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WO2025093541A1 - Combinaison d'interleukine 7 et de vaccin antigénique associé à une tumeur - Google Patents

Combinaison d'interleukine 7 et de vaccin antigénique associé à une tumeur Download PDF

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Publication number
WO2025093541A1
WO2025093541A1 PCT/EP2024/080568 EP2024080568W WO2025093541A1 WO 2025093541 A1 WO2025093541 A1 WO 2025093541A1 EP 2024080568 W EP2024080568 W EP 2024080568W WO 2025093541 A1 WO2025093541 A1 WO 2025093541A1
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Prior art keywords
cancer
seq
vaccine
hla
variant
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Inventor
Aurore MORELLO
Lyssia BELARIF
Nicolas Poirier
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OSE Immunotherapeutics SA
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OSE Immunotherapeutics SA
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    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2046—IL-7
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001148—Regulators of development
    • A61K39/00115—Apoptosis related proteins, e.g. survivin or livin
    • A61K39/001151—Apoptosis related proteins, e.g. survivin or livin p53
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/00118—Cancer antigens from embryonic or fetal origin
    • A61K39/001182—Carcinoembryonic antigen [CEA]
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
    • A61K39/001186—MAGE
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • 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
    • A61K2039/70—Multivalent vaccine

Definitions

  • the present invention relates to the field of medicine, more particularly the present invention relates to the treatment of cancer.
  • the present invention relates to a new therapy of cancer based on the combination of an anticancer vaccine and interleukin 7.
  • the present invention particularly combines IL-7 molecules with Type I HLA epitope vaccine to enhance anti-tumour T cell immune response.
  • the inventors surprisingly observed that IL-7 induces upregulation of type I HLA (HLA A, B, C) molecule at the surface of immune cells and tumour cells.
  • type I HLA HLA A, B, C
  • cotreatment of IL-7 with Type I HLA epitope vaccine allow higher cell surface peptide presentation and consequently a higher stimulation of tumour-specific T cell for an enhanced anti-tumour efficacy.
  • the combinations disclosed herein mediate immune responses against tumours in individuals who bear at least one allele of HLA-A2 and/or HLA-A2 supertype.
  • the invention relates to pharmaceutical composition comprising an interleukin 7 (IL-7) molecule or a variant thereof, for use to increase Human Leukocyte Antigen (HLA) class I molecules presentation of tumour associated antigen (TAA) by immune cells and/or tumoral cells of a patient suffering from cancer and treated or to be treated by an anti-cancer vaccine, preferably a TAA vaccine specific for HLA class I, even more preferably a TAA epitope peptide vaccine specific for HLA class I.
  • IL-7 interleukin 7
  • TAA tumour associated antigen
  • the invention in a second aspect, relates to pharmaceutical composition
  • IL-7 interleukin 7
  • IL-7 interleukin 7
  • a tumour associated antigen (TAA) vaccine specific for HLA class I preferably a TAA epitope peptide vaccine specific for HLA class I, by stimulating presentation of the TAA peptide in the vaccine to T cells, thereby activating the T cells and reversing, delaying or preventing immune suppression.
  • TAA tumour associated antigen
  • the HLA class I is selected from the group consisting of HLA-A, HLA-B, HLA-C and any combination thereof.
  • the TAA epitope peptide vaccine comprises the following peptides : RLLQETELV (SEQ ID No: 1), YLQLVFGIEV (SEQ ID No: 2), LLTFWNPPV (SEQ ID No: 3), KVFGSLAFV (SEQ ID No: 4), KLBPVQLWV (SEQ ID No: 5, with B indicating a-aminoisobutyric acid), SMPPPGTRV (SEQ ID No: 6), IMIGHLVGV (SEQ ID No: 7), KVAEIVHFL (SEQ ID No: 8), YLSGADLNL (SEQ ID No: 9), aKXVAAWTLKAAa (SEQ ID No: 10, with X and a respectively indicating cyclohexylalanine and d-alanine).
  • RLLQETELV SEQ ID No: 1
  • YLQLVFGIEV SEQ ID No: 2
  • LLTFWNPPV SEQ ID No: 3
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an interleukin 7 (IL-7) molecule or a variant thereof, for use in combination with a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I, in the treatment of a patient suffering from cancer
  • the vaccine comprises the following peptides : RLLQETELV (SEQ ID No: 1), YLQLVFGIEV (SEQ ID No: 2), LLTFWNPPV (SEQ ID No: 3), KVFGSLAFV (SEQ ID No: 4), KLBPVQLWV (SEQ ID No: 5, with B indicating a-aminoisobutyric acid), SMPPPGTRV (SEQ ID No: 6), IMIGHLVGV (SEQ ID No: 7), KVAEIVHFL (SEQ ID No: 8), YLSGADLNL (SEQ ID No: 9), aKXVAAWTLKAAa (SEQ ID No: 10, with X and a
  • the IL-7 molecule is a wild-type human IL-7.
  • the IL-7 molecule is a variant having at least 80% amino acid sequence identity with wild type human IL-7.
  • the IL-7 molecule comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs : 11-30 and 35.
  • the IL-7 molecule or variant or fragment thereof is fused to an Fc domain, preferably by a peptide linker.
  • the patient is a HLA-A positive patient, preferably a HLA-A2 positive patient.
  • the cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colorectal cancer, oesophageal cancer, gastric cancer, gastrointestinal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, lymphoma, glioma, mesothelioma, melanoma, ovarian cancer, prostate cancer, urethral cancer and any combination of said cancers.
  • the cancer cells have a decreased expression of HLA class I molecules, preferably a decreased expression of HLA-A, HLA-B and/or HLA-C.
  • the cancer is resistant or non-responsive to the anti-cancer vaccine.
  • the cancer is resistant or non-responsive to the TAA epitope peptide vaccine specific for HLA class I.
  • the anti-cancer vaccine is a mRNA vaccine.
  • MHC Major Histocompatibility Complex
  • HLA human leukocyte antigen
  • HLA Human Leukocyte Antigen
  • MHC Major Histocompatibility Complex
  • treatment refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of the disease or of the symptoms of the disease. It designates both a curative treatment and/or a prophylactic treatment of a disease.
  • a curative treatment is defined as a treatment resulting in cure or a treatment alleviating, improving and/or eliminating, reducing and/or stabilizing a disease or the symptoms of a disease or the suffering that it causes directly or indirectly.
  • a prophylactic treatment comprises both a treatment resulting in the prevention of a disease and a treatment reducing and/or delaying the progression and/or the incidence of a disease or the risk of its occurrence. In certain embodiments, such a term refers to the improvement or eradication of a disease, a disorder, an infection or symptoms associated with it.
