa + CAFs and (B) siCAFs among CD45'CD3TLectin PNA'EpCAM' CAFs determined by FACS analysis of pancreata from KC (squares) and 4KC mice (triangles) harvested at 1 , 1.5, 3, 4, and 6 months of age.
  • C Mean fluorescence intensity (MFI) of intracellular GFAP in PDGFRcF CAFs and siCAFs determined by FACS analysis.
  • E Frequencies of PDGFRa + CAFs and siCAFs generated in the absence or presence of ActRIIBFc.
  • FIG. 1 MFI of intracellular PDGFRa in PDGFRa + CAFs and siCAFs determined by FACS analysis.
  • F-G Proliferating (F) and Granzyme B (G)-producing CD8 + T cells at the indicated division numbers after coculture with BMDCs and CD3/CD28 activation beads in PDGFRa + CAF/tumor cell- (blue line) or siCAF/tumor cell-conditioned medium (green line).
  • A-D Cumulative data from at least two individual experiments with 3-4 mice per group are shown.
  • E-G Representative data from two individual experiments with technical replicates are shown.
  • PDGFRa + CAFs and siCAFs were isolated from three six-week-old 4KC mice. *p ⁇ 0.05; **p ⁇ 0.01. ***p ⁇ 0,001. Unpaired t test.
  • FIG. 5 PDGF neutralization reduces tumor growth and promotes PDGFRa surface expression.
  • A Graphical scheme representing the treatment schedule for 4KC mice: at 3, 4, and 5 weeks of age, 200 pg of neutralizing anti-PDGF antibody 06-127 (Merck) diluted in 100 pl of PBS was administered i.p. (the anti-PDGF antibody is designated “aPDGF”); age- matched control mice received PBS alone. One week after the last injection, the mice were sacrificed, and harvested pancreata were subjected to FACS and IHC analyses.
  • B Weight (mg) of pancreata excised from six-week-old 4KC mice. Lines connect age-matched littermates treated with the anti-PDGF antibody (white) or PBS alone (black).
  • C Representative FACS dot plots showing the surface expression of PDGFRa and CD61 on CAFs in pancreata from six-week-old 4KC mice treated with the anti-PDGF antibody (right) or PBS (left). Cells were gated on viable CD45'CD31 'Lectin PNA'EpCAM' CAFs.
  • D Frequencies of PDGFRcF CAFs and siCAFs among CD45'CD31 'Lectin PNA'EpCAM' CAFs in pancreata from six-week-old 4KC mice treated with the anti-PDGF antibody or PBS.
  • E- H FACS analysis of the percentages of CD44 + among CD8 + T cells (E), CD31 + cells among CD45- cells (F), and Lectin PNA + (G) and EpCAM + (H) cells among CD45'CD3T cells isolated from the pancreas of six-week-old 4KC mice treated with the anti-PDGF antibody or PBS.
  • FIG. 1 Graphical scheme representing the treatment schedule for implanted C57BI6 mice with 4KC-GFP cell line: at day 10, 17, and 22, 200 pg of neutralizing anti-PDGF antibody 06-127 (Merck) or of anti-pig-h3 antibody 18B3 or lgG1 control diluted in 100 pl of PBS was administered i.p. (the anti-PDGF antibody is designated “aPDGF”).
  • the mice were sacrificed, and harvested pancreata were subjected to FACS in order to count the number of tumor cells (GFP+).
  • Acvrl b flox/flox mutant mice has been previously described (Ripoche et al., 2013).
  • Acvrl b fl0X/fl0X ;LSL-Kras G12D/+ ;Ptf1a-Cre mice (termed 4KC mice) were generated by crossing Acvrl b flox/flox mice with previously established LSL-Kras G12D/+ ;Ptf1a-Cre mice (termed KC mice) (Hingorani et al., 2003).
  • pancreatic tissue areas were determined by AFM as described previously (Milani et al., 2014). Briefly, in AFM, the tip of a cantilever is pushed against sample tissue, and its deflection is monitored. Based on the stiffness constant of the cantilever, the deflection indicates the resisting force of the sample (Milani et al., 2014).
  • the applied protocol allows the measurement of tissue stiffness very locally in a minimally invasive manner by deforming the sample down to a depth of 100 nm.
  • Excised mouse pancreata were washed in phosphate-buffered saline (PBS) and minced into small fragments, followed by incubation in a collagenase solution (1 mg/ml collagenase P obtained from Sigma-Merck in HBSS) at 37°C for 20 minutes.
  • a single- pancreatic cell suspension was obtained by sequentially filtering the digested tissue through a 100 pm cell strainer followed by a 70 pm cell strainer. Spleens were homogenized by filtration through a 100 pm cell strainer to obtain single-cell suspensions. Red blood cells were lysed using NH4CI lysis buffer.
