WO2022074152A1 - Immunotherapy for the treatment of cancer - Google Patents

Immunotherapy for the treatment of cancer Download PDF

Info

Publication number
WO2022074152A1
WO2022074152A1 PCT/EP2021/077777 EP2021077777W WO2022074152A1 WO 2022074152 A1 WO2022074152 A1 WO 2022074152A1 EP 2021077777 W EP2021077777 W EP 2021077777W WO 2022074152 A1 WO2022074152 A1 WO 2022074152A1
Authority
WO
WIPO (PCT)
Prior art keywords
immune checkpoint
antibody
dupa
peg
pei
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2021/077777
Other languages
English (en)
French (fr)
Inventor
Esteban Pombo-Villar
Eric Kitas
Maya ZIGLER
Davor BAJIC
Babette SCHADE
Derrick BROKA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Targimmune Therapeutics AG
Original Assignee
Targimmune Therapeutics AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Targimmune Therapeutics AG filed Critical Targimmune Therapeutics AG
Priority to JP2023521092A priority Critical patent/JP2023544201A/ja
Priority to CN202180071576.5A priority patent/CN116348142A/zh
Priority to CA3192963A priority patent/CA3192963A1/en
Priority to EP21786976.7A priority patent/EP4225374A1/en
Priority to IL301906A priority patent/IL301906A/en
Priority to US18/247,961 priority patent/US20230372384A1/en
Priority to KR1020237009961A priority patent/KR20230084476A/ko
Priority to AU2021357354A priority patent/AU2021357354A1/en
Priority to MX2023004101A priority patent/MX2023004101A/es
Publication of WO2022074152A1 publication Critical patent/WO2022074152A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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 [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/17—Immunomodulatory nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