  • a or “an” can refer to one of or a plurality of the elements it modifies (e.g., “a reagent” can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elements is described.
  • the term “about” at the beginning of a string of values modifies each of the values (i.e., “about 1, 2 and 3” refers to about 1, about 2 and about 3). Further, when a listing of values is described herein (e.g., about 50%, 60%, 70%, 80%, 85% or 86%) the listing includes all intermediate and fractional values thereof (e.g., 54%, 85.4%).
  • the term “consist essentially of’ refers to those elements required for a given embodiment. This term indicates the inclusion of any recited characteristics and permits the optional presence of elements that do not materially affect nor change the characteristics or functions of said embodiment.
  • a vaccine composition it refers to a composition that comprises the recited elements (e.g., peptides), and optionally includes other elements that do not particular interfere with the structure or function of the peptide composition.
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an interleukin 7 (IL-7) molecule or a variant thereof, for use in combination with an anti-cancer vaccine.
  • IL-7 interleukin 7
  • the terms “combination”, “therapeutic combination”, “pharmaceutical combination”, “combination therapy” or “combined therapy” are used interchangeably and embrace administration of these agents (e.g., an anti-cancer vaccine as described herein and an IL- 7 molecule as described herein) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents in a substantially simultaneous manner. Sequential or substantially simultaneous administration of each agent can be affected by any appropriate route.
  • the anti-cancer vaccine and the IL-7 molecule or variant thereof can particularly be or to be administered sequentially, separately, simultaneously or substantially simultaneously.
  • the term “sequential” or “sequentially” means, unless otherwise specified, characterised by a regular sequence or order, e.g., if a dosage regimen includes the administration of the anti-cancer vaccine and the IL-7 molecule or variant thereof, a sequential dosage regimen could include administration of the anti-cancer vaccine before, simultaneously, substantially simultaneously, or after administration of the IL-7 molecule or variant thereof but both agents will be administered in a regular sequence or order.
  • the term “separate” means, unless otherwise specified, to keep apart one from the other.
  • the term “simultaneously” means, unless otherwise specified, happening or done at the same time, i.e., the agents of the invention are administered at the same time.
  • any combination as described herein may be used in any sequence for treating the disease described herein.
  • the combinations described herein may be selected on the basis of a number of factors, which include but are not limited to the effectiveness of inhibiting or preventing cancer progression, the effectiveness for mitigating the side effects of an agent of the combination, or the effectiveness of mitigating symptoms related to cancer.
  • a combined therapy described herein may reduce any of the side effects associated with each individual members of the combination.
  • the anti-cancer vaccine and the IL-7 molecule or variant thereof are administered or are to be administered separately and/or sequentially.
  • the combination of the invention is administered or to be administered sequentially, the anti-cancer vaccine being administered first or prior to the IL-7 molecule or variant thereof.
  • the combination of the invention is administered or to be administered sequentially, the IL-7 molecule or variant thereof being administered first or prior to the anti-cancer vaccine.
  • the anti-cancer vaccine and the IL-7 molecule or variant thereof defined herein are administered concomitantly.
  • concomitantly is used herein to refer to administration of the two agents (i.e., the anti-cancer vaccine and the IL-7 molecule or variant thereof), give in close enough temporal proximity where their individual therapeutic effects overlap in time.
  • the anti-cancer vaccine and the IL-7 molecule or variant thereof defined herein are administered independently at the same time or separately within time intervals that make it possible to increase the efficiency of the partners in combination on tumour cells/against cancer.
  • the efficiency of the combination is observed for decreasing the tumour size, which can be assessed by measuring the tumour volume (preferably in mm3), in particular after the administration of the combination to a patient suffering from a cancer.
  • the anti-cancer vaccine and the IL-7 molecule or variant thereof defined herein are administered independently at the same time or separately within time intervals that make it possible to increase Human Leukocyte Antigen (HLA) class I molecules presentation of tumour associated antigen (TAA) or fragment or epitope thereof by immune cells and/or tumour cells of a patient suffering from cancer.
  • HLA Human Leukocyte Antigen
  • TAA tumour associated antigen
  • the invention thus also concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an interleukin 7 (IL- 7) molecule or a variant thereof, for use to increase Human Leukocyte Antigen (HLA) class I molecules presentation of tumour associated antigen (TAA) or fragment or epitope thereof by immune cells and/or tumour cells of a patient suffering from cancer and treated or to be treated by an anti-cancer vaccine, preferably a TAA peptide vaccine.
  • IL- 7 interleukin 7
  • TAA tumour associated antigen
  • the invention concerns a method for increasing HLA class I expression in immune and/or tumour cells, wherein the method comprises the administration of an anti-cancer vaccine in combination with an interleukin 7 (IL-7) molecule or a variant thereof.
  • IL-7 interleukin 7
  • the invention concerns a method for increasing the effectiveness of HLA class I presentation of TAA or fragment or epitope thereof by immune and/or tumour cells, comprising contacting the tumour cells with an interleukin 7 (IL-7) molecule or a variant thereof in combination with an anti-cancer vaccine.
  • IL-7 interleukin 7
  • the HLA class I molecule expressed by the tumour/immune cells is selected from the group consisting of HLA- A, HLA-B, HLA-C and any combination thereof.
  • the uses and methods disclosed herein are particularly directed to the improvement of antigen presentation by immune cells, especially activated immune cells.
  • immune cell refers to cells that play a role in the immune response.
  • immune cells useful for the present disclosure are those cells that can play a role in the treatment and/or eradication of cancer (e.g., possess anti-tumour activity).
  • the immune cells comprise lymphocytes, neutrophils, monocytes, macrophages, dendritic cells, or any combination thereof.
  • the “lymphocytes” particularly comprise T cells, tumour-infiltrating lymphocytes (TIL), natural killer T (NKT) cells, or any combination thereof.
  • activated immune cells it is meant immune cells that are involved or have been activated during an immune response towards the presence of non-self cells such as cancer cells. Activated immune cells are particularly recruited in the localization wherein the inflammation, triggered by the presence of non-self cells, occurs.
  • the immune cells are lymphocytes, preferably T cells.
  • T cell or “T lymphocytes” as used herein includes CD4 + T cells, CD8 + T cells, T helper 1 type T cells, T helper 2 type T cells, T helper 17 type T cells, effector T cells, effector memory stem like T cells, Tumour Infiltrating Lymphocyte (TIL), anergic T cells and exhausted T cells.