  • Small pancreatic tissue blocks were obtained from patients with resectable PDAC during pancreatic surgery.
  • the experimental procedure relating to the use of patient-derived pancreatic tumor pieces was performed after approval by the South Mediterranean Personal Protection Committee under reference 2011-A01439-32.
  • Primary CAFs were isolated as previously described (Leca et al., 2016). Briefly, tumors were cut into small pieces (1 mm 3 ) using a razor blade. The tissue pieces were dissociated using the Tumor Dissociation Kit (Miltenyi Biotec; 130-095-929) according to the manufacturer’s recommendations. The cells were then resuspended, passed through a cell strainer (100 pM), and plated. Primary CAFs were used between passages 4 and 8.
  • Human primary CAFs were cultured in Dulbecco’s modified Eagle’s medium (DMEM)/F-12 supplemented with 10% fetal bovine serum (Biosera FB-1001/500), 2 mmol/l l-glutamine (Invitrogen; 25030-024), 1% antibiotic-antimycotic (Invitrogen; 15240- 062), and 0.5% sodium pyruvate (Invitrogen; 11360-039).
  • Human immortalized CAFs were cultured in DMEM/F-12 supplemented with 10% fetal bovine serum and 1 % antibiotic- antimycotic.
  • pancreatic cancer cell line PANC-1 was obtained from ATCC and cultured in DMEM GlutaMAX (Gibco 10566016) supplemented with 10% fetal bovine serum and 1 % antibiotic-antimycotic. For coculture experimental conditions, primary CAF medium was used. Cells were authenticated through an STR profile report (LGC Standard) and confirmed to be mycoplasma free (Lonza, LT07-318). PANC-1 cells were plated 24 h before coculture with CAFs in triplicate for each experimental condition and treated with 0.5 pg/ml ActRllbFc inhibitor.
  • human primary or immortalized CAFs were plated in monoculture or coculture according to the experimental conditions at a 2:1 ratio with PANC-1 cells and were treated with 0.5 pg/ml ActRllbFc inhibitor.
  • Half of the cell culture medium was refreshed every 48 h with the addition of 0.5 pg/ml ActRllbFc inhibitor until day 6 of culture.
  • Cells were detached using Stem Pro Accutase cell dissociation reagent (Gibco A1110501) and washed once with PBS.
  • RNA isolation For CAF and ductal cell isolation, cells were acquired on a BD FACSAria (BD Biosciences), and the sorted cells were collected in DM EM containing 10% (functional assays) or 20% fetal calf serum (FCS) (RNA isolation). FACS data were analyzed using FlowJo software (TreeStar).
  • FACS-purified CAFs and ductal tumor cells from a pool of five KC or 4KC mice were partitioned into nanoliter-scale gel bead-in-emulsions (GEMs) with the Chromium Single Cell Controller (10x Genomics) at the in-house Single Cell Platform (CLB/CRCL).
  • GEMs nanoliter-scale gel bead-in-emulsions
  • CMLs Chromium Single Cell Controller
  • CLB/CRCL Single Cell Platform
  • library preparation followed the standard 10x Genomics 3’scRNAseq protocol comprising reverse transcription, amplification, and indexing. Sequencing was performed using a NovaSeq Illumina device (Illumina).
  • Illumina bcl files were basecalled, demultiplexed and aligned to the mouse mm10 genome using CellRanger software (10x Genomics).
  • PSC isolation and CAF differentiation PSCs were isolated from wild-type (WT) C57BL/6 mice as previously described (Apte et al., 1998; Ohlund et al., 2017). Briefly, a single-pancreatic cell suspension was resuspended in 9 ml of GBSS containing 0.3% BSA and 43.75% Histodenz (Sigma-Merck), placed into a 15 ml conical tube and overlaid with 6 ml of GBSS containing 0.3% BSA. After gradient centrifugation, the cells within the gray band just above the interface between the GBSS and Histodenz layers were harvested and used for CAF differentiation.
  • WT wild-type
  • Acinar cells were isolated from KC and 4KC pancreata after digestion in a collagenase/soybean trypsin inhibitor solution (1 mg/ml collagenase P and 25 pg/ml soybean trypsin inhibitor, both obtained from Sigma-Merck, in HBSS).
  • PSCs and acinar cells were labeled using a CellTrace-CFSE or CellTrace-Violet proliferation kit (Invitrogen), respectively, and cocultured in DMEM (Gibco) containing 10% FCS, penicillin/streptomycin, and 0.2 mg/ml soybean trypsin inhibitor (Sigma-Merck) at a ratio of 1 :2 in 24-well plates equipped with discs made of rat tail collagen (Sigma-Merck).
  • the activin A inhibitor ActRIIBFc gift from Olli Ritvos, Helsinki, Finland
  • CAF subpopulations isolated by FACS were cocultured with cells from the KIC tumor cell line (Goehrig et al., 2019) at a ratio of 1 :1 in DMEM containing 10% FCS. After a 48 h incubation at 37°C and 5% CO2, the supernatants were collected and stored at -20°C until further use.