  • the present invention relates to the field of immunotherapeutic cancer treatment.
  • the present invention relates to a kit-of-parts and a composition comprising a polyplex comprising a double stranded RNA (dsRNA) and a polymeric conjugate comprising a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties and one or more targeting moieties, and wherein each of said one or more targeting moieties is capable of binding to PSMA; and at least one immune checkpoint modulator wherein said at least one immune checkpoint modulator is capable of modulating an immune checkpoint protein.
  • the invention relates to this composition or kit-of-parts for use in the treatment of cancer, especially prostate cancer.
  • Antibodies that target tumor-associated antigens have become an important treatment modality for malignancies.
  • mAbs monoclonal antibodies
  • mAbs monoclonal antibodies
  • their efficacy is often modest.
  • mAbs must overcome substantial obstacles to reach antigens presented on target cells to be of therapeutic value (Christiansen et al., Mol Cancer Ther, 2004, 3(11), 1493- 1501).
  • efficiency of antibodies that target tumor-associated antigens is lowered by insufficient activation of the anti-tumor response of the immune system and by inhibition of the immune reaction induced by the tumor itself.
  • Cytokines related to tumor necrosis factor provide a communication network essential for coordinating multiple cell types into an effective host defense system against pathogens and malignant cells.
  • the tumor necrosis factor superfamily of ligands (TNFSF) and receptors (TNFRSF) provide key communication signals between various cell types during development.
  • TNF receptors (TNFRs) share a conserved ectodomain defined by a cysteine-rich signature.
  • the TNFRs with a co-stimulatory reputation are encoded by genes residing within an immune-response locus in chromosomal region lp36 and include GITR (glucocorticoid- induced tumor necrosis factor), 0X40, 4-1BB, and CD30 (Ward-Kavanagh, et al., The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses, Immunity 44, May 17, 2016).
  • GITR glucocorticoid- induced tumor necrosis factor
  • 0X40 0X40
  • 4-1BB 4-1BB
  • CD30 Ward-Kavanagh, et al., The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses, Immunity 44, May 17, 2016.
  • a different approach for the treatment of malignancies is a vaccine-based therapy.
  • the molecular definition of tumor-associated antigens introduced the possibility of specific vaccines aiming to target the tumor cells.
  • Recombinant vaccines which are based on peptides or proteins from defined tumor-associated antigens (TAAs) are usually administered together with an adjuvant or an immune modulator. Although these vaccines were able to induce antigen-specific T cell responses, clinical outcomes have been disappointing (Guo et al., Adv Cancer Res, 2013, 119: 421-475).
  • a further approach in cancer immunotherapy refers to the combination of vaccines with antibodies that activate antitumor immunity by blocking or inhibiting immune checkpoints.
  • Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are important for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses. Tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked or inhibited by antibodies or modulated by recombinant forms of ligands or receptors.
  • CTL-4 Cytotoxic T-lymphocyte-associated antigen 4
  • the present invention provides a novel combinatorial immunotherapeutic approach for the treatment of cancer.
  • the invention relates to a kit-of-parts or composition
  • a polyplex comprising a double stranded RNA (dsRNA) and a polymeric conjugate
  • said polymeric conjugate comprises a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties and one or more targeting moieties, wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one or more targeting moieties, and wherein each of said one or more targeting moieties is capable of binding to prostate specific membrane antigen (PSMA); and b. at least one immune checkpoint modulator, wherein said immune checkpoint modulator is capable of modulating an immune checkpoint protein.
  • PSMA prostate specific membrane antigen
  • the invention relates to the composition or the kit-of-parts for use in the treatment of cancer.
  • combination treatment according to the invention with (i) the polyplex comprising double stranded RNA (dsRNA) and the polymeric conjugate comprising one or more targeting moieties capable of binding to PSMA, and (ii) one or more immune checkpoint modulators capable of modulating an immune checkpoint protein enforces activity of the immune system and leads to potent antitumor activity.
  • Antitumor activity of the immune system was more enhanced by the combination of (i) the PSMA binding polyplex comprising dsRNA and the polymeric conjugate plus (ii) one or more immune checkpoint modulators as compared to the polyplex alone.
  • the combination of the polyplex and the at least one immune checkpoint modulator generated a sustained tumor defense against the cancer cells.
  • PBMCs peripheral blood mononuclear cells
  • the combination of the PSMA targeted polyplex and at least one immune checkpoint modulator in accordance with the present invention is capable of broadening the efficacy of the immunomodulatory antibodies to cancer patients, especially prostate cancer patients that are currently not showing any response.
  • PSMA targeted delivery of dsRNA, preferably polylC in combination with anti-checkpoint antibodies shows significant efficacy due to the capabilities of the inventive compositions and kits-of-parts to reinstate the immune system against the prostate tumor.
  • FIGURE 1 IP- 10 (CXCL10) secretion from cancer cells following treatment with PEI-
  • PEG-DUPA/polylC LNCaP and MCF7 cells (40,000 cells per well) were treated for 5 hours with PEI-PEG-DUPA/polylC at various concentrations (0.125, 0.25, 0.5, 1.0 pg/ml), and human IP- 10 secreted to the medium was measured by ELISA. Human IP- 10 secretion increased in PSMA overexpressing cells, LNCaP, compared to MCF7 cells which do not express PSMA. IP- 10 secretion was induced following treatment with PEI-PEG-DUPA/polylC in LNCaP cells, which overexpress PSMA, but not in MCF7 cells, which do not express PSMA.
  • LNCaP is a human prostate adenocarcinoma cell line commonly used in the field of oncology.
  • FIGURE 2 Flow cytometry analysis of PD-L1 expression on LNCaP cells following treatment with PELPEG-DUPA/polylC.
  • LNCaP cells were treated for 5 hours with PELPEG- DUPA/polylC at concentrations of 0.031 pg/ml, 0.063 pg/ml, or 0.125 pg/ml and then subjected to flow cytometry, using PE-conjugated anti-PD-Ll antibody or IgGl isotype control.
  • FIGURE 3 IFN-y secretion from PBMCs co-cultured with LNCaP cancer cells, following combined treatment with anti-4-lBB antibody and PELPEG-DUPA/polylC.
  • PBMCs unstimulated or stimulated with anti-CD3 antibody (5 ng/ml)
  • PELPEG-DUPA/polylC 0.125 pg/ml
  • 4- IBB 10 pg/ml
  • PBMCs were not stimulated or stimulated with anti-CD3 antibody (5ng/ml) and co-cultured with LNCaP cells treated with antibodies against 4-1BB (10 pg/ml) alone or in combination with PEI-PEG-DUPA/polylC (0.125pg/ml) ((+)4-lBB).
  • FIGURE 4 Combination of PEI-PEG-DUPA/polylC polyplex with Nivolumab, an anti-
  • PD-1 antibody led to increased PBMC activation, as demonstrated by IFN-y ELISA.
  • LNCaP cells or medium alone (in the absence of any cells) were untreated or treated with PELPEG- DUPA/polylC polyplex (0.125 pg/ml) for 5 hours.
  • PBMCs were either unstimulated or stimulated with anti-CD3 antibody (500 ng/ml) and treated with or without Nivolumab (20 pg/ml).
  • the invention refers to a composition
  • a composition comprising a. a polyplex comprising a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate comprises a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties and one or more targeting moieties, wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one or more targeting moieties, and wherein each of said one or more targeting moieties is capable of binding to prostate specific membrane antigen (PSMA); and b. at least one immune checkpoint modulator, wherein said at least one immune checkpoint modulator is capable of modulating an immune checkpoint protein.
  • PSMA prostate specific membrane antigen
  • the invention refers to a kit-of-parts comprising a. a composition, wherein said composition comprises a polyplex comprising a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate comprises a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties and one or more targeting moieties, wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one or more targeting moieties, and wherein each of said one or more targeting moieties is capable of binding to prostate specific membrane antigen (PSMA); and b. at least one immune checkpoint modulator, wherein said immune checkpoint modulator is capable of modulating an immune checkpoint protein.
  • PSMA prostate specific membrane antigen
  • said composition of the invention comprises at least one pharmaceutically acceptable diluent, excipient or carrier.
  • the composition according to the invention is a fixed-dose composition that comprises the polyplex and one or more immunomodulatory antibodies in a single dosage form.
  • said pharmaceutical composition includes one or more adjuvants.
  • kit-of-parts as used herein preferably refers to a combination of at least two separate parts, namely said polyplex and said one or more immunomodulatory antibodies.
  • said composition is a pharmaceutical composition.
  • said arrangement and construction of such kit-of-parts is conventionally known to one skilled in the art.
  • said kit-of-parts of the invention or said parts of the kit-of- parts of the invention, i.e. the polyplex and/or the one or more immunomodulatory antibodies comprise independently of each other at least one pharmaceutically acceptable diluent, excipient or carrier.
  • said kit-of-parts of the invention or said parts of the kit-of-parts of the invention, i.e. the polyplex and/or the one or more immunomodulatory antibodies comprise independently of each other one or more adjuvants.
  • composition and kit-of-parts according to the invention is formulated for administration by any known method.
  • the composition and kit-of-parts according to the invention i.e. the polyplex and/or the one or more immunomodulatory antibodies, and the pharmaceutical composition may be formulated for any suitable route of administration including but not limited to intravenous, intra-brain (intracerebral), oral, intramuscular, subcutaneous, transdermal, intradermal, transmucosal, intranasal, sublingual, intraperitoneal or intraocular administration.
  • composition or kit-of-parts according to the invention is formulated for systemic administration.
  • the composition and kit-of-parts according to the invention i.e. the polyplex and/or the one or more immunomodulatory antibodies
  • the composition and kit-of-parts according to the invention, i.e. the polyplex and/or the one or more immunomodulatory antibodies are formulated as one or more dosage forms suitable for injection, preferably as solution, emulsion or suspension suitable for injection.
  • composition and kit-of-parts according to the invention comprising the polyplex of the invention and one or more immunomodulatory antibodies, wherein said polyplex and said one or more immunomodulatory antibodies are present in the composition and kit-of-parts in a therapeutically effective amount.
  • kits-of-parts of the invention may include containers that contain the polyplex and/or the one or more antibodies and/or an apparatus for administering the parts of the kit, i.e. the polyplex and/or the one or more antibodies.
  • said kit-of-parts of the invention comprises at least one container comprising an effective dose of said polyplex and at least one container comprising an effective dose of said one or more antibodies, and optionally an instruction leaflet.
  • said one or more targeting moieties capable of binding to prostate specific membrane antigen are PSMA antibodies, PSMA aptamers or smallmolecule PSMA targeting moieties.
  • the PSMA targeting moiety is an anti-PSMA antibody, i.e. an antibody that binds to PSMA.
  • PSMA antibodies include, but are not limited to, scFv antibodies A5, GO, Gl, G2, and G4 and mAbs 3ZE7, 3/F11, 3/A12, K7, K12, and D20 (Elsasser- Beile et al., 2006, Prostate, 6611359); mAbs E99, J591, J533, and J415 (Liu et al., 1997, Cancer Res., 5713629; Liu et al., 1998, Cancer Res., 5814055; Fracasso et al., 2002, Prostate, 5319; McDevitt et al., 2000, Cancer Res., 6016095; McDevitt et al., 2001, Science, 29411537; Smith- Jones et al., 2000, Cancer Res., 6015237; Vallabhajos
  • said one or more targeting moieties capable of binding to PSMA is a small molecule PSMA targeting moiety, again more preferably a small molecule PSMA targeting peptidase inhibitor.
  • said small molecule PSMA peptidase inhibitors include 2-PMPA, GPI5232, VA-033, phenylalkylphosphonamidates (Jackson et al., 2001, Curr. Med. Chem., 8:949; Bennett et al., 1998, J. Am. Chem. Soc., 120112139; Jackson et al., 2001, J Med. Chem., 4414170; Tsukamoto et al., 2002, Bioorg. Med. Chem.
  • said small molecule PSMA targeting moieties are proteins, peptides, amino acids or derivatives thereof.
  • said small molecule PSMA targeting moiety includes thiol and indole thiol derivatives, such as 2-MPPA and 3-(2- mercaptoethyl)-lH-indole-2-carboxylic acid derivatives (Majer et al., 2003, J Med. Chem., 4611989; and U.S. Patent Publication 2005/0080128).
  • said small molecule PSMA targeting moieties comprise hydroxamate derivatives (Stoerrner et al., 2003, Bioorg. Med. Chem. Lett., 1312097).
  • said small molecule PSMA peptidase inhibitors include androgen receptor targeting agents (ARTAs), such as those described in U.S. Patents 7,026,500; 7,022,870; 6,998,500; 6,995,284; 6,838,484; 6,569,896; 6,492,554; and in U.S.
  • ARTAs androgen receptor targeting agents
  • said small molecule PSMA targeting moieties include polyamines, such as putrescine, spermine, and spermidine (U.S. Patent Publications 2005/0233948 and 2003/0035804). All of the foregoing documents (scientific and other publications, patents and patent applications) are incorporated herein by reference in their entirety.
  • said small molecule PSMA peptidase inhibitors include PBDA- and urea-based inhibitors, such as ZJ 43, ZJ 11, ZJ 17, ZJ 38 (Nan et al., 2000, J. Med. Chem., 431772; and Kozikowski et al., 2004, J. Med. Chem., 4711729), and/or and analogs and derivatives thereof.
  • said one or more targeting moieties capable of binding to prostate specific membrane antigen (PSMA) are small-molecule PSMA targeting moieties, more preferably small urea-based inhibitors.
  • said molecule PSMA targeting moieties are urea-based inhibitors (herein also called urea-based peptidase inhibitors), more preferably small urea-based inhibitors, such as disclosed in Kularatne et al., Mol Pharmaceutics 2009, 6, 780; Kularatne et al., Mol. Pharmaceutics 2009, 6, 790; Kopka et al., J Nucl Med 2017, 58: 17S-26S, Kozikowski et al., J Med Chem. 2001, 44:298-301, Kozikowski et al., J Med Chem.
  • small molecule as used herein relates to an organic molecule that has a molecular weight of less than about 2000 g/mol. In some embodiments, the small molecule has a molecular weight of less than about 1500 g/mol, more preferably less than about 1000 g/mol. In a further preferred embodiment, the small molecule has a molecular weight of less than about 800 g/mol, again more preferably less than about 500 g/mol.
  • said one or more targeting moieties capable of binding to prostate specific membrane antigen are dipeptide urea based PSMA peptidase inhibitors, more preferably, small molecule dipeptide urea-based PSMA peptidase inhibitors.
  • urea based PSMA peptidase inhibitors relate to PSMA peptidase inhibitors comprising a urea group.
  • dipeptide urea based PSMA peptidase inhibitors relate to PSMA peptidase inhibitors comprising a urea group and two peptides or amino acids each independently attached to the -NH2 groups of the urea group.
  • PSMA peptidase inhibitors reduce activity of the PSMA transmembrane zinc(II) metalloenzyme that catalyzes the cleavage of terminal glutamates. More preferably, said small molecule urea-based PSMA peptidase inhibitor has a molecular weight of less than about 500 g/mol. Again more preferably, said small molecule urea-based PSMA peptidase inhibitor is a Glutamate-urea based PSMA peptidase inhibitor, preferably such as mentioned in Kopka et al., J Nuc Med, 58(9), suppl. 2, 2017; Wirtz et al., EJNMMI Research (2016) 8:84 and references cited therein, all incorporated herein by reference in their entirety.