  • TIL Tumour Infiltrating Lymphocyte
  • the T cell is an effector T cell, an exhausted T cell, a Tumour Infiltrating Lymphocyte (TIL) or an effector memory stem like T cell.
  • Activated T cell or “Activated T lymphocytes” are T cells activated by simultaneously receiving signal- 1 from T-cell recognition of antigen via the T cell receptor and signal-2 from costimulatory molecule. During the immune response, immune cells such as T cells become “activated” and undergo clonal expansion followed by differentiation into effector cells and induction of cell-mediated cytotoxicity and/or cytokine release.
  • One of the most common ways to measure immune cell activation in vitro is the assessment of T cell proliferation upon antigen- or TCR-mediated stimulation.
  • Antigen presentation or “presentation” is the expression of antigen molecules on the surface of immune cells and/or tumour cells in association with MHC class I or II.
  • increasing presentation or “stimulating presentation” refers to an increase of the amount of HLA class I molecules on the surface of immune and/or tumour cells and/or of the amount of antigens (e.g., the peptides of the anti-cancer vaccine) present on the cell surface.
  • the increase in antigen presentation corresponds to an increase of at least 10% of the amount of antigen (e.g., the peptides of the anti-cancer vaccine) expressed on the surface of tumour and/or immune cells in comparison of comparable cells in the absence of treatment.
  • the increase in antigen presentation is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, more preferably at least 100%, 125%, 150%, 250%, or 300%.
  • the increase in antigen presentation corresponds to an increase of the amount of TAA or fragment or epitope thereof specific for HLA class I expressed on the surface of tumour and/or immune cells in comparison of comparable cells in the absence of treatment.
  • the increase in antigen presentation corresponds to an increase of the amount of TAA peptides of the anti-cancer vaccine expressed by HLA class I molecules on the surface of tumour and/or immune cells in comparison of comparable cells in the absence of treatment.
  • the increase in antigen presentation corresponds to an increase of at least 10% of the amount of HLA class I molecules expressed on the surface of tumour and/or immune cells in comparison of comparable cells in the absence of treatment.
  • the increase in HLA class I expression is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, more preferably at least 100%, 125%, 150%, 250%, or 300%.
  • the increase in antigen presentation corresponds to an increase of at least 10% of the amount of HLA-A, HLA-B, HLA-C and any combination thereof expressed on the surface of tumour and/or immune cells.
  • HLA class I molecules and/or antigens can be detected by any methods known in the art, such as flow cytometry.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an interleukin 7 (IL-7) molecule or a variant thereof, for use in reversing, delaying or preventing immune suppression by cancer cells in the treatment of a patient suffering from cancer and treated by a tumour associated antigen (TAA) vaccine specific for HLA class I, preferably a TAA epitope peptide vaccine specific for HLA class I, by stimulating presentation of the TAA peptide in the vaccine to T cells, thereby activating the T cells and reversing, delaying or preventing immune suppression.
  • TAA tumour associated antigen
  • the invention concerns a method of reversing, delaying or preventing immune suppression by tumour cells, wherein the method comprises the steps of administering an interleukin 7 (IL-7) molecule or a variant thereof in combination with an anti-tumour associated antigen (TAA) vaccine, stimulating presentation of the tumour associated antigen in the cancer vaccine to immune cells, preferably T cells, thereby activating the immune cells, preferably T cells, and reversing, delaying or preventing immune suppression.
  • IL-7 interleukin 7
  • TAA anti-tumour associated antigen
  • reversing, delaying or preventing immune suppression refers to a mechanism that counteract cancer immune escape, especially the loss of cancer cell recognition by immune cells such as T cells.
  • the present invention also relates to a combination of i) a TAA epitope peptide vaccine specific for HLA class I and ii) an interleukin-7 (IL-7) molecule or a variant thereof, in particular for use in the treatment of cancer.
  • IL-7 interleukin-7
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an interleukin 7 (IL-7) molecule or a variant thereof, for use in combination with a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I, in the treatment of a patient suffering from cancer
  • the vaccine comprises the following peptides : RLLQETELV (SEQ ID No: 1), YLQLVFGIEV (SEQ ID No: 2), LLTFWNPPV (SEQ ID No: 3), KVFGSLAFV (SEQ ID No: 4), KLBPVQLWV (SEQ ID No: 5, with B indicating a-aminoisobutyric acid), SMPPPGTRV (SEQ ID No: 6), IMIGHLVGV (SEQ ID No: 7), KVAEIVHFL (SEQ ID No: 8), YLSGADLNL (SEQ ID No: 9), aKXVAAWTLKAAa (SEQ ID No: 10, with X and a respectively
  • the invention concerns a tumour associated antigen (TAA) epitope peptide vaccine comprising the peptides : RLLQETELV (SEQ ID No: 1), YLQLVFGIEV (SEQ ID No: 2), LLTFWNPPV (SEQ ID No: 3), KVFGSLAFV (SEQ ID No: 4), KLBPVQLWV (SEQ ID No: 5, with B indicating a-aminoisobutyric acid), SMPPPGTRV (SEQ ID No: 6), IMIGHLVGV (SEQ ID No: 7), KVAEIVHFL (SEQ ID No: 8), YLSGADLNL (SEQ ID No: 9), aKXVAAWTLKAAa (SEQ ID No: 10, with X and a respectively indicating cyclohexylalanine and d-alanine) for use in combination with a pharmaceutical composition comprising an interleukin 7 (IL-7) molecule or a variant thereof, in the treatment of a patient
  • the invention also provides a method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of an interleukin 7 (IL-7) molecule or a variant thereof, wherein the subject has received or will receive a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I comprising the following peptides : RLLQETELV (SEQ ID No: 1), YLQLVFGIEV (SEQ ID No: 2), LLTFWNPPV (SEQ ID No: 3), KVFGSLAFV (SEQ ID No: 4), KLBPVQLWV (SEQ ID No: 5, with B indicating a-aminoisobutyric acid), SMPPPGTRV (SEQ ID No: 6), IMIGHLVGV (SEQ ID No: 7), KVAEIVHFL (SEQ ID No: 8), YLSGADLNL (SEQ ID No: 9), aKXVAAWTLKAAa (SEQ ID No: 10, with
  • the invention also provides a method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I, wherein the vaccine comprises the following peptides : RLLQETELV (SEQ ID No: 1), YLQLVFGIEV (SEQ ID No: 2), LLTFWNPPV (SEQ ID No: 3), KVFGSLAFV (SEQ ID No: 4), KLBPVQLWV (SEQ ID No: 5, with B indicating a- aminoisobutyric acid), SMPPPGTRV (SEQ ID No: 6), IMIGHLVGV (SEQ ID No: 7), KVAEIVHFL (SEQ ID No: 8), YLSGADLNL (SEQ ID No: 9), aKXVAAWTLKAAa (SEQ ID No: 10, with X and a respectively indicating cyclohexylalanine and d-alanine).