  • BMDC bone marrow-derived dendritic cell
  • bone marrow cell suspensions were isolated by flushing the femurs and tibias of 8- to 12-week-old C57BL/6 mice (Charles River) with DMEM containing 10% FCS as previously described (Inaba et al., 1992). Cell aggregates were dislodged by passing the suspension through a 70 pm cell strainer. Lysis of red blood cells was performed with ammonium-chloride-potassium (AKC) lysis buffer. The obtained cells were incubated for 6 days at 37°C and 5% CO2, and every other day, fresh DMEM containing 10% FCS and GM-CSF was added.
  • APC ammonium-chloride-potassium
  • PDGF-AA human PDGF AA ELISA kit obtained from Abeam was used according to the manufacturer’s protocol.
  • GraphPad Prism was used for graphical representation of the data and for statistical analysis. P values were calculated using Student’s test. For multiple comparisons, one-way analysis of variance with Tukey’s post-hoc test was used. Significance was indicated as follows: *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001 , and ****p ⁇ 0.0001.
  • CAFs have been determined to be the main ECM producers, to our knowledge, there are no data available linking stromal tissue stiffness to the phenotypic and functional properties of CAFs after their initial instruction/activation by neoplastic cells.
  • KC and 4KC mouse models representing opposing ends of the tissue stiffness scale and performed scRNAseq analysis of pancreatic CAFs and neoplastic enriched cell fractions.
  • CD61 integrin (ITG) b3/CD61 , which has been shown to be key in CAF-mediated tumor cell invasion via the assembly of the ECM protein fibronectin (Attieh et al., 2017) and thereby might promote tissue stiffness.
  • CD61 is known to interact with the ECM protein big-h3/TGFbi (Tumbarello et al., 2012), which has been described as a key ECM protein in the pancreatic TME hampering conventional (Goehrig et al., 2019; Patry et al., 2015) and unconventional T-cell responses (Lecker et al., 2021).
  • CD61 was also expressed in the CAF compartment (Fig. 1G). Altogether, these results indicate that PDGF-PDGFR interactions play a key role in the early establishment of tissue stiffness independent of CAF origin and subtype.
  • siCAFs stiffness-induced CAFs
  • PDGFRa + CAFs stiffness-induced CAFs
  • Loss of PDGFRa surface expression on siCAFs is a tumor cell-driven early event accompanied by PDGF ligand accumulation
  • siCAFs had significantly lower expression of the qPSC marker glia fibrillary acidic protein (GFAP) than PDGFRa + CAFs (Fig. 3C), further highlighting the different activation statuses of these two cell populations.
  • GFAP qPSC marker glia fibrillary acidic protein
  • CD8 + T cells including CD8 + T cells (Fig. 4A, B), CD4 + T cells, CD4 + /Foxp3 + regulatory T cells (Tregs), NK-p46 natural killer cells, TCRgd T cells or neutrophils, between KC and 4KC pancreata.
  • Tregs CD8 + T cells
  • Tregs CD4 + /Foxp3 + regulatory T cells
  • NK-p46 natural killer cells TCRgd T cells or neutrophils
  • pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 145:1121-1132.
  • the activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma.
  • Clinical gastroenterology and hepatology the official clinical practice journal of the American Gastroenterological Association 6:1155-1161.
  • TGFbetaR2-mutant tumors exposes vulnerabilities to stromal TGFbeta blockade in pancreatic cancer.
  • beta-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer. Theranostics 9:324-336.
  • TGFBI transforming growth factor beta induced

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention porte sur la combinaison d'un antagoniste de βig-h3 et d'un antagoniste de PDGF-AA, destinée à être utilisée dans la prévention ou le traitement d'un patient atteint d'une maladie cancéreuse. En particulier, la combinaison restaure l'activation des lymphocytes T CD8+ et donc la réponse cytotoxique anti-tumorale. Le cancer peut être un adénocarcinome canalaire pancréatique. L'antagoniste de PDGF-AA peut être un anticorps ou un aptamère neutralisant anti-PDGF-AA. Ledit antagoniste de βig-h3 peut être un anticorps ou un aptamère neutralisant anti-βig-h3. Le cancer est plus particulièrement un cancer associé à un stroma exprimant/sécrétant PDGF-AA et βig-h3. L'invention concerne également des méthodes de traitement d'une maladie cancéreuse à l'aide de ladite combinaison.
PCT/EP2024/076742 2023-09-25 2024-09-24 COMBINAISON D'UN ANTAGONISTE DE βIG-H3 ET D'UN ANTAGONISTE DE PDFG-AA POUR LE TRAITEMENT DU CANCER Pending WO2025068157A1 (fr)

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