  • said urea based PSMA peptidase inhibitors is a glutamateurea moiety of formula I, preferably of formula I*: wherein R is Cl-6-alkyl, preferably C2-C4-alkyl, substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point of covalent attachment for linking to the PEG moiety and wherein the alkyl group is optionally be interrupted by N(H), S or O.
  • R is Cl-6-alkyl, preferably C2-C4-alkyl, substituted one time with OH, SH, NH2, or COOH, wherein said NH2, OH, or SH or COOH group serve as the point of covalent attachment for linking to the PEG moiety.
  • R is C2-alkyl substituted one time with COOH, wherein said COOH group serve as the point of covalent attachment for linking to the PEG moiety.
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one or more linkers.
  • said one or more targeting moieties is a glutamate-urea moiety of formula I: wherein R is C1-6-alkyl, preferably C2-C4-alkyl, substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point of covalent attachment for linking to the PEG moiety and wherein the alkyl group is optionally be interrupted by N(H), S or O.
  • R is C1-6-alkyl, preferably C2-C4-alkyl, substituted one time with OH, SH, NH 2 , or COOH, wherein said NH2, OH, or SH or COOH group serve as the point of covalent attachment for linking to the PEG moiety.
  • R is C2-alkyl substituted one time with COOH, wherein said COOH group serve as the point of covalent attachment for linking to the PEG moiety.
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one or more linkers.
  • said one or more targeting moieties is a glutamate- urea moiety of formula I* wherein R is C1-6-alkyl, preferably C2-C4-alkyl, substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point of covalent attachment for linking to the PEG moiety and wherein the alkyl group is optionally be interrupted by N(H), S or O.
  • R is C1-6-alkyl, preferably C2-C4-alkyl, substituted one time with OH, SH, NH2, or COOH, wherein said NH2, OH, or SH or COOH group serve as the point of covalent attachment for linking to the PEG moiety.
  • R is C2-alkyl substituted one time with COOH, wherein said COOH group serve as the point of covalent attachment for linking to the PEG moiety.
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties one or more linkers.
  • alkyl refers to a straight or branched hydrocarbon chain radical, preferably a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, having typically and preferably from one to six carbon atoms (e.g., (C1-6alkyl). Whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range.
  • alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are not limited to methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methyl- prop-1-yl or 2-methyl-prop-2-yl.
  • said one or more targeting moieties comprises or preferably consists of a DUPA derivative (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH- CH(COOH)-CH 2 -) or DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)- (CH 2 ) 2 -CO-).
  • said one or more targeting moieties comprises or preferably consists of a DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)- (CH 2 ) 2 -CO-).
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one or more linkers.
  • said one or more targeting moieties consists of a DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO-).
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one or more linkers.
  • said one or more targeting moieties consists of a DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO-), wherein both chiral C-atoms having (S)-configuration, as depicted in formula I*.
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one or more linkers.
  • said one or more targeting moieties capable of binding to prostate specific membrane antigen (PSMA) or said small molecule urea-based PSMA peptidase inhibitor comprises a DUPA derivative defined herein as HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH- CH(COOH)-CH 2 -, or a DUPA moiety defined herein as HOOC(CH 2 ) 2 -CH(COOH)-NH-CO- NH-CH(COOH)-(CH 2 ) 2 -CO-.
  • said one or more targeting moieties capable of binding to prostate specific membrane antigen (PSMA) or said small molecule urea-based PSMA peptidase inhibitor consists of the DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO- NH-CH(COOH)-(CH 2 ) 2 -CO-) or the DUPA derivative (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO- NH-CH(COOH)-CH 2 -).
  • said DUPA moiety or said DUPA derivative is linked to said one or more PEG moieties either directly or preferably via a linker.
  • said linker is as disclosed e.g.
  • said linker is a peptide linker or a C1-C10 alkylene linker or a combination of both. More preferably, said linker is a peptide linker.
  • said peptide linker is of SEQ ID NO: 1 (-(NH-(CH 2 ) 7 -CO)-Phe-Phe- (NH-CH 2 -CH(NH2)-CO)-Asp-Cys-) or SEQ ID NO: 2 (-(NH-(CH 2 )7-CO)-Phe-Gly-Trp-Trp- Gly-Cys-).
  • said peptide linker is of SEQ ID NO: 2 (-(NH-(CH 2 )7-CO)- Phe-Gly-Trp-Trp-Gly-Cys-).
  • said linker is of SEQ ID NO: 1 or 2 and the targeting moiety is HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 - CO- (DUPA moiety). More preferably, said linker is of SEQ ID NO: 2 and the targeting moiety is HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO- (DUPA moiety).
  • immune checkpoint protein or “immune checkpoint” is known and described in the art (see for instance Pardoll, 2012, Nature Rev Cancer 12: 252-264; Darvin et al., 2018, Experimental & Molecular Medicine 50:165) and includes protein regulators of the immune system that inhibit or activate (co-stimulate) the immune system, especially T cells.
  • said immune checkpoint protein refers to receptors of T cells and dendritic cells, B cells, natural killer (NK) cells, neutrophils and macrophages as well as their soluble or bound ligands and counter-receptors that can stimulate or inhibit activity of the immune system.
  • said immune checkpoint protein refers to receptors of T cells and NK cells as well as their soluble or bound ligands and counter-receptors that can co-stimulate or co-inhibit activity of the immune system.
  • said activity of the immune system is detected by measuring a T cell response, as shown herein.
  • the immune checkpoint protein is a human immune checkpoint protein.
  • Immune checkpoints refer to inhibitory and activating proteins of the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in order to minimize collateral tissue damage. Tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens.
  • T cells have been the major focus of efforts to therapeutically manipulate endogenous anti-tumor immunity owing to: their capacity for the selective recognition of peptides derived from proteins in all cellular compartments; their capacity to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; CTLs); and their ability to orchestrate diverse immune responses (by CD4+ helper T cells), which integrates adaptive and innate effector mechanisms.
  • CTLs CD8+ effector T cells
  • CD4+ helper T cells CD4+ helper T cells
  • the kit-of-parts or composition of the invention comprises (a) the polyplex, and (b) at least one immune checkpoint modulator.
  • immune checkpoint modulator as used herein relates to a compound that is capable of modulating the function of an immune checkpoint protein and promoting activity of the immune system, especially T cells.
  • the term ”immune checkpoint modulator” includes (i) agonistic immune checkpoint modulators of co- stimulatory checkpoint proteins and their ligands and (ii) antagonistic immune checkpoint modulators of inhibitory checkpoint proteins and their ligands, all of which result in the promotion of the immune system. Promotion of immune system activity includes generation of enhanced immune responses to an antigen and/or reduction in immunosuppressive immune responses against the antigen.
  • immune checkpoint modulator includes compounds selected from RNA, DNA or peptide aptamers, antibodies, receptor ligands, antibody mimetics, e.g., ankyrin repeats (DARPins), adnectins, affibodies, anti-calins, or engineered Kunitz-type inhibitors etc..
  • said immune checkpoint modulator is an antibody, a DARPin or a single-stranded oligonucleotide aptamer.
  • modulating includes activation, which relates to functional stimulation or enhancement of a co-stimulatory immune checkpoint protein as well as inhibition of a co-inhibitory immune checkpoint protein which relates to reduction in activity and full blockade of a co-inhibitory immune checkpoint protein.
  • modulating activity of an immune checkpoint protein or “modulating an immune checkpoint protein” includes stimulation of T cells including T helper cells, CTLs natural killer T cells, natural killer cells (NK), B cells, monocytes, macrophages, and dendritic cells.
  • Stimulation (or activation) induced by modulation of an immune checkpoint protein is preferably detected via measuring increased levels of cytokines such as interferon, especially IFN- ⁇ , produced or released, in particular, by T and NK cells as compared to controls without administration of immune checkpoint protein modulating antibodies, as herein demonstrated via ELISA assays on IFN- ⁇ secretion of PBMCs.
  • cytokines such as interferon, especially IFN- ⁇
  • immune checkpoint proteins include, without limitation, and are preferably selected from the group consisting of PD-1 (Programmed Death 1, interchangeable used herein and equivalent to PD-1, PD-L1, PD-L2, CTLA-4/B7-1/CD152 (Cytotoxic T-Lymphocyte- Associated protein 4), CD137/4-1BB, 4-1BB ligand (4-1BBL), TIM-3 (T-cell Immunoglobulin domain and Mucin domain 3)/HAVCR2, LAG-3, By-He, H4, IDO1, CD40/TNFRSF5, CD40 ligand, OX40/CD134, OX-40 ligand/OX-40L, GITR (Glucocorticoid-Induced TNFR family Related gene)/TNFRSF18, GITR ligand/TNFSF18, ICOS/AILIM/CD278, CD122, CD155/PVR, CD226/DNAM-1, CD27, TNFSF14/LIGHT/CD258, CD70/CD27L/
  • said immune checkpoint protein is a T cell-associated checkpoint inhibitor or a non-T-cell associated checkpoint inhibitor, preferably a T cell- associated checkpoint inhibitor.
  • said immune checkpoint protein is selected from the group consisting of CD137/4-1BB, CD40/TNFRSF5, OX40/CD134, GITR/TNFRSF18, ICOS (Inducible T-cell Co-stimulator)/AILIM/CD278, CD122, A2AR (Adenosine A2A receptor), KIR, NOX2, SIGLEC7/CD328, SIGLEC9/CD329, PD-1, PD-L1, PD-L2, CTLA-4, CD80/B7- 1, CD86/B7-2, B7-H3/CD276, B7-H4/B7S1/7x, VISTA/B7-H5/GI24, LAG- 3/CD223/Lymphocyte activation gene 3, 2,3-dioxygenase/IDO, Galect
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, 4- 1BB, TIGIT, LAG-3, TIM3, GITR, CD40, OX40, and ICOS.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, 4-1BB, TIGIT, LAG-3, TIM-3, GITR, CD40, OX40, and ICOS.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB, TIGIT, LAG-3, TIM3, GITR, CD40, OX40, and ICOS.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB, GITR, CD40, and OX40.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB, GITR, CD40, and OX40.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB, GITR, CD40, and OX40. In a further preferred embodiment, said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB, GITR, and OX40. In a further preferred embodiment, said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB, and OX40. In a further preferred embodiment, said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB, LAG-3, and TIM3.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB, LAG-3, and TIM3.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4- 1BB, TIGIT, LAG-3, TIM-3, GITR, and ICOS.
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB, LAG-3, TIGIT, TIM-3 and GITR.
  • said immune checkpoint protein is selected from the group consisting of PD-1, CTLA-4, 4-1BB, LAG-3, TIGIT, TIM-3, GITR, and ICOS. In a further preferred embodiment, said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB. In a further preferred embodiment of the composition or kit-of-parts of the invention, said immune checkpoint protein is selected from the group consisting of 4-1BB, PD-1, PD-L1, PD-L2 and CTLA-4. In a further very preferred embodiment, said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said immune checkpoint protein is PD-1 or 4-1BB. In a further preferred embodiment, said immune checkpoint protein is PD-1. In another preferred embodiment, said immune checkpoint protein is PD-1, PD-L1, or PD-L2. In a further preferred embodiment, said immune checkpoint protein is PD-1, or PD-L1. In a further preferred embodiment, said immune checkpoint protein is PD-1. In a further preferred embodiment, said immune checkpoint protein is PD-L1. In a further preferred embodiment, said immune checkpoint protein is PD-L2. In a further preferred embodiment, said immune checkpoint protein is 4-1BB. In another preferred embodiment, said immune checkpoint protein is CTLA-4.
  • said immune checkpoint modulator is an antibody capable of modulating activity of an immune checkpoint protein, mentioned herein also as immunomodulatory antibody.
  • said immune checkpoint modulator is an immunomodulatory agonistic or antagonistic antibody.
  • Said immunomodulatory antibody includes agonistic antibodies of co- stimulatory checkpoint proteins and their ligands and antagonistic antibodies of inhibitory checkpoint protein and their ligands.
  • the term “antibody” or “anti-...” binding to a target mentioned after the term “anti-“) to immunoglobulin molecules and portions of immunoglobulin molecules, preferably said portions contain an antigen binding site that selectively binds an antigen wherein the antigen comprises haptens, epitopes, receptors or ligands or parts thereof.
  • antibody capable of modulating an immune checkpoint protein refers preferably to antibodies that modulate activity of checkpoint receptors, counter-receptors or bound and soluble ligands thereof.
  • antibody encompasses not only whole antibody molecules, but also antibody fragments as well as variants (including derivatives), antibody fragments, fusion proteins, and antibody mimetics, such as ankyrin repeats (DARPins), adnectins, affibodies, or engineered Kunitz-type inhibitors.
  • DARPins ankyrin repeats
  • adnectins adnectins
  • affibodies affibodies
  • Kunitz-type inhibitors such as ankyrin repeats (DARPins), adnectins, affibodies, or engineered Kunitz-type inhibitors.
  • antibody includes antibodies comprising two immunoglobulin heavy chains and two immunoglobulin light chains as well as a variety of forms including full length antibodies and portions thereof; including, for example, an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, Fab, Fab′, F(ab′)2, Fv, disulfide linked Fv, scFv, single domain antibody (dAb), a diabody; DNA, RNA or peptidic aptamers; affibodies; naked antibodies, antibody-drug conjugates and bi- or tri-specific antibodies, an anti-idiotypic antibody, anticalin and a functionally active epitope-binding fragment of these.
  • an immunoglobulin molecule a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, Fab, Fab′, F(ab′)2, Fv, disulfide linked Fv, sc
  • said antibody capable of modulating an immune checkpoint protein is a monoclonal antibody, a humanized antibody or a full human antibody.
  • the term “affibody” refers to proteins engineered to bind to target proteins or peptides with high affinity, imitating monoclonal antibodies, and are therefore a member of the family of antibody mimetics.
  • the affibody has a high affinity binding domain derived from protein A.
  • said immune checkpoint modulator capable of modulating the immune checkpoint protein is a monoclonal antibody, chimeric antibody, humanized antibody, human antibody, a fusion protein or a combination thereof.
  • said antibody is selected from the group consisting of anti- 4- 1BB, anti-CD40/TNFRSF5, anti-OX40/CD134, anti-GITR/TNFRSF18, anti-ICOS (Inducible T-cell Co-stimulator)/AILIM/CD278, anti-/B7-H2, anti-CD122, anti-A2AR (Adenosine A2A receptor), anti-KIR, anti-NOX2, anti-SIGLEC7/CD328, anti-SIGLEC9/CD329, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD80/B7-1, anti-CD86/B7-2, anti-B7-H3/CD276, anti-B7-H4/B7S1/7x, anti-VISTA/B7-H5/GI24, anti-LAG-3/CD223/Lymphocyte activation gene 3, anti-2,3-dioxygenase/IDO, anti-Galectin
  • said antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-4-1BB, anti-LAG-3, anti-TIGIT, anti- TIM-3, anti-GITR, and anti-ICOS.
  • said antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, anti-4-1BB, anti-GITR, anti- CD40, anti-ICOS and anti-OX40.
  • said antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, anti-4-1BB, anti-GITR, anti- CD40 and anti-OX40.
  • said antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, anti-4-1BB, anti-GITR and anti-OX40. In a further preferred embodiment, said antibody is selected from the group consisting of anti- PD-1, anti-PD-L1, anti-PD-L2, anti-4-1BB, and anti-OX40. In a further preferred embodiment, said antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, anti- CTLA-4, and anti-4-1BB. In a very preferred embodiment, said antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-4-1BB.