  • the invention also provides a) a method for treating a cancer, said method comprising administering a pharmaceutical composition, combination or combined preparation of the invention to a patient suffering from cancer; b) the use of a pharmaceutical composition, kit, combination or combined preparation of the invention for the treatment of a cancer; c) the use of a pharmaceutical composition, kit, combination or combined preparation of the invention for the manufacture of a medicament for the treatment of a cancer; and/or d) a pharmaceutical composition, kit, combination or combined preparation of the invention for use in the treatment a cancer.
  • the invention also relates to :
  • an anti- cancer vaccine of the invention preferably a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I such as described herein;
  • TAA tumour associated antigen
  • a method of increasing the potentiality of response of a cancer vaccine against tumors cells comprising the administration of an IL7 compound inducing over expression of HLA by tumor cell and/or by myeloid immune cells to a patient that has been and/or will be treated by an anticancer vaccine of the invention, preferably a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I such as described herein;
  • TAA tumour associated antigen
  • T eff cytotoxic T lymphocytes
  • an anti-cancer vaccine of the invention preferably a tumour associated antigen (TAA) epitope peptide vaccine specific for HLA class I such as described herein.
  • TAA tumour associated antigen
  • the combination therapy disclosed herein comprises an interleukin 7, or a variant or fragment thereof, preferably a pharmaceutical composition comprising an interleukin 7, or a variant or fragment thereof.
  • the IL-7 protein is a human IL-7 or variants thereof.
  • the IL-7 or variant thereof has an amino acid sequence having at least 80% of identity with the wild type IL-7, especially with the protein of SEQ ID No: 11.
  • the combination of the invention comprises the typical wild-type IL-7 human protein of 152 amino acids (SEQ ID NO: 11).
  • the IL-7 protein is the protein of SEQ ID No: 11.
  • the IL-7 proteins can comprise its peptide signal or be devoid of it.
  • the combination of the invention comprises an IL-7 variant or mutant.
  • the IL-7 variant or mutant can comprise its peptide signal or be devoid of it.
  • interleukin-7 mutant refers to the terms “interleukin-7 mutant”, “mutated IL-7”, “IL-7 mutant”, “IL-7 variant”, “IL-7m” or IL- 7v” are used interchangeably herein.
  • a "variant” or “mutant” of an IL-7 protein is defined as an amino acid sequence that is altered by one or more amino acids.
  • the variant can have “conservative” modifications or “non-conservative” modifications. Such modifications can include amino acid substitution, deletions and/or insertions.
  • Guidance in determining which and how many amino acid residues may be substituted, inserted or deleted without abolishing biological properties can be found using computer programs well known in the art, for example software for molecular modelling or for producing alignments.
  • the variant IL-7 proteins included within the invention specifically include IL-7 proteins that retain substantially equivalent biological IL-7 property in comparison to a wild-type IL-7.
  • the variant IL-7 proteins included within the invention specifically include IL-7 proteins that do not retain substantially equivalent biological property (e.g., activity, binding capacity and/or structure) in comparison to a wild-type IL-7.
  • a variant of IL-7 also includes altered polypeptides sequence of IL-7 (e.g., oxidised, reduced, deaminated or truncated forms). Particularly, truncations or fragment of IL-7 which retain comparable biological property as the full-length IL-7 protein are included within the scope of the invention.
  • the interleukin 7 is any biological active fragment thereof.
  • Variants of IL-7 include, more preferably, natural allelic variants resulting from natural polymorphism, including SNPs, splicing variants, etc.
  • the IL-7 variant or fragment has an agonist activity on the interleukin 7 receptor.
  • the biological activity of IL-7 protein can be measured using in vitro cellular proliferation assays.
  • the IL-7 variants according to the invention maintain biological activity of at least 1%, 5%, 10 %, 20%, 30%, 40%, 50%, 60% in comparison with the wild type human IL-7, preferably at least 80%, 90%, 95% and even more preferably 99% in comparison with the wild type IL-7.
  • the agonist activity of IL-7 on IL-7R can be measured by any technique known to the man skilled in the art.
  • the IL-7 variants or fragments according to the invention maintain the agonist activity of at least 1%, 5%, 10 %, 20%, 30%, 40%, 50%, 60% in comparison with the wild type human IL-7, preferably at least 80%, 90%, 95% and even more preferably 99% in comparison with the wild type IL-7.
  • Variant IL-7 proteins also include polypeptides that have at least about 65%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, 99%, or more sequence identity with wild-type IL-7, especially with the protein of SEQ ID No: 11.
  • Preferred IL-7 according to the invention are human IL-7 polypeptides comprising or consisting of an amino acid sequence as described in SEQ ID No: 11, EP 314415 or in W02004/018681 A2, as well as any natural variants and homologs thereof.
  • the IL-7 polypeptide used in the present invention is a recombinant IL-7.
  • the term "recombinant”, as used herein, means that the polypeptide is obtained or derived from a recombinant expression system, i.e., from a culture of host cells (e.g., microbial or insect or plant or mammalian) or from transgenic plants or animals engineered to contain a nucleic acid molecule encoding an IL-7 polypeptide.
  • the recombinant IL-7 is a human recombinant IL-7,, (e.g., a human IL-7 produced in recombinant expression system).
  • the invention also provides IL-7 molecules that have an enhanced biological activity compared to wild-type IL-7 proteins.
  • IL-7 proteins having the disulfide bonding pattern of Cys2-Cys92, Cys34-Cysl29 and Cys47-141 are more active in vivo than a wild-type recombinant IL-7 protein.
  • Hyperglycosylation of IL-7 such as described in EP1904635 also improve IL-7 biological activity such as IL-7 proteins where Asnl l6 is nonglycosylated but Asn70 and Asn91 are glycosylated.
  • the invention provides IL-7 molecules that have a reduced immunogenicity compared to wild-type IL-7 proteins, particularly by the removing T-cell epitopes within IL-7 that may stimulate to an immune response. Examples of such IL-7 are described in WO 2006061219.
  • the IL-7 variant or mutant does not retain substantially equivalent biological property (e.g., activity, binding capacity and/or structure) in comparison to a wild-type IL-7.
  • the IL-7 mutant or variant comprises at least one mutation.