  • said antibody is anti-PD-1 or anti-4-1BB. In a further preferred embodiment, said antibody is anti-PD-1. In another preferred embodiment, said antibody is anti-PD-1, anti-PD- L1, or anti-PD-L2. In a further preferred embodiment, said antibody is anti-PD-1, or anti-PD- L1. In a further preferred embodiment, said antibody is anti-PD-1. In a further preferred embodiment, said antibody is anti-PD-L1. In a further preferred embodiment, said antibody is anti-PD-L2. In a further preferred embodiment, said antibody is anti-4-1BB. In another preferred embodiment said antibody is an anti-CTLA-4.
  • said at least one antibody is selected from the group consisting of (i) anti-4-1BB (also called anti-CD137 or anti-4-1BB herein), anti- CD40/TNFRSF5, anti-OX40/CD134, anti-GITR/TNFRSF18, anti-ICOS/AILIM/CD278, and anti-B7-H2 or (ii) anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD80/B7-1, anti- CD86/B7-2, anti-B7-H3/CD276, anti-B7-H4/B7S1/7x, anti-VISTA/B7-H5/GI24, anti-LAG- 3/CD223/Lymphocyte activation gene 3, anti-Galectin-/LGALS9, anti-TIM-3/HAVCR2, and anti-TIGIT/VSTM3; or (iii) a mixture of at least one antibody of (i) and at least one antibody of (ii).
  • anti-4-1BB also called anti
  • said at least one antibody is selected from the group consisting of (i) anti-4-1BB, anti-GITR, anti-OX40, anti-ICOS, and anti-CD40; or (ii) anti-PD- 1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-TIGIT, anti-LAG-3, anti-TIM3, anti-B7-H3, anti-B7-H4, anti-VISTA, and anti-CCR4; or (iii) a mixture of at least one antibody of (i) and at least one antibody of (ii).
  • said at least one antibody is selected from the group consisting of (i) anti-CD137/4-1BB; or (ii) anti-PD-1, anti-PD-L1, anti- PD-L2, anti-CTLA-4; or (iii) a mixture of at least one antibody of (i) and at least one antibody of (ii).
  • said at least one antibody is selected from the group consisting of (i) anti-CD137/4-1BB; or (ii) anti-PD-1, anti-PD-L1, anti-PD-L2; or (iii) a mixture of at least one antibody of (i) and at least one antibody of (ii).
  • said at least one antibody is a mixture of at least one antibody selected from the group consisting of (i) anti-CD137/4-1BB; and (ii) anti-PD-1, anti- PD-L1, anti-PD-L2.
  • said at least one antibody is a mixture of anti-4-1BB and at least one antibody selected from the group consisting of (ii) anti-PD-1, anti-PD-L1, anti-PD-L2.
  • said at least one antibody is a mixture of (i) anti-4-1BB and (ii) anti-PD-1.
  • said antibody capable of modulating an immune checkpoint protein is a bispecific antibody.
  • said bispecific antibody is capable of binding to (i) 4-1BB; and/or (ii) PD-1, PD-L1 or PD-L2.
  • said bispecific antibody is capable of binding to (i) 4-1BB; and/or (ii) PD-1, PD-L1 or PD-L2.
  • said bispecific antibody is capable of binding to (i) 4-1BB and/or (ii) PD-L1.
  • said immune checkpoint modulator is a bispecific antibody with specificity for PSMA and the immune checkpoint protein.
  • said immune checkpoint modulator is a bispecific antibody capable of binding to the cancer antigen PSMA, and an immune checkpoint protein selected from the group consisting of PD-1, CTLA-4, and 4-1BB. More preferably, said immune checkpoint modulator is a bi-specific PSMA-targeted oligonucleotide, a PSMA-targeted multimeric antibody or a bispecific DARPin, each of them binds to PSMA and an immune checkpoint modulator, preferably, said immune checkpoint protein is selected from the group consisting of PD-1, CTLA-4, and 4-1BB, more preferably selected from the group consisting of PD-1, and 4-1BB.
  • Preferred examples of said antibody capable of modulating an immune checkpoint protein are human or humanized monoclonal anti-CTLA-4, anti-PD-1, anti-PD-L1 or anti-PD-L2 antibodies.
  • Preferred examples of said antibody capable of modulating an immune checkpoint protein are human or humanized monoclonal anti-CTLA-4 antibodies or human or humanized monoclonal anti-PD-1 antibodies.
  • said human or humanized monoclonal antibody is an IgG4 ⁇ antibody.
  • Preferred examples of said antibody capable of modulating the immune checkpoint PD- 1 (anti-PD-1) are human or humanized monoclonal anti-PD-1 antibodies.
  • said human or humanized monoclonal anti-PD-1 antibody is an IgG4 ⁇ antibody.
  • anti-PD-1 preferred examples of said antibody capable of modulating the immune checkpoint protein PD-1 (anti-PD-1) are human or humanized antibodies selected from the group consisting of pembrolizumab, nivolumab (known also as MDX-1106 or BMS-936558, Topalian et al., 2012. N. Eng. J. Med. 366:2443-2454, disclosed in US8008449 B2), cemiplimab, IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, pidilizumab (disclosed in Rosenblatt et al., 2011, J Immunother. 34:409-18), and lambrolizumab (e.g.
  • hPD-109A and its humanized derivatives h409All, h409A16 and h409A17 in WO2008/156712; Hamid et al., 2013, N. Engl. J. Med.369: 134-144) and soluble PD-1 ligands including without limitation PD-L2 Fc fusion protein (also known as B7-DC-Ig or AMP-244; disclosed in Mkrtichyan M, et al., 2012, J Immunol. 189: 2338-47). More preferred examples of said antibody capable of modulating the immune checkpoint protein PD-1 (anti-PD-1) are pembrolizumab or nivolumab.
  • said immune checkpoint modulator is nivolumab.
  • Preferred examples of said antibody capable of modulating the immune checkpoint protein PD-L1 or PD-L2 are human or humanized anti-PD-L1 or PD-L2 monoclonal antibodies.
  • said human or humanized monoclonal anti-PD-L1 or -L2 antibody is an IgG4 ⁇ antibody.
  • Preferred examples of said antibody capable of modulating the immune checkpoint protein PD-L1 (anti-PD-L1) are antibodies selected from the group consisting of durvalumab, avelumab, and atezolizumab, MEDI-4736 (disclosed e.g.
  • said antibody capable of modulating the immune checkpoint protein PD-L1 are antibodies selected from the group consisting of durvalumab, avelumab, and atezolizumab.
  • Preferred examples of said antibody capable of modulating the immune checkpoint protein CTLA-4 are human or humanized anti-CTLA-4 monoclonal antibodies.
  • said human or humanized monoclonal anti-CTLA-4 antibody is an IgG4 ⁇ antibody.
  • ipilimumab or tremelimumab Preferred examples of said antibody capable of modulating the immune checkpoint protein CTLA-4 are ipilimumab or tremelimumab, more preferably ipilimumab.
  • Ipilimumab is a fully human CTLA-4 blocking antibody presently marketed under the name Yervoy (Bristol-Myers Squibb).
  • a further CTLA-4 inhibitor is tremelimumab (referenced in Ribas et al., 2013, J. Clin. Oncol.31:616-22).
  • a preferred example of said antibody capable of modulating the immune checkpoint protein CD27 is CDX-1127, an agonistic anti-CD27 monoclonal antibody.
  • Preferred examples of said antibody capable of modulating the immune checkpoint protein OX40 are MEDI0562, a humanized OX40 agonist; MEDI6469, a murine OX40 agonist; and MEDI6383, an OX40 agonist.
  • a preferred example of said antibody capable of modulating the immune checkpoint protein KIR is lirilumab, a monoclonal antibody to KIR.
  • a preferred example of said antibody capable of modulating the immune checkpoint protein 4-1BB is urelumab.
  • a preferred example of said antibody capable of modulating the immune checkpoint protein LAG-3 is relatlimab.
  • a preferred example of said antibody capable of modulating the immune checkpoint protein LAG-3 is the monoclonal antibody BMS-986016.
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, pidilizumab, lambrolizumab, h409All, h409A16, h409A17, soluble PD-1 ligands such as PD- L2 Fc fusion protein, durvalumab, avelumab, atezolizumab, MEDI-4736, MPD-L328 OA, CDX-1127, MIH1, MEDI0562, MEDI6469, MEDI6383, ipilimumab, tremelimumab, relatlimab, urelumab, anti-TIGIT antibody, anti-TIM3 antibody, anti-GITR antibody and anti- ICOS antibody.
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, IBI308, BMS-986016, BCD-100, PDR001, tislelizumab, camrelizumab, pidilizumab, lambrolizumab, h409All, h409A16, h409A17, soluble PD-1 ligands such as PD-L2 Fc fusion protein, durvalumab, avelumab, atezolizumab, Lirilumab, MEDI-4736, MPDL328 OA, MIH1, ipilimumab, tremelimumab, relatlimab and urelumab.
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, pidilizumab, lambrolizumab, h409All, h409A16, h409A17, soluble PD-1 ligands such as PD- L2 Fc fusion protein, durvalumab, avelumab, atezolizumab, MEDI-4736, MPDL328 OA, MIH1, ipilimumab, tremelimumab, and urelumab.
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, pidilizumab, lambrolizumab, h409All, h409A16, h409A17, soluble PD-1 ligands such as PD-L2 Fc fusion protein, durvalumab, avelumab, atezolizumab, MEDI-4736, MPDL328 OA, MIH1, tremelimumab, and urelumab.
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, pidilizumab, lambrolizumab, h409All, h409A16, h409A17, soluble PD-1 ligands such as PD-L2 Fc fusion protein, durvalumab, avelumab, atezolizumab, MEDI-4736, MPDL328 OA and MIH1.
  • said at least one modulator capable of modulating an immune checkpoint protein is (i) at least one modulator, preferably an antibody, capable of agonizing co-stimulatory immune checkpoint proteins (called herein also checkpoint activator); (ii) at least one modulator, preferably an antibody, capable of antagonizing inhibitory immune checkpoint proteins (called herein checkpoint inhibitor); or (iii) a mixture of both (i) and (ii).
  • the term “antagonizing” as used herein refers to reduction or blocking activity.
  • said at least one immune checkpoint modulator is a checkpoint inhibitor.
  • said at least one immune checkpoint modulator is a checkpoint activator.
  • said at least one immune checkpoint modulator preferably at least one antibody
  • said at least one immune checkpoint modulator is an immune checkpoint activator or inhibitor.
  • said at least one immune checkpoint modulator preferably antibody
  • Said checkpoint activator activates co-stimulatory immune checkpoint proteins.
  • Checkpoint activators deliver (either directly or indirectly) activating signals preferably to T cells, B cells or natural killer cells by agonizing the receptors of said cell types or by agonizing counter-receptors on antigen-presenting cells (APCs).
  • APCs antigen-presenting cells
  • Said checkpoint inhibitor disinhibits, i.e. reduces or blocks inhibitory function of inhibitory immune checkpoint proteins.
  • Checkpoint inhibitors deliver antagonizing signals to T cells, B cells or natural killer cells either directly by antagonizing the receptors of said cell types, agonizing of inhibitory ligands or antagonizing counter-receptors on antigen-presenting cells (APCs).
  • APCs antigen-presenting cells
  • said at least one immune checkpoint modulator is (i) at least one modulator capable of agonizing a co-stimulatory immune checkpoint protein, wherein said co-stimulatory immune checkpoint protein is selected from the group consisting of CD155/PVR, CD226/DNAM-1, CD137/4-1BB, CD40/TNFRSF5, OX40/CD134, CD27, CD122, HVEM/TNFRSF14, TNFSF14/LIGHT/CD258, CD70/CD27L/TNFSF7, CD28/TP44, CD30, TMIGD2, HHLA2, CD80/B7-1, CD86/B7-2, GITR/TNFRSF18, DR3, TL1A, TMIGD2, HHLA2, TL1A, DR3, LT ⁇ R, TNF, TNFR2, ICOS/AILIM/CD278, and B7-H2 or (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-stimul
  • said at least one immune checkpoint modulator is (i) at least one modulator capable of agonizing a co- stimulatory immune checkpoint protein, wherein said co-stimulatory immune checkpoint protein is selected from the group consisting of 4-1BB, CD40, OX40, GITR, ICOS or (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-inhibitory immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, B7-H3, B7-H4, VISTA, LAG-3, Galectin-9, TIM- 3, and TIGIT; or (iii) a mixture of (i) and (ii).
  • said at least one immune checkpoint modulator is (i) at least one modulator capable of agonizing 4-1BB; or (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-inhibitory immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4; or (iii) a mixture of both.
  • said at least one immune checkpoint modulator is (i) at least one modulator capable of agonizing 4-1BB; or (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-inhibitory immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2; or (iii) a mixture of both.
  • said at least one modulator capable of modulating an immune checkpoint protein is (i) at least one modulator capable of agonizing CD137/4-1BB; or (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-inhibitory immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, preferably PD-1; or (iii) a mixture of both.
  • said at least one immune checkpoint modulator is a mixture of (i) at least one modulator capable of agonizing CD137/4-1BB; and (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-inhibitory immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, preferably PD-1.
  • said at least one modulator capable of modulating an immune checkpoint protein is (ii) at least one modulator capable of antagonizing a co-inhibitory immune checkpoint protein, wherein said co-inhibitory immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, and PD-L2.
  • said composition or kit-of-parts of the invention comprises more than one antibody capable of modulating an immune checkpoint protein.
  • said composition or kit-of-parts of the invention comprises 1, 2 or 3 antibodies capable of modulating an immune checkpoint protein.
  • said composition or kit-of-parts of the invention comprises 2 or 3 antibodies capable of modulating an immune checkpoint protein.
  • said composition or kit-of-parts of the invention comprises 2 antibodies capable of modulating an immune checkpoint protein. In a preferred embodiment, said composition or kit-of-parts of the invention comprises 3 antibodies capable of modulating an immune checkpoint protein. In a preferred embodiment, said composition or kit-of-parts of the invention further comprises a chemotherapeutic agent. In a preferred embodiment, said composition or kit-of- parts of the invention is combined with radiotherapy.
  • said polyplex of the invention comprises a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate comprises a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties; wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one or more targeting moieties via one of said one or more linkers, and wherein each of said one or more targeting moieties is capable of binding to a cancer antigen.
  • dsRNA double stranded RNA
  • said polymeric conjugate comprises a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties; wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one
  • said polyplex of the invention comprises a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate consists of a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties; wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one or more targeting moieties via one of said one or more linkers, and wherein each of said one or more targeting moieties is capable of binding to a cancer antigen.
  • PEI polyethyleneimine
  • PEG polyethylene glycol
  • said polyplex of the invention consists of a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate consists of a polyethyleneimine (PEI), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties; wherein said PEI is covalently bound to one or more PEG moieties, and each of said one or more PEG moieties is linked to one of said one or more targeting moieties via one of said one or more linkers, and wherein each of said one or more targeting moieties is capable of binding to a cancer antigen.
  • the polyplex of the invention comprises a double stranded RNA (dsRNA).
  • dsRNA typically and preferably refers to double stranded ribonucleotide polymers of any length in which one or more ribonucleotides can be chemical analogues or modified derivatives of a corresponding naturally occurring ribonucleotide.
  • dsRNA typically and preferably also includes mismatched dsRNA.
  • said dsRNA is polyinosinic-polycytidylic acid double stranded RNA (polyIC or pIC).
  • PolyIC is a double-stranded RNA with one strand being a polymer of inosinic acid, the other a polymer of cytidylic acid.
  • the polyIC of the polyplex for use according to the invention may be composed of dsRNA, wherein each strand consists of at least 22, preferably at least 45 ribonucleotides. In a certain embodiment, each strand consists of 20 to 8000 ribonucleotides.
  • PolyIC is bound to the polymeric conjugate via non-covalent or covalent bonds, wherein non-covalent binding is preferred. In a preferred embodiment, said polyIC is non-covalently bound to PEI, preferably by ionic bonds.
  • the polyplex according to the invention comprises a polymeric conjugate, wherein said polymeric conjugate comprises polyethyleneimine (PEI) which is a polycation with the capacity to condense and associate non-covalently with nucleic acid molecules due to the polyanionic nature of the latter.
  • said polyethyleneimine (PEI) is linear polyethyleneimine (LPEI).
  • LPEI includes a hydroxyl group located at one or either end of LPEI.