  • the at least one mutation decreases the affinity of IL-7 variant or mutant to IL-7 receptor (IL-7R) but does not lead to the loss of the recognition of IL-7R.
  • the IL-7 mutant or variant retains a capacity to activate IL-7R, for instance as measured by the pStat5 signal, for example such as disclosed in Bitar et al., Front. Immunol., 2019, volume 10).
  • the biological activity of IL-7 protein can be measured using in vitro cellular proliferation assays or by measuring the P-Stat5 into the T cells by ELISA or FACS.
  • the IL-7 variants according to the invention has reduced biological properties (e.g., activity, binding capacity and/or structure) by at least a factor 2, 5, 10, 20, 30, 40, 50, 100, 250, 500, 750,1000, 2500 or 5000in comparison with the wild type IL-7, preferably the wth-IL7. More preferably, the IL-7 variants have a reduced binding to the IL-7 receptor but retains a capacity to activate IL-7R.
  • the binding to the IL-7 receptor can be reduced by at least 1%, 5%, 10 %, 20%, 30%, 40%, 50%, 60% in comparison with the wild type IL-7, and retains a capacity to activate IL-7R by at least 90%, 80%, 70%, 60%, 50%, 40%, 30% or 20% in comparison with the wild type IL-7.
  • the IL-7 variant or fragment envision herein particularly has the capacity of increasing HLA class I expression, especially HLA-A, HLA-B, and/or HLA-C.
  • the IL-7 variant or fragment envision herein particularly has the capacity of increasing antigen presentation by HLA class I expression, especially HLA-A, HLA-B, and/or HLA-C.
  • the IL-7 variant or mutant differs from wt-IL-7 by at least one amino acid mutation which i) reduces affinity of the IL-7 variant for IL-7 receptor (IL-7R) in comparison to the affinity of wt-IL-7 for IL-7R, and ii) improves pharmacokinetics of the IL7 variant in comparison to the wt-IL7. More particularly, the IL-7 variant or mutant further retains the capacity to activate IL- 7R, in particular through the pStat5 signalling.
  • IL-7R IL-7 receptor
  • the binding of the IL-7 variant or mutant to the IL-7 receptor can be reduced by at least 10 %, 20%, 30%, 40%, 50%, 60% in comparison with the wild type IL-7, and retains a capacity to activate IL-7R by at least 90%, 80%, 70%, 60%, 50%, 40%, 30% or 20% in comparison with the wild type IL-7.
  • the IL-7 variant or mutant presents a reduced affinity for IL-7 receptor (IL- 7R) in comparison to the affinity of wth-IL-7 for IL-7R.
  • the IL-7 variant or mutant presents a reduced affinity for CD 127 and/or CD 132 in comparison to the affinity of wth-IL-7 for CD127 and/or CD132, respectively.
  • the IL-7 variant or mutant presents a reduced affinity for CD127 in comparison to the affinity of wth-IL-7 for CD127.
  • the at least one amino acid mutation decreases the affinity of IL-7 variant or mutant for IL-7R, in particular CD132 or CD127, by at least a factor 10, 100, 1000, 10 000 or 100 000 in comparison to the affinity of wt-IL-7 for IL-7R.
  • affinity comparison may be performed by any methods known by the skilled of the art, such as ELISA or Biacore.
  • the at least one amino acid mutation decreases affinity of IL-7 variant or mutant for IL-7R but do not decrease the biological activity of IL-7 variant or mutant in comparison to IL-7 wt, in particular as measured by pStat5 signal.
  • the at least one amino acid mutation decreases affinity of IL-7 variant or mutant for IL-7R but do not decrease significatively the biological activity of IL-7m in comparison to IL-7 wt, in particular as measured by pStat5 signal.
  • the IL-7 variant or mutant improves pharmacokinetics in comparison to a wild type IL-7.
  • the IL-7 variant or mutant according to the invention improves pharmacokinetics by at least a factor 10, 100 or 1000 in comparison wth-IL-7.
  • Pharmacokinetics profile comparison may be performed by any methods known by the skilled of the art, such as in vivo injection of the drug and dosage ELISA of the drug in the sera at multiple time point.
  • Pharmacokinetics and “PK” are used interchangeably and refer to the fate of compounds, substances or drugs administered to a living organism.
  • Pharmacokinetics particularly comprise the ADME or LADME scheme, which stands for Liberation (i.e., the release of a substance from a composition), Absorption (i.e., the entrance of the substance in blood circulation), Distribution (i.e., dispersion or dissemination of the substance trough the body) Metabolism (i.e., transformation or degradation of the substance) and Excretion (i.e., the removal or clearance of the substance from the organism).
  • the two phases of metabolism and excretion can also be grouped together under the title elimination.
  • pharmacokinetics parameters can be monitored by the man skilled in the art, such as elimination half-life, elimination constant rate, clearance (i.e., the volume of plasma cleared of the drug per unit time), Cmax (Maximum serum concentration), and Drug exposure (determined by Area under the curve) (Scheff et al, Pharm Res., 2011, 28, 1081-9).
  • the improvement of the pharmacokinetics by the use of IL-7 variant or mutant refers to the improvement of at least one of the above-mentioned parameters.
  • it refers to the improvement of the elimination half-life of the IL-7 molecule, i.e., the increase of half-life duration, or of Cmax.
  • the at least one mutation of IL-7 variant or mutant improves the elimination half-life of the IL-7 variant or mutant in comparison to IL-7 wt.
  • the IL-7 variant or mutant presents at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% of identity with the wild-type human IL-7 (wth-IL-7) protein of 152 amino acids, such as disclosed in SEQ ID NO: 11.
  • the IL-7 variant or mutant presents at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99% of identity with SEQ ID No: 11.
  • the at least one mutation occurs at amino acid position 74 and/or 142 of IL-7. Additionally, or alternatively, the least one mutation occurs at amino acid positions 2 and 141, 34 and 129, and/or 47 and 92. These positions refer to the position of amino acids set forth in SEQ ID NO: 11.
  • the at least one mutation is an amino acid substitution or a group of amino acid substitutions is selected from the group consisting of C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, C47S-C92S and C34S-C129S, W142A, W142H, W142F, W142Y, QI IE, Y12F, M17L, Q22E, K81R, D74E, D74Q and D74N or any combination thereof.
  • These mutations refer to the position of amino acid set forth in SEQ ID NO: 11.
  • the mutation W142H stands for the substitution of tryptophan of the wth-IL7 into a histidine, to obtain an IL- 7m having a histidine in amino acid position 142.
  • Such mutant is for example described under SEQ ID No: 15.
  • the IL-7 variant or mutant comprises sets of substitutions in order to disrupt disulfide bonds between C2 and C141, C47 and C92, and C34-C129.
  • the IL-7 variant or mutant comprises two sets of substitutions in order to disrupt disulfide bonds between C2 and C141, and C47 and C92; C2 and C141, and C34-C129; or C47 and C92, and C34-C129.
  • the cysteine residues can be substituted by serine in order to prevent disulfide bonds formation.
  • the amino acid substitutions can be selected from the group consisting of C2S-C141S and C47S-C92S (referred as “SS2”), C2S-C141S and C34S-C129S (referred as “SSI”), and C47S-C92S and C34S-C129S (referred as “SS3”).
  • SS2 C2S-C141S and C47S-C92S
  • SSI C2S-C141S and C34S-C129S
  • SS3 C47S-C92S and C34S-C129S
  • These mutations refer to the position of amino acids set forth in SEQ ID NO: 11.
  • Such IL-7 variants or mutants are particularly described under the sequence set forth in SEQ ID Nos : 12 to 14 (SSI, SS2 and SS3, respectively).
  • the IL-7 variant or mutant comprises the amino acids substitutions C2S-C141S and C47S-C92S.
  • the IL-7 variant or mutant comprises at least one mutation selected from the group consisting of W142A, W142H, W142F, and W142Y, preferably W142H, W142F, and W142Y.
  • W142A, W142H, W142F, and W142Y are particularly described in under the sequence set forth in SEQ ID NOs: 15 to 17 and 35, respectively.
  • the IL-7 variant or mutant comprises the mutation W142H.
  • the IL-7 variant or mutant presents the sequence set forth in SEQ ID NO: 15.
  • the IL-7 variant or mutant comprises at least one mutation selected from the group consisting of QI IE, Y 12F, M17L, Q22E, these mutations refer to the position of amino acids set forth in SEQ ID NO: 11.
  • Such IL-7 variant or mutant are particularly described in under the sequence set forth in SEQ ID NOs: 18-21, respectively.
  • the IL-7 variant or mutant comprises at least one mutation selected from the group consisting of K81R, K81E, G85K, G85E, K81+G85K and K81E+G85E. These mutations refer to the position of amino acids set forth in SEQ ID NO: 11. Such IL-7 variant or mutant are particularly described in under the sequence set forth in SEQ ID NOs: 22, 23, 24, 25, 26 and 27, respectively. In other embodiments, the IL-7 variant or mutant comprises at least one mutation selected from the group consisting of D74E, D74Q and D74N, preferably D74E and D74Q. Such IL-7 variant or mutant are particularly described in under the sequence set forth in SEQ ID NOs: 28-30, respectively. Preferably, the IL-7 variant or mutant comprises the mutation D74E. Even more preferably, the IL-7 variant or mutant presents the sequence set forth in SEQ ID NO: 28.
  • the IL-7 variant or mutant comprises at least one mutation that consists in i) W142A, W142H, W142F or W142Y, preferably W142H and/or ii) D74E, D74Q or D74N, preferably D74E or D74Q, iii) C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, or C47S-C92S and C34S-C129S, and/or iv) K81R, K81E, G85K, G85E, K81+G85K and K81E+G85E.
  • the IL-7 variant or mutant comprises the W142H substitution and at least one mutation selected from the group consisting of i) D74E, D74Q or D74N, preferably D74E and/or ii) C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, or C47S-C92S and C34S-C129S, and iii) K81R, K81E, G85K, G85E, K81+G85K or K81E+G85E.
  • the IL-7 variant or mutant comprises i) D74E and W142H substitutions and one or more mutation selected from the group consisting of C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, C47S-C92S and C34S-C129S, K81R, K81E, G85K, G85E, K81+G85K and K81E+G85E.
  • the combination according to the invention comprises an IL-7 variant that comprises or consists of the amino acid sequence set forth in SEQ ID NO: 11-30 and 35. Even more preferably, the combination of the invention comprises an IL-7 variant that comprises or consists of the amino acid sequence set forth in SEQ ID NO 15-17, preferably SEQ ID NO: 15.
  • the IL-7 molecule is a fragment of IL-7, preferably a fragment of IL-7wt or of a variant thereof.
  • the fragment has a length of at least 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130 or 140 amino acids.
  • the IL-7 molecule or variant thereof is fused to an Fc domain, preferably by a peptide linker.
  • the IL-7 molecule or variant thereof is fused by its N-terminal end to the C-terminal end of the Fc domain, preferably by a peptide linker.
  • the IL-7 molecule or variant or fragment thereof is fused by its the N-terminal end to each of the heavy chain of the Fc domain, preferably by a peptide linker.
  • the IL-7 molecule or variant or fragment thereof is fused by its the N-terminal end to only one of the heavy chain of the Fc domain, preferably by a peptide linker.
  • the IL-7 molecule or variant or fragment thereof is fused by its C-terminal end to the N-terminal end of the Fc domain, preferably by a peptide linker.
  • an Fc region refers to the C-terminal region of the heavy chain of an antibody that mediates the binding of the immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells) or to the first component (Clq) of the classical complement system.
  • an Fc region comprises the constant region of an antibody excluding the first constant region immunoglobulin domain (e.g., CHI or CL).
  • the Fc region comprises two identical protein fragments, derived from the second (CH2) and third (CH3) constant domains of the antibody's two heavy chains; IgM and IgE Fc regions comprise three heavy chain constant domains (CH domains 2-4) in each polypeptide chain.
  • the Fc region comprises immunoglobulin domains CH2 and CH3 and the hinge between CHI and CH2 domains.
  • the human IgG heavy chain Fc region is defined to stretch from an amino acid residue D221 for IgGl, V222 for IgG2, L221 for IgG3 and P224 for IgG4 to the carboxy -terminus of the heavy chain, wherein the numbering is according to the EU index as in Kabat.
  • the CH2 domain of a human IgG Fc region extends from amino acid 237 to amino acid 340, and the CH3 domain is positioned on C-terminal side of a CH2 domain in an Fc region, it extends from amino acid 341 to amino acid 447 or 446 (if the C-terminal lysine residue is absent) or 445 (if the C- terminal glycine and lysine residues are absent) of an IgG.
  • the Fc region can be a native sequence Fc, including any allotypic variant, or a variant Fc (e.g., a non-naturally occurring Fc).
  • the Fc domain of the invention is devoid of antigen binding regions (i.e., VH and VL).
  • the Fc domain is derived from a human immunoglobulin heavy chain, for example, IgGl, IgG2, IgG3, IgG4, or other classes.