  • said hydroxyl group is instead of the terminal -NH2 group or terminal- NHCH 3 of LPEI.
  • PEI or preferably LPEI has a molecular weight from about 10-30 kDa.
  • PEI or preferably LPEI has a molecular weight from about 15-25 kDa (PEI 15-25k // LPEI 15-25k ). In a preferred embodiment, said PEI or preferably LPEI has a low dispersity. Preferably, the polydispersity index PDI of PEI or LPEI is about 1 (SPECS NMT 1.1). In a preferred embodiment, said one or more PEG moieties each independently forms - NH-CO- bond with said PEI or preferably LPEI.
  • the polyplex for use according to the invention includes one or more polyethylene glycol (PEG) moieties.
  • PEG moieties according to the invention are also known as polyethylene oxide (PEO) or polyoxyethylene (POE) moieties, depending on its molecular weight.
  • PEG moiety typically and preferably refers to a PEG moiety comprising two functionalities located on either end of polyethylene glycol (PEG). Said functionalities are capable of reacting with either said PEI or preferably LPEI or said targeting moiety.
  • said PEG moiety is linear or branched.
  • said PEG moiety is branched.
  • said PEG moiety is linear.
  • each of said at least one PEG moiety has a molecular weight from 1 kD or more. In another embodiment, each of said at least one PEG moiety has a molecular weight from about 0.3-8 kDa, preferably about 0.5-5 kDa, more preferably, 1-3 kDa (PEG1-3k). Said molecular weight corresponds to average molecular weight.
  • said PEI has a molecular weight of about 10-30 kDa, and said at least one PEG moiety has a molecular weight of about 0.3-8 kDa
  • PEI is covalently linked to one to five PEG moieties, preferably PEI is covalently linked to one to three PEG moieties.
  • LPEI is covalently linked to one to five PEG moieties, wherein preferably LPEI is covalently linked to one to three PEG moieties.
  • PEI15-25k is covalently linked to one to five PEG1-3k, moieties, wherein preferably PEI15-25k, is covalently linked to one to three PEG1-3k, preferably PEG2k, moieties.
  • said PEI of the polyplex is covalently bound to one, two or three PEG moieties.
  • said PEI of the polyplex is covalently bound to one or three PEG moieties.
  • said PEI of the polyplex is LPEI covalently bound to one, two or three PEG moieties. More preferably, said PEI of the polyplex is LPEI covalently bound to one or three PEG moieties.
  • PEI-PEG 1:1 PEI-PEG 1:1
  • LPEI-PEG 1:1 LPEI
  • PEI-PEG 1:1 LPEI
  • PEI-PEG 1:1 typically and preferably means that approximately one mole PEG per one mole PEI or LPEI is included in the polymeric conjugate.
  • PEI-PEG 1:3 PEI-PEG 1:3
  • LPEI-PEG 1:3 LPEI
  • LPEI-PEG 1:3 typically and preferably means that approximately three moles PEG per one mole PEI or LPEI are included in the polymeric conjugate. The values are preferably determined by 1H-NMR analysis.
  • the relative integral values of the hydrogen atoms on PEG (-CH 2 -CH 2 -O-) and the integral values of the hydrogen atoms on PEI or LPEI (-CH 2 -CH 2 -NH-) are preferably used for determining the values via 1H-NMR.
  • the term “approximately” herein refers preferably to a deviation of about 0 %-10%, more preferably about 0 %-5%, again more preferably about 0 %-2%.
  • said dsRNA is polyIC and said PEI is covalently linked to one to three PEG moieties.
  • said dsRNA is polyIC and said PEI is covalently linked to one, two or three PEG moieties.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one to three PEG moieties. In a more preferred embodiment, said dsRNA is polyIC and said PEI is LPEI covalently linked to one, two or three PEG moieties. In a preferred embodiment, said dsRNA is polyIC and said PEI is covalently linked to one, two or three PEG moieties. In a more preferred embodiment, said dsRNA is polyIC and said PEI is LPEI covalently linked to one, two or three PEG moieties. In a more preferred embodiment, said dsRNA is polyIC and said PEI is LPEI covalently linked to one, two or three PEG0.3-8k moieties.
  • said dsRNA is polyIC and said PEI is covalently linked to one PEG moiety (PEI-PEG 1:1). In a more preferred embodiment, said dsRNA is polyIC and said PEI is LPEI covalently linked to one PEG moiety (LPEI-PEG 1:1). In a preferred embodiment, said dsRNA is polyIC and said PEI is covalently linked to three PEG moieties. In a more preferred embodiment, said dsRNA is polyIC and said PEI is LPEI covalently linked to one PEG moiety. In a preferred embodiment, said dsRNA is polyIC and said LPEI is covalently linked to one or three PEG0.3-8k moieties.
  • cancer antigen refers to an antigenic substance produced in tumor cells or presented on tumor cells which triggers an immune response in the host.
  • Said cancer antigen is PSMA.
  • said dsRNA is polyIC.
  • said PEI is LPEI covalently linked to one to three PEG moieties and said cancer antigen is PSMA.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one to three PEG moieties and said targeting moiety is DUPA moiety or DUPA derivative.
  • vector polyIC/PEI-PEG-DUPA comprising PEI-PEG tethered to the DUPA moiety selectively delivered polyIC into PSMA- expressing cancer cells inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs).
  • PBMCs peripheral blood mononuclear cells
  • pIC/PPD led to the production of IFN- ⁇ , IP-10, and RANTES, to chemotaxis, and to PBMC activation which was evident from strong expression of IL-2 and led to the secretion of high levels of TNF- ⁇ and IFN- ⁇ (Langut et al., PNAS, December 26, 2017, vol.114, no.52, and Figure 1, Example 1 for IP-10 release).
  • compositions comprising polyplexes, wherein said cancer antigen is PSMA and said one or more targeting moieties are a DUPA moiety or DUPA derivative, and wherein said antibody is capable of modulating an immune checkpoint protein, preferably an anti-4-1BB (mentioned herein also as anti-CD137), anti-PD-1, anti-PD-L1 or anti-PD-L2 antibody.
  • said dsRNA is polyIC and said PEI is LPEI15-25k, covalently linked to one to three PEG moieties and said targeting moiety is the DUPA moiety or DUPA derivative.
  • said dsRNA is polyIC and said PEI is LPEI15-25k, covalently linked to one or three PEG moieties and said targeting moiety is the DUPA moiety or DUPA derivative.
  • said dsRNA is polyIC and said PEI is LPEIcovalently linked to one, two or three PEG0.3-8k, preferably PEG1-3k, further preferably PEG2k moieties and said targeting moiety is the DUPA moiety or DUPA derivative.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one or three PEG 0.3-8k , preferably PEG 1-3k , further preferably PEG 2k moieties and said targeting moiety is the DUPA moiety or DUPA derivative.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one or three PEG 0.3-8k , preferably PEG 1-3k , further preferably PEG 2k moieties and said targeting moiety is the DUPA moiety or DUPA derivative, and said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one or three PEG 0.3-8k , preferably PEG 1-3k , further preferably PEG 2k moieties and said targeting moiety is the DUPA moiety or DUPA derivative, and said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one or three PEG0.3-8k, preferably PEG1-3k, further preferably PEG2k moieties and said targeting moiety is the DUPA moiety or DUPA derivative, and said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said dsRNA is polyIC and said PEI is LPEI covalently linked to one or three PEG0.3-8k, preferably PEG1-3k, further preferably PEG2k moieties and said targeting moiety is the DUPA moiety or DUPA derivative, and said immune checkpoint protein is PD-1 or 4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, 4-1BB, TIGIT, LAG-3, TIM3, B7-H3, B7-H4, VISTA, CCR4, GITR, OX40, ICOS, and CD40.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB, TIGIT, LAG-3, TIM3, B7-H3, B7-H4, VISTA, CCR4, GITR, OX40, ICOS, and CD40.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one to three PEG moieties, said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one or three PEG moieties, said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is PD-1 or 4-1BB.
  • said dsRNA is polyIC
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, 4-1BB, CTLA-4, GITR, CD40, OX40, and ICOS.
  • said dsRNA is polyIC
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said dsRNA is polyIC
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1 and 4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties and said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein is PD-1 and/or 4-1BB, preferably PD-1 or 4-1BB.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one, two or three PEG moieties and said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein is PD-1, PD-L1, or PD-L2.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one, two or three PEG moieties, said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein is PD-1.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one, two or three PEG moieties and said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein is 4-1BB.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one, two or three PEG moieties, said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein modulating antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD- L2, anti-CTLA-4, and anti-4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein modulating antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, and anti-4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties
  • said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein modulating antibody is selected from the group consisting of anti-PD-1, anti-PD-L1, anti-PD-L2, and anti-4-1BB.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties and said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative
  • said immune checkpoint protein modulating antibody is anti-PD-1 or anti-4- 1BB.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one, two or three PEG moieties and said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein modulating antibody is anti-PD-1, anti-PD-L1, or anti-PD-L2.
  • said dsRNA is polyIC, said PEI is LPEI covalently linked to one, two or three PEG moieties, said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein modulating antibody is anti-PD-1.
  • said dsRNA is polyIC
  • said PEI is LPEI covalently linked to one, two or three PEG moieties and said targeting moiety is a PSMA targeting moiety, preferably the DUPA moiety or DUPA derivative, and said immune checkpoint protein modulating antibody is anti-4-1BB.
  • said dsRNA is polyIC
  • said PEI is covalently linked to one, two or three PEG0.3-8k
  • said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, 4-1BB, TIGIT, LAG-3, TIM3, B7-H3, B7-H4, VISTA, CCR4, GITR, OX40, ICOS, and CD40.
  • said dsRNA is polyIC
  • said PEI is covalently linked to one, two or three PEG 0.3-8k moieties
  • said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, 4-1BB, GITR, CD40, OX40, and ICOS.
  • said dsRNA is polyIC
  • said PEI is covalently linked to one, two or three PEG0.3-8k moieties
  • said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB.
  • said dsRNA is polyIC
  • said PEI is covalently linked to one or three PEG 0.3-8k moieties
  • said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB.
  • said dsRNA is polyIC, said PEI is covalently linked to one, two or three PEG0.3-8k moieties, said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative, and said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4-1BB.
  • said dsRNA is polyIC, said PEI is covalently linked to one, two or three PEG0.3-8k moieties and said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative, and said immune checkpoint protein is PD-1 or 4-1BB.
  • said dsRNA is polyIC, said PEI is covalently linked to one, two or three PEG0.3-8k moieties and said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative, and said immune checkpoint protein is PD-1, PD-L1, or PD-L2.
  • said dsRNA is polyIC, said PEI is covalently linked to one, two or three PEG0.3-8k, said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative, and said immune checkpoint protein is PD-1.
  • said dsRNA is polyIC
  • said PEI is covalently linked to one, two or three PEG 0.3-8k moieties and said targeting moiety is a PSMA targeting moiety, preferably DUPA moiety or DUPA derivative
  • said immune checkpoint protein is 4-1BB.
  • said composition or kits-of-parts of the invention do not include, i.e. exclude a cancer vaccine or a tumor associated antigen.
  • said composition or kits-of-parts of the invention includes a cancer vaccine or a tumor associated antigen.
  • said one or more PEG moieties are linked to one of said one or more targeting moieties.
  • said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one of said one or more linkers.
  • said one or more targeting moieties comprises or preferably consists of a DUPA derivative (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH- CH(COOH)-CH 2 -) or DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)- (CH 2 ) 2 -CO-), wherein said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one of said one or more linkers.
  • said one or more targeting moieties consists of a DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO-), wherein said one or more PEG moieties are directly linked to one of said one or more targeting moieties or linked to one of said one or more targeting moieties via one of said one or more linkers.
  • said one or more targeting moieties consists of a DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO-), wherein said one or more PEG moieties are linked to one of said one or more targeting moieties via one of said one or more linkers.
  • said linker is selected from -CO-R2-RX-R3 or a peptide moiety consisting of 3 to 7 amino acid residues, wherein R2 is selected from (C1- C 8 )alkylene, (C 2 -C 8 )alkenylene, (C 2 -C 8 ) alkynylene, (C 6 -C 10 )arylene-diyl, or heteroarylenediyl; RX is absent or -S-; R3 is absent or of the formula wherein R4 is selected from (C1-C8)alkylene, (C2-C8)allkenylene, (C2-C8) alkynylene(C1- C 8 )alkylene -(C 3 -C 8 )cycloallkylene, (C 2 -C 8 )allkenylene-(C 3 -C 8 )cycloallkylene, (C 2 - C 8 )alkynylene-(C 3 -C 8 )cyclooallkylene, (
  • said polymeric conjugate is of formula (i)-(iv): (i) wherein R6 is wherein R7 is wherein said T represents said targeting moiety, n corresponds to a molecular weight of 0.3-8kD, preferably 0.5-5kD, more preferably l-3kD, most preferably 2kD; and m corresponds to a molecular weight of 10-30kD, preferably 15-25kD, further preferably 22kD.
  • said targeting moiety is HOOC(CH 2 ) 2 -CH(COOH)- NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO- (DUPA moiety), and said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said polymeric conjugate is of formula (i) or (iii), wherein R6 is SEQ ID NO: 1 (-(NH-(CH 2 ) 7 -CO)-Phe-Phe-(NH-CH 2 - CH(NH2)-CO)-Asp-Cys-), and wherein T represents the targeting moiety HOOC(CH 2 ) 2 - CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO- (DUPA moiety).
  • said polymeric conjugate is of formula (ii) or (iv), wherein R7 is SEQ ID NO: 2 (-(NH-(CH 2 )7-CO)-Phe-Gly-Trp-Trp-Gly-Cys-), and wherein T represents the targeting moiety HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)-(CH 2 ) 2 -CO- (DUPA moiety).
  • said dsRNA is polylC
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, 4-1BB, TIGIT, LAG-3, TIM3, B7-H3, B7-H4, VISTA, CCR4, , GITR, 0X40, ICOS, and CD40, and wherein said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, B7-1, B7-2, 4-1BB, TIGIT, LAG-3, TIM-3, GITR, CD40, 0X40, and ICOS, and wherein said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is PSMA binding targeting moiety, preferably DUPA moiety or DUPA derivative
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB.
  • said dsRNA is polylC
  • said targeting moiety is PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, and 4-1BB
  • said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is selected from the group consisting of PD-1, PD-L1, PD-L2, and 4- IBB, and wherein said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is PD-1 or 4- IBB, and wherein said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is PD- 1, PD-L1, or PD-L2
  • said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is PD- 1, and wherein said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said immune checkpoint protein is 4- IBB
  • said polymeric conjugate is of the formula (i), (ii), (iii) or (iv).
  • said dsRNA is polylC
  • said polymeric conjugate is of the formula (ii) or (iv)
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of 4-1BB, PD-1, PD-L1, PD-L2, and CTLA-4.
  • said dsRNA is polylC
  • said polymeric conjugate is of the formula (ii) or (iv)
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said at least one antibody capable of modulating an immune checkpoint protein is selected from the group consisting of 4-1BB, PD-1, PD-L1, and PD-L2.
  • said dsRNA is polylC
  • said polymeric conjugate is of the formula (ii) or (iv)