  • the Fc domain is a IgGl or IgG4 Fc domain.
  • the Fc domain is a human IgGl heavy chain constant domain or an IgGl Fc domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F;
  • substitution or combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P331S; E333A;
  • L234A/L235A N297A + M252Y/S254T/T256E; K322A and K444A, preferably selected from the group consisting of N297A optionally in combination with M252Y/S254T/T256E, and L234A/L235A.
  • the Fc domain is a human IgG4 heavy chain constant domain or a human IgG4 Fc domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P; L234A/L235A; L234A/L235A/P329G, P329G, S228P +
  • the Fc domain comprises a hinge region.
  • the hinge region can be derived from an immunoglobulin heavy chain, e.g., IgGl, IgG2, IgG3, IgG4, or other classes.
  • the hinge region is derived from human IgGl, IgG2, IgG3, IgG4, or other suitable classes.
  • the IgGl hinge region has three cysteines, two of which are involved in disulfide bonds between the two heavy chains of the immunoglobulin. These same cysteines permit efficient and consistent disulfide bonding formation between Fc portions. Therefore, a preferred hinge region of the present invention is derived from IgGl, more preferably from human IgGl.
  • the constant region contains a mutation that reduces affinity for an Fc receptor or reduces Fc effector function.
  • the constant region can contain a mutation that eliminates the glycosylation site within the constant region of an IgG heavy chain.
  • the peptide linker sequence may be a naturally occurring sequence or a non-naturally occurring sequence. If used for therapeutic purposes, the peptide linker is preferably non-immunogenic in the subject to which the IL-7 molecule is administered.
  • One useful group of peptide linker sequences are derived from the hinge region of heavy chain antibodies as described in WO 96/34103 and WO 94/04678. Other examples are poly-alanine sequences.
  • peptide linker sequences are Gly/Ser linkers of different length including (Gly4Ser)3 (SEQ ID NO: 31), (Gly4Ser)4 (SEQ ID NO: 32), (Gly4Ser)2 (SEQ ID NO: 33), Gly4Ser, Gly3Ser, Gly3, Gly2Ser and (Gly3Ser2)3 (SEQ ID NO: 34).
  • the invention also envisions any agonist of interleukin 7 receptor (IL-7R). Therefore, in any of the embodiments described herein, the IL-7 molecule or fragment or variant thereof can be replaced by an agonist of interleukin 7 receptor.
  • IL-7R interleukin 7 receptor
  • agonist refers to a substance that activates the functionality of an activating receptor such as IL-7R. Particularly, this term refers to a small molecule or peptide that binds to a cellular activating receptor as a reference substance, and have at least partially the same effect of the biologically natural ligand, such as IL-7 (e.g. inducing the activator effect of the receptor).
  • the IL-R agonist is a small molecule.
  • Small molecules refer in particular to small organic molecules with a molecular mass inferior to 1000 Da.
  • Small molecules and other drug candidates can readily be obtained, for example, from combinatorial and natural product libraries and using methods known to the art, or screening methods for their IL-7R agonizing activity.
  • Synthetic compound libraries are commercially available from a number of companies. Combinatorial libraries are available or can be prepared according to known synthetic techniques. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available from e.g.. or are readily producible by methods well known in the art.
  • the agonist of interleukin 7 receptor is a peptide.
  • Such peptide preferably has a length comprised between 40 and 150 amino acids, between 40 and 100 amino acids or between 40 and 50 amino acids.
  • Random peptide libraries consisting of all possible combinations of amino acids, attached to a solid phase or in solution, may also be used to identify peptides that act as agonists of IL-7R.
  • the agonist of interleukin 7 receptor is a peptide agonist such as described in Dower et al., 2023, https://doi.org/10.1101/2023.05.24.542196, the disclosure of which being incorporated herein by reference.
  • the peptide is MDK1472.
  • the agonist of IL-7R is a peptide having an amino acid sequence as set forth in SEQ ID NO: 36.
  • the peptide agonist of IL-7R is linked to a Fc domain, such as MDK-703.
  • the agonist of IL-7R is a peptide having an amino acid sequence as set forth in SEQ ID NO: 36 and conjugated/linked to a Fc domain such as disclosed herein.
  • the peptide agonist of IL-7R is fused by its N- terminal to the C-terminal of each heavy chain of the Fc domain, , preferably by a peptide linker.
  • the peptide agonist of IL-7R is fused by its N-terminal to the C-terminal of only one heavy chain of the Fc domain, preferably by a peptide linker.
  • anti-cancer vaccine refers to an agent that is capable of inducing an immune in a subject upon administration, in particular against cancer, and preferably T cell response to the antigen(s) delivered.
  • the vaccine can include various other components such as a carrier or other stimulatory molecules.
  • the vaccines can be DNA-based vaccines and/or RNA- based vaccines, peptide-based vaccines, or protein-based vaccines encoded in various viral/bacterial vectors or cells.
  • the vaccine is a "preventive" vaccine, which is administered to a subject not afflicted with cancer. Such vaccines are also referred to herein as "prophylactic" vaccines.
  • the vaccine is a therapeutic vaccine.
  • therapeutic vaccine refers to a vaccine that is administered to a subject to treat cancer.
  • Cancer vaccines mainly use tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) to activate the patient's immune system.
  • TAAs tumour-associated antigens
  • TSAs tumour-specific antigens
  • the anti-cancer vaccine is a tumour associated antigen vaccine.
  • tumor associated antigen denotes a protein or peptide or other molecule capable of inducing an immune response to a tumour. This can include, but is not limited to, PSMA peptides, MAGE peptides (Sahin, 1997; Wang, 1999), Papilloma virus peptides (E6 and E7), NY ESO-1 or other similar antigens, and any epitope or fragment thereof.
  • the TAA cancer vaccine can be best achieved with optimised epitopes targeting multiple Tumour Associated Antigens (TAAs) as a multi-epitopes combination targeting at least 2, 3, 4, 5 or 6 tumour antigens and based on epitopes combination.
  • TAAs Tumour Associated Antigens
  • An "epitope” is the collective features of a molecule, such as primary, secondary and tertiary peptide structure, and charge, that together form a site recognised by an immunoglobulin, T cell receptor or HLA molecule.
  • an epitope can be defined as a set of amino acid residues which is involved in recognition by a particular immunoglobulin, or in the context of T cells, those residues necessary for recognition by T cell receptor proteins and/or Major Histocompatibility Complex (MHC) receptors.