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said at least one antibody capable of modulating an immune checkpoint protein is 4- IBB or PD-1.
  • said dsRNA is polylC
  • said polymeric conjugate is of the formula (ii) or (iv)
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said at least one antibody capable of modulating an immune checkpoint protein is 4- IBB.
  • said dsRNA is polylC
  • said polymeric conjugate is of the formula (ii) or (iv)
  • said targeting moiety is a PSMA binding targeting moiety, preferably DUPA moiety
  • said at least one antibody capable of modulating an immune checkpoint protein is PD-1.
  • the polyplex of the invention comprises one or more targeting moieties.
  • Said targeting moiety may be a native, natural or modified ligand or a paralog thereof, or a non-native ligand such as an antibody, a single-chain variable fragment (scFv), or an antibody mimetic such as an affibody or aptamer to any one of the cancer antigens.
  • said one or more targeting moieties of the polyplex of the invention are a DUPA moiety (HOOC(CH 2 ) 2 -CH(COOH)-NH-CO-NH-CH(COOH)- (CH 2 ) 2 -CO-).
  • the invention relates to the composition or the kit-of-parts according to the invention for use in the treatment of cancer.
  • the invention relates to the composition or the kit-of-parts according to the invention for use in the treatment of cancer in a mammal.
  • said mammal is a human.
  • the invention relates to a method for treatment of cancer, wherein said composition or said kit-of-parts according to the invention is administered to a patient in need thereof.
  • said cancer is a solid tumor.
  • said cancer is a solid cancer, wherein at least one cell type included in said solid cancer expresses PSMA.
  • PSMA expressing cells are prostatic, neovasculature, and endothelial cells (Mhawech- Fauceglia et al., Histopathology 2007, 50:472-483; Israeli RS et al., Cancer Res 1994, 54: 1807- 1811; Chang SS et al, Cancer Res 1999, 59:3192-198; Morgenroth et al., Breast Cancer Research 2019, 21 : 116). More preferably, said PSMA expressing cells are prostatic cells.
  • said cancer is a solid PSMA expressing cancer type.
  • PSMA expression is not restricted to prostatic cancer cells, but also expressed in other tumor types (Mhawech-Fauceglia et al., Histopathology 2007, 50:472-483; Israeli RS et al, Cancer Res 1994, 54: 1807-1811; Chang SS et al, Cancer Res 1999, 59:3192-198).
  • PSMA expression is detected preferably by immunohistochemical methods using a monoclonal antibody targeting PSMA, as e.g. described in Mhawech-Fauceglia et al., 2007.
  • PSMA expressing cancer types have preferably a cut-off of 5% or more positive cells of the investigated tissue, wherein PSMA expression is detected by immunohistochemical methods using a monoclonal antibody targeting PSMA, preferably as described in Mhawech-Fauceglia et al..
  • said cancer is an adenocarcinoma, more preferably a PSMA expressing adenocarcinoma.
  • said cancer is selected from the group consisting of prostate cancer, endometrial cancer, renal cell carcinoma, urothelial cell carcinoma, bladder cancer, colon carcinoma, glioblastoma (GBM), melanoma, non-small cell lung cancer, gastric cancer, oral squamous cell carcinoma, breast cancer, and metastatic cancer.
  • GBM glioblastoma
  • said cancer is a solid PSMA expressing cancer
  • said solid PSMA expressing cancer is selected from the group consisting of prostate cancer, urothelial cell carcinoma; bladder cancer, especially urothelial bladder carcinoma; glioblastoma (GBM); non-small cell lung cancer; breast cancer; salivary gland tumors, especially salivary adenoid cystic carcinoma; hepatocellular carcinoma; adenocarcinoma of the oesophagus, stomach, especially intestinal type of the stomach, and small intestine; and head and neck squamous cell carcinomas.
  • GBM glioblastoma
  • said cancer is a solid cancer, preferably, said solid cancer is selected from the group consisting of prostate cancer, urothelial cell carcinoma; bladder cancer, especially urothelial bladder carcinoma; glioblastoma (GBM); non-small cell lung cancer; breast cancer; salivary gland tumors, especially salivary adenoid cystic carcinoma; hepatocellular carcinoma; adenocarcinoma of the oesophagus, stomach, especially intestinal type of the stomach, and small intestine; and head and neck squamous cell carcinomas.
  • GBM glioblastoma
  • said cancer is a solid cancer selected from the group consisting of prostate cancer, urothelial cell carcinoma, bladder cancer, salivary gland tumors, especially salivary adenoid cystic carcinoma, hepatocellular carcinoma, non-small cell lung cancer, and breast cancer. More preferably, said cancer types express PSMA.
  • said cancer is a solid cancer selected from the group consisting of squamous cell carcinomas of the head and neck; adenocarcinoma of the oesophagus, stomach and small intestine, especially the intestinal type of the stomach; glioblastoma; prostate cancer; urothelial carcinoma, especially of the bladder and a combination thereof. More preferably, said cancer types express PSMA.
  • said cancer is a solid cancer selected from the group consisting of adenocarcinoma of the stomach, especially the intestinal type of the stomach; prostate cancer; urothelial carcinoma, especially of the bladder and a combination thereof. More preferably, said cancer types express PSMA. In an even more preferred embodiment, said cancer is a solid PSMA expressing cancer is prostate cancer or urothelial carcinoma of the bladder or a combination thereof. In an even more preferred embodiment, said cancer is prostate cancer or urothelial carcinoma of the bladder or a combination thereof.
  • said cancer is prostate cancer.
  • said polyplex included in the kit-of-parts according to the invention is administered separately from the one or more antibodies capable of modulating an immune checkpoint protein.
  • the invention provides use of the pharmaceutical composition or kit- of-parts of the invention for the treatment of cancer, wherein said polyplex is administered to a patient in a therapeutically effective amount in combination with a therapeutically effective amount of said at least one antibody capable of modulating an immune checkpoint protein.
  • Said polyplex and said at least one antibody capable of modulating an immune checkpoint protein can be administered simultaneously or sequentially (consecutive), i.e. chronologically staggered.
  • Said polyplex and said at least one antibody capable of modulating an immune checkpoint protein, as included in the kit-of-parts of the invention can be combined prior to administration and can be administered together as composition or can be administered separately.
  • said polyplex and said at least one antibody capable of modulating an immune checkpoint protein, as included in the kit-of-parts of the invention are administered separately.
  • kits-of-parts or the composition for use according to the invention are administered by any suitable route.
  • the kits-of-parts or the composition for use according to the invention may be administered by an intravenous, intra-brain (intracerebral), oral, intramuscular, subcutaneous, transdermal, intradermal, transmucosal, intranasal, sublingual, intraperitoneal or intraocular route.
  • kits-of-parts or the composition for use according to the invention are systemically administered, i.e. enterally or parenterally. More preferably, kits-of-parts or the composition for use according to the invention are intravenously, subcutaneously or intraperitoneally administered.
  • kits-of-parts or the composition according to the invention are for systemic administration. More preferably, kits-of-parts or the composition according to the invention are intravenously or intraperitoneally administered, again more preferably intravenously administered. Said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention can be administered via the same route or preferably via different routes. More preferably, said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention are administered via the same routes.
  • said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention are administered sequentially or simultaneously, preferably sequentially. In a preferred embodiment, said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention are administered sequentially via different routes. More preferably, said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention are administered simultaneously via the same route.
  • said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention are administered sequentially, or simultaneously, preferably sequentially, wherein one compound (or part) of the kits of parts of the invention is administered via intraperitoneal injection and at least one other compound (or part) is administered via intravenous injection.
  • said polyplex and said at least one antibody capable of modulating an immune checkpoint protein of the kits-of-parts according to the invention are administered sequentially or simultaneously, preferably sequentially, wherein the polyplex is administered via intravenous injection and the immunomodulatory antibodies are administered via intraperitoneal or intravenous injection.
  • the polyplex is administered prior to said at least one antibody capable of modulating an immune checkpoint protein.
  • the polyplex and said at least one antibody capable of modulating an immune checkpoint protein are administered sequentially, wherein the polyplex is administered via intravenous injection and said at least one antibody capable of modulating an immune checkpoint protein are administered via intraperitoneal or intravenous injection, and wherein the polyplex is administered prior to the antibody.
  • the ratio of the amount or concentration of the polyplex to the amount or concentration the one or more antibody to be administered in the kits-of-parts or composition of the invention can be varied, e.g. in order to cope with the needs of a single patient or a patient sub-population to be treated, wherein the needs can be different due to patient’s age, sex, body weight, condition etc..
  • kits-of-parts of the invention further may be used as add-on therapy.
  • additive-on therapy means an assemblage of said polyplex and said at least one antibody for use in therapy, wherein the subject receiving the therapy begins a first treatment regimen with one or more different parts of the kits-of-parts prior to beginning a second treatment regimen of one or more different parts of the kits-of-parts in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time.
  • one or more immunomodulatory antibodies are administered to a patient already receiving the polyplex of the invention or vice versa.
  • IP-10/CXCL10 IFN-y-induced protein 10
  • LNCaP and MCF7 cells 40,000 cells seeded per well in a 96-well plate
  • PEI-PEG-DUPA/polylC at various concentrations (0.125, 0.25, 0.5, 1.0 pg/ml).
  • Human IP-10 (CXCL10) secretion was quantified by ELISA assay (ABTS ELISA Development Kit, Peprotech, cat#900-K39).
  • LNCaP cells (ATCC) were seeded in flat-bottom 12-well plates and treated with PEI-PEG-DUPA/polylC at a concentration of 0.031, 0.063, or 0.125 pg/ml for 5 hours at 37°C. Then, LNCaP cells were detached using trypsin, washed and stained with anti-PD-Ll-PE labelled antibody (Biolegend, cat# 393607) or with an IgGl isotype control (Biolegend, cat#400114) for 35 minutes on ice in PBS with 2% FCS, washed and analyzed by FACS instrument (FACS Aria II, BD).
  • IP- 10 secretion of the potent chemokine, IP- 10 was strongly induced in the PSMA over-expressing cell line, LNCaP, following treatment with PEI-PEG-DUPA/polylC.
  • MCF7 cells which do not express PSMA
  • IP- 10 levels were undetectable.
  • the increase in IP- 10 following PEI-PEG-DUPA/polylC treatment provided the rationale to address the immunostimulatory properties of the inventive combination.
  • PD-L1 cell surface expression was induced following treatment with PEI-PEG-DUPA/polylC and was stronger than in untreated PSMA over-expressing LNCaP cells, providing the rationale for developing the combination with Nivolumab.
  • PSMA over-expressing LNCaP cells (40,000 cells seeded per well in a 96-well plate) were treated with PELPEG-DUPA/polylC at a concentration of 0.125 pg/ml for 5 hours.
  • Anti- CD3 -stimulated (clone OKT3, 5 ng/ml) or unstimulated PBMCs (200,000 cells) from healthy donors were added in the presence or absence of an antibody against 4-lBB
  • the PBMCs were then co-cultured with LNCaP cells treated with an antibody against 4- IBB (Biolegend clone, 4B4-1; 10 pg/ml) alone or in combination with PELPEG-DUPA/polylC for 16 hours (+4- IBB; Figure 3B).
  • PBMCs were co-cultured with LNCaP cells untreated or treated with PELPEG-DUPA/polylC for 16 hours without 4-1BB ((-) 4-1BB; Figures 3A and B). After 16 hours of co-culture, the medium was collected and human IFN-y was measured by ELISA assays (BD Bioscience, cat# 555142).
  • PEI-PEG-DUPA triconjugates and PEI-PEG-DUPA/polylC polyplexes were prepared according to WO 2015/173824, Example 12; Langut et al., PNAS, December 26, 2017, vol. 114, no. 52; and W02019063705A1.
  • Anti-PD-1 antibody (Nivolumab) was used to test the combination of PEI-PEG- DUPA/polylC polyplex and checkpoint blockade.
  • Anti-PD-1 antibody (Nivolumab) was utilized either alone or in combination with PEI-PEG-DUPA/polylC polyplex.
  • Anti-CD3 antibody (clone OKT3, 500 ng/ml) was used to stimulate PBMCs after transfer of medium from treated LNCaP cells.
  • Anti-PD-1 antibody (Nivolumab) was used to test the combination of PEI-PEG-DUPA/polylC polyplex and checkpoint blockade. Human IFN-y secretion was determined with an ELISA kit (BD Bioscience), according to the manufacturer’s instructions.
  • LNCaP cells were seeded in a flat-bottom 96-well plate (40,000 cells per wellRPMI- 1640 medium). In parallel, a plate with medium alone (90 pl medium without cells) was prepared as a negative control. The next day, LNCaP cells or medium alone were treated with 0.125pg/ml of PEI-PEG-DUPA/polylC polyplex (10 pl/well) or untreated (UT) for 5 hours at 37°C. Frozen PBMCs were thawed and allowed to recover in RPMI-1640 medium at 37°C for at least 5 h in U-bottom 96-well plates (200,000 cells/100 pl).
  • the SN from LNCaP cells that had been treated with PEI-PEG-DUPA/polylC polyplex was transferred to human PBMCs from a healthy donor and were treated in combination with Nivolumab, as follows: LNCaP cells were treated with PEI-PEG-DUPA/polylC polyplex at the indicated concentrations for 5 hours. As a control, medium without cells was “treated” with PEI-PEG-DUPA/polylC polyplex and incubated for 5 hours as well.
  • PBMCs stimulated or unstimulated with anti-CD3 antibody were treated with the following: Nivolumab alone; SN from PEI-PEG-DUPA/polylC polyplex- treated LNCaP cells alone; PELPEG-DUPA/polylC polyplex-”treated” medium alone; Nivolumab plus SN from PELPEG-DUPA/polylC polyplex treated LNCaP cells; or Nivolumab plus PELPEG-DUPA/polylC polyplex-”treated” medium.
  • PBMCs were incubated o/n at 37 °C. To assess PBMC activation, IFN-y secreted from the PBMCs was quantified by ELISA.
  • anti-CD3 -stimulated PBMCs secreted low levels of IFN-y.
  • addition of SN from LNCaP cells led to increased IFN-y secretion (1788.6 pg/ml) which further elevated with SN from PELPEG-DUPA/polylC -treated LNCaP cells (“LNCaP Supernatant”) (2893.4 pg/ml).
  • CD3 -stimulated PBMCs that received SN from PELPEG-DUPA/polylC polyplex-treated LNCaP cells (“LNCaP Supernatant”) induced the secretion of higher concentrations of IFN-y (2893.4 pg/ml) than PBMCs that received SN from untreated (UT) cells (1788.6 pg/ml).
  • IFN-y secretion was further significantly enhanced by the addition of Nivolumab to PBMCs that received medium from PELPEG-DUPA/polylC polyplex-treated LNCaP (4448.2 pg/ml).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Mycology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
PCT/EP2021/077777 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer Ceased WO2022074152A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2023521092A JP2023544201A (ja) 2020-10-08 2021-10-07 がんを処置するための免疫療法
CN202180071576.5A CN116348142A (zh) 2020-10-08 2021-10-07 用于治疗癌症的免疫疗法
CA3192963A CA3192963A1 (en) 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer
EP21786976.7A EP4225374A1 (en) 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer
IL301906A IL301906A (en) 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer
US18/247,961 US20230372384A1 (en) 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer
KR1020237009961A KR20230084476A (ko) 2020-10-08 2021-10-07 암의 치료를 위한 면역요법
AU2021357354A AU2021357354A1 (en) 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer
MX2023004101A MX2023004101A (es) 2020-10-08 2021-10-07 Inmunoterapia para el tratamiento de cancer.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20200835.5 2020-10-08
EP20200835 2020-10-08

Publications (1)

Publication Number Publication Date
WO2022074152A1 true WO2022074152A1 (en) 2022-04-14

Family

ID=72811720

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/077777 Ceased WO2022074152A1 (en) 2020-10-08 2021-10-07 Immunotherapy for the treatment of cancer

Country Status (10)

Country Link
US (1) US20230372384A1 (https=)
EP (1) EP4225374A1 (https=)
JP (1) JP2023544201A (https=)
KR (1) KR20230084476A (https=)
CN (1) CN116348142A (https=)
AU (1) AU2021357354A1 (https=)
CA (1) CA3192963A1 (https=)
IL (1) IL301906A (https=)
MX (1) MX2023004101A (https=)
WO (1) WO2022074152A1 (https=)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024100040A1 (en) * 2022-11-07 2024-05-16 Targimmune Therapeutics Ag Psma-targeting linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same
WO2024100046A1 (en) * 2022-11-07 2024-05-16 Targimmune Therapeutics Ag Targeted linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same
WO2024100044A1 (en) * 2022-11-07 2024-05-16 Targimmune Therapeutics Ag Polyplexes of nucleic acids and targeted conjugates comprising polyethyleneimine and polyethylene glycol

Citations (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162504A (en) 1988-06-03 1992-11-10 Cytogen Corporation Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients
US20020099096A1 (en) 2000-08-24 2002-07-25 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US20020173495A1 (en) 2000-08-24 2002-11-21 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US6492554B2 (en) 2000-08-24 2002-12-10 The University Of Tennessee Research Corporation Selective androgen receptor modulators and methods of use thereof
US20030022868A1 (en) 2001-06-25 2003-01-30 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US20030035804A1 (en) 1996-09-16 2003-02-20 Beth Israel Deaconess Medical Center Drug complex for treatment of metastatic prostate cancer
WO2003045436A1 (en) 2001-11-28 2003-06-05 Biopolymed Inc. Biologically active non-antigenic copolymer and conjugates thereof and methods for producing the same
US20030162761A1 (en) 2000-08-24 2003-08-28 Steiner Mitchell S. Formulations comprising selective androgen receptor modulators
US20030225040A1 (en) 2000-08-24 2003-12-04 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US20030232792A1 (en) 2000-08-24 2003-12-18 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US20030232013A1 (en) 2002-02-22 2003-12-18 Gary Sieckman Therapeutic and diagnostic targeting of cancers cells with tumor homing peptides
US20040014975A1 (en) 2000-08-24 2004-01-22 Dalton James T. Synthesis of selective androgen receptor modulators
US20040029913A1 (en) 2000-08-24 2004-02-12 Dalton James T. Halogenated selective androgen receptor modulators and methods of use thereof
US20040052727A1 (en) 2002-02-28 2004-03-18 Dalton James T. Radiolableled selective androgen receptor modulators andtheir use in prostate cancer imaging and therapy
US20040067979A1 (en) 2002-06-17 2004-04-08 Dalton James T. N-bridged selective androgen receptor modulators and methods of use thereof
US20040087810A1 (en) 2002-10-23 2004-05-06 Dalton James T. Irreversible selective androgen receptor modulators and methods of use thereof
US20040147550A1 (en) 2002-10-15 2004-07-29 Dalton James T. Methylene-bridged selective androgen receptor modulators and methods of use thereof
US20040147489A1 (en) 2002-02-28 2004-07-29 Dalton James T. Haloacetamide and azide substituted compounds and methods of use thereof
US20040167103A1 (en) 2003-02-24 2004-08-26 Dalton James T. Haloacetamide and azide substituted compounds and methods of use thereof
US20040260092A1 (en) 2003-01-13 2004-12-23 Miller Duane D. Large-scale synthesis of selective androgen receptor modulators
US20040260108A1 (en) 2001-06-25 2004-12-23 Dalton James T. Metabolites of selective androgen receptor modulators and methods of use thereof
US20050033074A1 (en) 2002-02-28 2005-02-10 Dalton James T. Multi-substitued selective androgen receptor modulators and methods of use thereof
US20050080128A1 (en) 2001-12-28 2005-04-14 Takashi Tsukamoto Indoles as naaladase inhibitors
US20060004042A1 (en) 2001-08-23 2006-01-05 Dalton James T Formulations comprising selective androgen receptor modulators
US20060009529A1 (en) 1996-11-27 2006-01-12 Dalton James T Synthesis of selective androgen receptor modulators
US20060183931A1 (en) 2002-02-28 2006-08-17 Dalton James T Multi-substituted selective androgen receptor modulators and methods of use thereof
US20060241180A1 (en) 2002-06-17 2006-10-26 Dalton James T Selective androgen receptor modulators and methods of use thereof
US20060258628A1 (en) 2004-07-20 2006-11-16 Steiner Mitchell S Compositions comprising 5-alpha reductase inhibitors, and SARMs and methods of use thereof
US20060276540A1 (en) 2000-08-24 2006-12-07 Dalton James T Selective androgen receptor modulators
US20060287547A1 (en) 1996-11-27 2006-12-21 Dalton James T Selective androgen receptor modulators
US7163680B2 (en) 1996-05-06 2007-01-16 Cornell Research Foundation, Inc. Treatment and diagnosis of cancer
US20070225213A1 (en) 2006-03-23 2007-09-27 Kosak Matthew K Nucleic acid carriers for delivery of therapeutic agents
WO2008105773A2 (en) 2006-03-31 2008-09-04 Massachusetts Institute Of Technology System for targeted delivery of therapeutic agents
WO2008121949A1 (en) 2007-03-30 2008-10-09 Bind Biosciences, Inc. Cancer cell targeting using nanoparticles
WO2008124634A1 (en) 2007-04-04 2008-10-16 Massachusetts Institute Of Technology Polymer-encapsulated reverse micelles
WO2008156712A1 (en) 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
WO2009026177A1 (en) 2007-08-17 2009-02-26 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
WO2009131435A1 (en) 2008-04-23 2009-10-29 Erasmus University Medical Center Rotterdam Linker containing bungarotoxin and a binding peptide
WO2010005740A2 (en) 2008-06-16 2010-01-14 Bind Biosciences, Inc. Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles
US20100278927A1 (en) 2009-04-30 2010-11-04 Intezyne Technologies, Incorporated Polymeric micelles for polynucleotide encapsulation
WO2011066389A1 (en) 2009-11-24 2011-06-03 Medimmmune, Limited Targeted binding agents against b7-h1
WO2011084513A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
WO2011084521A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising epothilone and methods of making and using same
WO2011084518A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising corticosteroids and methods of making and using same
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
WO2011108930A1 (en) 2010-03-04 2011-09-09 Interna Technologies Bv A MiRNA MOLECULE DEFINED BY ITS SOURCE AND ITS DIAGNOSTIC AND THERAPEUTIC USES IN DISEASES OR CONDITIONS ASSOCIATED WITH EMT
US20110288152A1 (en) 2008-10-17 2011-11-24 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
WO2012005572A1 (en) 2010-07-06 2012-01-12 Interna Technologies Bv Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated braf pathway
WO2012016188A2 (en) 2010-07-30 2012-02-02 Alnylam Pharmaceuticals, Inc. Methods and compositions for delivery of active agents
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2012135592A2 (en) 2011-03-31 2012-10-04 The Johns Hopkins University Theranostic imaging agents and methods of use
WO2012166923A2 (en) 2011-05-31 2012-12-06 Bind Biosciences Drug loaded polymeric nanoparticles and methods of making and using same
WO2014072357A1 (en) 2012-11-06 2014-05-15 Interna Technologies B.V. Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated b-raf pathway
US20150258102A1 (en) 2014-03-14 2015-09-17 Pfizer Inc. Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using same
WO2015168379A2 (en) 2014-04-30 2015-11-05 President And Fellows Of Harvard College Combination vaccine devices and methods of killing cancer cells
WO2015173824A1 (en) 2014-05-14 2015-11-19 Alex Levitzki Management And Holdings Ltd Improved polyethyleneimine polyethyleneglycol vectors
WO2016183447A1 (en) 2015-05-14 2016-11-17 The Johns Hopkins University Compositions of nucleic acid-containing nanoparticles for in vivo delivery
WO2017044936A1 (en) 2015-09-11 2017-03-16 Pfizer Inc. Methods of controlling morphology of polymeric nanoparticles
WO2017086467A1 (ja) 2015-11-19 2017-05-26 公立大学法人名古屋市立大学 抗腫瘍性ドラッグデリバリー製剤
WO2017089942A1 (en) 2015-11-25 2017-06-01 Pfizer Inc. Therapeutic nanoparticles comprising an antibiotic and methods of making and using same
WO2019063705A1 (en) 2017-09-27 2019-04-04 Targimmune Therapeutics Ag CANCER OF THE PROSTATE RESISTANT TO CASTRATION
WO2020077077A1 (en) * 2018-10-10 2020-04-16 The Regents Of The University Of California Combination immunotherapies
WO2020201568A1 (en) * 2019-04-03 2020-10-08 Targimmune Therapeutics Ag Immunotherapy for the treatment of cancer

Patent Citations (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162504A (en) 1988-06-03 1992-11-10 Cytogen Corporation Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients
US7163680B2 (en) 1996-05-06 2007-01-16 Cornell Research Foundation, Inc. Treatment and diagnosis of cancer
US20050233948A1 (en) 1996-09-16 2005-10-20 Beth Israel Deaconess Medical Center Drug complex for treatment of metastatic prostate cancer
US20030035804A1 (en) 1996-09-16 2003-02-20 Beth Israel Deaconess Medical Center Drug complex for treatment of metastatic prostate cancer
US20060009529A1 (en) 1996-11-27 2006-01-12 Dalton James T Synthesis of selective androgen receptor modulators
US20060287547A1 (en) 1996-11-27 2006-12-21 Dalton James T Selective androgen receptor modulators
US20030162761A1 (en) 2000-08-24 2003-08-28 Steiner Mitchell S. Formulations comprising selective androgen receptor modulators
US6492554B2 (en) 2000-08-24 2002-12-10 The University Of Tennessee Research Corporation Selective androgen receptor modulators and methods of use thereof
US7026500B2 (en) 2000-08-24 2006-04-11 University Of Tennessee Research Foundation Halogenated selective androgen receptor modulators and methods of use thereof
US20030225040A1 (en) 2000-08-24 2003-12-04 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US20030232792A1 (en) 2000-08-24 2003-12-18 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US6998500B2 (en) 2000-08-24 2006-02-14 University Of Tennessee Research Foundation Selective androgen receptor modulators and methods of use thereof
US20040014975A1 (en) 2000-08-24 2004-01-22 Dalton James T. Synthesis of selective androgen receptor modulators
US20040029913A1 (en) 2000-08-24 2004-02-12 Dalton James T. Halogenated selective androgen receptor modulators and methods of use thereof
US6995284B2 (en) 2000-08-24 2006-02-07 The University Of Tennessee Research Foundation Synthesis of selective androgen receptor modulators
US20020099096A1 (en) 2000-08-24 2002-07-25 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US6569896B2 (en) 2000-08-24 2003-05-27 The University Of Tennessee Research Corporation Selective androgen receptor modulators and methods of use thereof
US20020173495A1 (en) 2000-08-24 2002-11-21 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US6838484B2 (en) 2000-08-24 2005-01-04 University Of Tennessee Research Foundation Formulations comprising selective androgen receptor modulators
US20060276540A1 (en) 2000-08-24 2006-12-07 Dalton James T Selective androgen receptor modulators
US20030022868A1 (en) 2001-06-25 2003-01-30 Dalton James T. Selective androgen receptor modulators and methods of use thereof
US20040260108A1 (en) 2001-06-25 2004-12-23 Dalton James T. Metabolites of selective androgen receptor modulators and methods of use thereof
US20060004042A1 (en) 2001-08-23 2006-01-05 Dalton James T Formulations comprising selective androgen receptor modulators
WO2003045436A1 (en) 2001-11-28 2003-06-05 Biopolymed Inc. Biologically active non-antigenic copolymer and conjugates thereof and methods for producing the same
US20050080128A1 (en) 2001-12-28 2005-04-14 Takashi Tsukamoto Indoles as naaladase inhibitors
US20030232013A1 (en) 2002-02-22 2003-12-18 Gary Sieckman Therapeutic and diagnostic targeting of cancers cells with tumor homing peptides
US20050033074A1 (en) 2002-02-28 2005-02-10 Dalton James T. Multi-substitued selective androgen receptor modulators and methods of use thereof
US20040052727A1 (en) 2002-02-28 2004-03-18 Dalton James T. Radiolableled selective androgen receptor modulators andtheir use in prostate cancer imaging and therapy
US20040147489A1 (en) 2002-02-28 2004-07-29 Dalton James T. Haloacetamide and azide substituted compounds and methods of use thereof
US20060183931A1 (en) 2002-02-28 2006-08-17 Dalton James T Multi-substituted selective androgen receptor modulators and methods of use thereof
US20040067979A1 (en) 2002-06-17 2004-04-08 Dalton James T. N-bridged selective androgen receptor modulators and methods of use thereof
US20060241180A1 (en) 2002-06-17 2006-10-26 Dalton James T Selective androgen receptor modulators and methods of use thereof
US7022870B2 (en) 2002-06-17 2006-04-04 University Of Tennessee Research Foundation N-bridged selective androgen receptor modulators and methods of use thereof
US20040147550A1 (en) 2002-10-15 2004-07-29 Dalton James T. Methylene-bridged selective androgen receptor modulators and methods of use thereof
US20060035966A1 (en) 2002-10-23 2006-02-16 Dalton James T Irreversible selective androgen receptor modulators and methods of use thereof
US20040087810A1 (en) 2002-10-23 2004-05-06 Dalton James T. Irreversible selective androgen receptor modulators and methods of use thereof
US20040260092A1 (en) 2003-01-13 2004-12-23 Miller Duane D. Large-scale synthesis of selective androgen receptor modulators
US20040167103A1 (en) 2003-02-24 2004-08-26 Dalton James T. Haloacetamide and azide substituted compounds and methods of use thereof
US20060258628A1 (en) 2004-07-20 2006-11-16 Steiner Mitchell S Compositions comprising 5-alpha reductase inhibitors, and SARMs and methods of use thereof
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US20070225213A1 (en) 2006-03-23 2007-09-27 Kosak Matthew K Nucleic acid carriers for delivery of therapeutic agents
WO2008105773A2 (en) 2006-03-31 2008-09-04 Massachusetts Institute Of Technology System for targeted delivery of therapeutic agents
WO2008121949A1 (en) 2007-03-30 2008-10-09 Bind Biosciences, Inc. Cancer cell targeting using nanoparticles
WO2008124634A1 (en) 2007-04-04 2008-10-16 Massachusetts Institute Of Technology Polymer-encapsulated reverse micelles
WO2008156712A1 (en) 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
WO2009026177A1 (en) 2007-08-17 2009-02-26 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US20100324008A1 (en) 2007-08-17 2010-12-23 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US20200188523A1 (en) 2007-08-17 2020-06-18 Purdue Technology Center Aerospace Psma binding ligand-linker conjugates and methods for using
WO2009131435A1 (en) 2008-04-23 2009-10-29 Erasmus University Medical Center Rotterdam Linker containing bungarotoxin and a binding peptide
WO2010005740A2 (en) 2008-06-16 2010-01-14 Bind Biosciences, Inc. Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles
US20110288152A1 (en) 2008-10-17 2011-11-24 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
US20100278927A1 (en) 2009-04-30 2010-11-04 Intezyne Technologies, Incorporated Polymeric micelles for polynucleotide encapsulation
WO2011066389A1 (en) 2009-11-24 2011-06-03 Medimmmune, Limited Targeted binding agents against b7-h1
WO2011084518A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising corticosteroids and methods of making and using same
WO2011084513A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
WO2011084521A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising epothilone and methods of making and using same
WO2011108930A1 (en) 2010-03-04 2011-09-09 Interna Technologies Bv A MiRNA MOLECULE DEFINED BY ITS SOURCE AND ITS DIAGNOSTIC AND THERAPEUTIC USES IN DISEASES OR CONDITIONS ASSOCIATED WITH EMT
WO2012005572A1 (en) 2010-07-06 2012-01-12 Interna Technologies Bv Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated braf pathway
WO2012016188A2 (en) 2010-07-30 2012-02-02 Alnylam Pharmaceuticals, Inc. Methods and compositions for delivery of active agents
WO2012135592A2 (en) 2011-03-31 2012-10-04 The Johns Hopkins University Theranostic imaging agents and methods of use
WO2012166923A2 (en) 2011-05-31 2012-12-06 Bind Biosciences Drug loaded polymeric nanoparticles and methods of making and using same
WO2014072357A1 (en) 2012-11-06 2014-05-15 Interna Technologies B.V. Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated b-raf pathway
US20150258102A1 (en) 2014-03-14 2015-09-17 Pfizer Inc. Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using same
WO2015168379A2 (en) 2014-04-30 2015-11-05 President And Fellows Of Harvard College Combination vaccine devices and methods of killing cancer cells
WO2015173824A1 (en) 2014-05-14 2015-11-19 Alex Levitzki Management And Holdings Ltd Improved polyethyleneimine polyethyleneglycol vectors
WO2016183447A1 (en) 2015-05-14 2016-11-17 The Johns Hopkins University Compositions of nucleic acid-containing nanoparticles for in vivo delivery
WO2017044936A1 (en) 2015-09-11 2017-03-16 Pfizer Inc. Methods of controlling morphology of polymeric nanoparticles
WO2017086467A1 (ja) 2015-11-19 2017-05-26 公立大学法人名古屋市立大学 抗腫瘍性ドラッグデリバリー製剤
WO2017089942A1 (en) 2015-11-25 2017-06-01 Pfizer Inc. Therapeutic nanoparticles comprising an antibiotic and methods of making and using same
WO2019063705A1 (en) 2017-09-27 2019-04-04 Targimmune Therapeutics Ag CANCER OF THE PROSTATE RESISTANT TO CASTRATION
WO2020077077A1 (en) * 2018-10-10 2020-04-16 The Regents Of The University Of California Combination immunotherapies
WO2020201568A1 (en) * 2019-04-03 2020-10-08 Targimmune Therapeutics Ag Immunotherapy for the treatment of cancer

Non-Patent Citations (55)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Poly-ICLC (Hiltonol) and Anti-PD1 or Anti-PD-L1", CLINICALTRIALS.GOV, 22 April 2015 (2015-04-22), pages 1 - 9, XP055765557, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT03721679> [retrieved on 20210115] *
BANDER ET AL., J. UROL., 2003, pages 17011717
BENNETT ET AL., J. AM. CHEM. SOC., 1998, pages 120112139
CHANG ET AL., CANCER RES., 1999, pages 5913192
CHANG SS ET AL., CANCER RES, vol. 59, 1999, pages 3192 - 198
CHRISTIANSEN ET AL., MOL CANCER THER, vol. 3, no. 11, 2004, pages 1493 - 1501
DARVIN ET AL., EXPERIMENTAL & MOLECULAR MEDICINE, vol. 50, 2018, pages 165
ELSASSER-BEILE ET AL., PROSTATE, 2006, pages 6611359
FRACASSO ET AL., PROSTATE, 2002, pages 5319
GRAUER ET AL., CANCER RES., 1998, pages 5814787
GUO ET AL., ADV CANCER RES, vol. 119, 2013, pages 421 - 475
HAMID ET AL., N. ENGL. J. MED., vol. 369, 2013, pages 134 - 144
HOROSZEWICZ ET AL., ANTICANCER RES., vol. 7, 1987, pages 1927
I MARQUEZ RODAS ET AL: "LBA39 Intratumoral BO-112, a double-stranded RNA (dsRNA), alone and in combination with systemic anti-PD-1 in solid tumors", ANNALS OF ONCOLOGY, VOL 29, SUPPL 8, 1 October 2018 (2018-10-01), pages viii732, XP055664726, Retrieved from the Internet <URL:https://watermark.silverchair.com/mdy424.049.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAnowggJ2BgkqhkiG9w0BBwagggJnMIICYwIBADCCAlwGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMjmv6Rp1Zsl9X2s70AgEQgIICLV4v16uF0PlhOYgMpRd6dSvZzp3vqQMIvH5jiYyQnITtc1JIEVGmnP64Yq3dxu3ssb4ERH5-h4_Py9AXNm4eWPeBU> [retrieved on 20200204], DOI: 10.1093/annonc/mdy424.049 *
ISRAELI RS ET AL., CANCER RES, vol. 54, 1994, pages 1807 - 1811
JACKSON ET AL., CURR. MED. CHEM., vol. 8, 2001, pages 949
JACKSON ET AL., J MED. CHEM., 2001, pages 4414170
KOPKA ET AL., J NUC MED, vol. 58, no. 9, 2017
KOPKA ET AL., J NUCL MED, vol. 58, 2017, pages 17S - 26S
KOZIKOWSK ET AL., J MED CHEM., vol. 47, 2004, pages 1729 - 1738
KOZIKOWSKI ET AL., J MED CHEM., vol. 44, 2001, pages 298 - 301
KOZIKOWSKI ET AL., J. MED. CHEM., 2004, pages 4711729
KULARATNE ET AL., MOL PHARMACEUTICS, vol. 6, 2009, pages 780
KULARATNE ET AL., MOL. PHARMACEUTICS, vol. 6, 2009, pages 790
LANGUT ET AL., PNAS, vol. 114, no. 52, 26 December 2017 (2017-12-26)
LANGUT YAEL ET AL: "Supporting Information: PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 114, no. 52, 11 December 2017 (2017-12-11), US, pages 13655 - 13660, XP055785106, ISSN: 0027-8424, DOI: 10.1073/pnas.1714587115 *
LIU ET AL., CANCER RES., 1997, pages 5713629
MA ET AL.: "Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 9, 2016, pages 47
MAJER ET AL., J MED. CHEM., 2003, pages 4611989
MAUNG ET AL., BIOORG. MED. CHEM., 2004, pages 1214969
MCDEVITT ET AL., SCIENCE, 2001, pages 29411537
MHAWECH-FAUCEGLIA ET AL., HISTOPATHOLOGY, vol. 50, 2007, pages 472 - 483
MKRTICHYAN M ET AL., J IMMUNOL., vol. 189, 2012, pages 2338 - 47
MORGENROTH ET AL., BREAST CANCER RESEARCH, vol. 21, 2019, pages 116
MORRISEY ET AL., CLIN. TRANSL. SCI, vol. 9, 2016, pages 89 - 104
MURPHY ET AL., J. UROL., 1998, pages 16012396
NAGATO ET AL., ONCOLMMUNOLOGY, vol. 3, 2014, pages e28440
NAN ET AL., J. MED. CHEM., 2000, pages 431772
OLIVER ET AL., BIOORG. MED. CHEM., 2003, pages 1114455
PARDOLL, NAT REV CANCER, vol. 12, no. 4, 2012, pages 252 - 264
PARDOLL, NATURE REV CANCER, vol. 12, 2012, pages 252 - 264
PATRI ET AL., BIOCONJ. CHEM., 2004, pages 1511174
RIBAS ET AL., J. CLIN. ONCOL., vol. 31, 2013, pages 616 - 22
ROSENBLATT ET AL., J IMMUNOTHER, vol. 34, 2011, pages 409 - 18
SMITH-JONES ET AL., CANCER RES., 2000, pages 6015237
STOERRNER ET AL., BIOORG. MED. CHEM. LETT., 2003, pages 1312097
TANG ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 307, 2003, pages 8
TOPALIAN ET AL., N. ENG. J. MED., vol. 366, 2012, pages 2443 - 2454
TSUKAMOTO ET AL., BIOORG. MED. CHEM. LETT., 2002, pages 1212189
VALLABHAJOSULA ET AL., PROSTATE, 2004, pages 581145
WANG ET AL., INT. J. CANCER, vol. 92, 2001, pages 871
WARD-KAVANAGH ET AL.: "The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses", IMMUNITY, vol. 44, 17 May 2016 (2016-05-17), XP029537985, DOI: 10.1016/j.immuni.2016.04.019
WEN LIANG ET AL: "An Efficient Combination Immunotherapy for Primary Liver Cancer by Harmonized Activation of Innate and Adaptive Immunity in Mice : Hepatology", HEPATOLOGY, vol. 69, no. 6, 1 June 2019 (2019-06-01), pages 2518 - 2532, XP055784977, ISSN: 0270-9139, DOI: 10.1002/hep.30528 *
WIRTZ ET AL., EJNMMI RESEARCH, vol. 8, 2018, pages 84
YAEL LANGUT ET AL: "PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 114, no. 52, 11 December 2017 (2017-12-11), US, pages 13655 - 13660, XP055477349, ISSN: 0027-8424, DOI: 10.1073/pnas.1714587115 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024100040A1 (en) * 2022-11-07 2024-05-16 Targimmune Therapeutics Ag Psma-targeting linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same
WO2024100046A1 (en) * 2022-11-07 2024-05-16 Targimmune Therapeutics Ag Targeted linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same
WO2024100044A1 (en) * 2022-11-07 2024-05-16 Targimmune Therapeutics Ag Polyplexes of nucleic acids and targeted conjugates comprising polyethyleneimine and polyethylene glycol

Also Published As

Publication number Publication date
AU2021357354A1 (en) 2023-04-20
KR20230084476A (ko) 2023-06-13
MX2023004101A (es) 2023-10-11
US20230372384A1 (en) 2023-11-23
JP2023544201A (ja) 2023-10-20
CN116348142A (zh) 2023-06-27
IL301906A (en) 2023-06-01
CA3192963A1 (en) 2022-04-14
EP4225374A1 (en) 2023-08-16
AU2021357354A9 (en) 2023-04-27

Similar Documents

Publication Publication Date Title
CN113286811B (zh) 改善过继性细胞疗法的效力和安全性
JP7713390B2 (ja) がん治療のための免疫療法
CN110511278B (zh) 抗b7-h6抗体、融合蛋白及其使用方法
ES2754557T3 (es) Combinación de un anticuerpo CD30XCD16A con un anticuerpo antagonista anti-PD-1 para terapia
JP2022113913A (ja) 抗ｐｄ１抗体と組み合わせて使用されるペプチドおよびその使用
US20230372384A1 (en) Immunotherapy for the treatment of cancer
AU2021308702A1 (en) Receptors providing targeted costimulation for adoptive cell therapy
TW201625270A (zh) 用於治療贅瘤形成的治療組合及方法
US20200405881A1 (en) Cell based methods and compositions for therapeutic agent delivery and treatments using same
KR20200029543A (ko) 암 면역요법을 위해 면역 조절제와 조합된 수용체 서브타입 및 기능 선택적 레티노이드 및 렉시노이드 화합물
CN115989033B (zh) 用于使用cd70特异性融合蛋白进行tcr重编程的组合物和方法
US20200276318A1 (en) Engineered cells and agent compositions for therapeutic agent delivery and treatments using same
WO2021259237A1 (en) GENETIC ENGINEERING OF γδ T CELLS FOR IMMUNOTHERAPY
WO2023230534A2 (en) Use of fusion constructs for il-2 independent t cell therapy
US20230338422A1 (en) Engineering gamma delta t cells with interleukin-36 for immunotherapy
WO2025128002A1 (en) Anti-cd137 antibody and the use thereof
WO2025252993A1 (en) Chimeric antigen receptor targeting glioma-associated antigens
CA3255332A1 (en) ANTI-WT1 ANTIGEN-BINDING PROTEINS AND THEIR USES
JP2024517986A (ja) 抗－ＣＤ３００ｃ抗体を利用した併用療法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21786976

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: AU2021357354

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 3192963

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2023521092

Country of ref document: JP

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023006554

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2021357354

Country of ref document: AU

Date of ref document: 20211007

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 202347031930

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2023105750

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2021786976

Country of ref document: EP

Effective date: 20230508

ENP Entry into the national phase

Ref document number: 112023006554

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20230406

WWW Wipo information: withdrawn in national office

Ref document number: 2023105750

Country of ref document: RU