  • Epitopes are present in nature, and can be isolated, purified or otherwise prepared or derived by humans.
  • epitopes can be prepared by isolation from a natural source, or they can be synthesised in accordance with standard protocols in the art. Throughout this disclosure, epitopes may be referred in some cases as peptides or peptide epitopes.
  • the anti-cancer vaccine is a tumour associated antigen (TAA) vaccine specific for HLA class I, preferably HLA-A, HLA-B and/or HLA-C, even more preferably HLA-A.
  • TAA tumour associated antigen
  • TAA tumour associated antigen
  • Tumour antigens processed and presented by human leukocyte antigen (HLA) Class I alleles are important targets in tumour immunotherapies.
  • Clinical trials showed that presence of CD8+ T cells specific to tumour associated antigens (TAAs) and tumour neoantigens is one of the main factors resulting in tumour regression (Hu et al., PLoS One. 2020 Feb 27;15(2):e0229327. doi: 10.1371/joumal. pone.0229327. PMID: 32106223; PMCID: PMC7046239.)
  • the anti-cancer vaccine is a nucleotide or peptide vaccine.
  • the anticancer vaccine is a peptide vaccine.
  • peptide vaccine refers to a vaccine comprising peptides that mimic the epitopes of the antigen that triggers direct or potent immune responses.
  • the anti-cancer vaccine is a TAA epitope peptide vaccine specific for HLA class I.
  • a " epitope peptide specific for HLA class I” is a peptide that comprises an allele-specific motif or supermotif such that the peptide will bind an HLA class I molecule and induce a CTL and/or HTL response.
  • peptide epitopes of the invention are capable of binding to an appropriate HLA-class I molecule (e.g., HLA-A2) and thereafter inducing a cytotoxic T lymphocyte (CTL) response, or a helper T lymphocyte (HTL) response, to the peptide.
  • CTL cytotoxic T lymphocyte
  • HTL helper T lymphocyte
  • the peptides of the cancer vaccine are synthetic peptides.
  • Synthetic peptide refers to a peptide that is obtained from a non-natural source, e.g., is man-made. Such peptides may be produced using such methods as chemical synthesis or recombinant DNA technology.
  • the peptide cancer vaccine comprises at least 5 epitopes.
  • the combination of epitopes comprises at least 5 epitopes chosen among those disclosed in Table 6 of the US application US2014/01474790 (incorporated herein by reference).
  • the peptide cancer vaccine comprises at least 5 epitopes allowing to target the combination of the following 5 tumour antigens: HER2/neu, CEA, MAGE2, MAGE3 and p53.
  • the peptide vaccine may comprise at least 3, 4, 5, 6, 7, 8 or 9 epitopes chosen among those disclosed in Table 6 of the US application US2014/01474790.
  • the anti-cancer vaccine comprises or consists essentially of one or more of the peptides of OSE-2101 vaccine.
  • the anti-cancer vaccine is OSE-2101.
  • the present invention particularly relates to a new therapy of cancer based on the combination of OSE-2101 peptide vaccine and interleukin 7 and a variant thereof.
  • OSE-2101 vaccine is made by wild-type epitopes and modified epitopes (heteroclitic and fixed anchors epitopes). More detailed information on heteroclitic and fixed anchors epitopes can be found for instance in the patent EP 1620456. OSE-2101 vaccine is more particularly described in W02004/094454, WO2009/143843 and WO2016/070928, which are incorporated herein by reference in their entirety.
  • OSE-2101 is a multi-epitope T specific cancer vaccine composed of 10 synthetic peptides.
  • Nine of the peptides have been designed to induce a CTL response against TAAs.
  • the T specific immune therapy is designed for administration to patients for the induction of CTL directed against carcinoembryonic antigen (CEA), p53, human epidermal receptor-2/neurological (HER-2/neu) and melanoma antigen 2 and 3 (MAGE-2 and MAGE-3).
  • CEA carcinoembryonic antigen
  • HER-2/neu human epidermal receptor-2/neurological
  • MAGE-2 and MAGE-3 melanoma antigen 2 and 3
  • Each CTL epitope is restricted by HLA-A2 superfamily of major histocompatibility complex class I molecules, thereby providing coverage of approximately 45 % of the general population.
  • the tenth synthetic peptide is the pan-DR epitope (PADRE), a rationally designed helper T-lymphocyte (HTL) epitope included only to increase the magnitude of CTL responses.
  • PADRE pan-DR epitope
  • HTL helper T-lymphocyte
  • a "PanDR peptide” or “PADRE®” peptide is a member of a family of molecules that binds more than one HLA class II molecule.
  • the pattern that defines the PADRE® family of molecules can be referred to as an HLA Class II supermotif.
  • a PADRE® molecule binds to HLA class II molecules and stimulates in vitro and in vivo human HTL responses. PADRE peptides are described in the patent EP735893, WO 95/07707, and WO 97/26784.
  • OSE-2101 particularly comprises or consists of the peptides of Table 1.
  • B a-aminoisobutyric acid
  • a d-alanine
  • X cyclohexylalanine
  • SEQ ID NO: 5 is also described as KLXPVQLWV with X indicating a- aminoisobutyric acid.
  • SEQ ID NO: 10 is also described as XKXVAAWTLKAAX with X in position 1 and 13 indicating d-alanine and X in position 3 indicating cyclohexylalanine.
  • the anti-cancer vaccine according to the invention comprises the peptide aKXVAAWTLKAAa (SEQ ID No 10, with X and a respectively indicating cyclohexylalanine and d-alanine) and at least 4, 5, 6, 7, 8 or 9 peptides selected from the group consisting of RLLQETELV (SEQ ID No 1), YLQLVFGIEV (SEQ ID No 2), LLTFWNPPV (SEQ ID No 3), KVFGSLAFV (SEQ ID No 4), KLBPVQLWV (SEQ ID No 5, with B indicating a- aminoisobutyric acid), SMPPPGTRV (SEQ ID No 6), IMIGHLVGV (SEQ ID No 7), KVAEIVHFL (SEQ ID No 8), and YLSGADLNL (SEQ ID No 9).
  • RLLQETELV SEQ ID No 1
  • YLQLVFGIEV SEQ ID No 2
  • LLTFWNPPV SEQ ID No 3
  • the anti-cancer vaccine according to the invention comprises or consists essentially of the peptides RLLQETELV (SEQ ID No 1), YLQLVFGIEV (SEQ ID No 2), LLTFWNPPV (SEQ ID No 3), KVFGSLAFV (SEQ ID No 4), KLBPVQLWV (SEQ ID No 5, with B indicating a- aminoisobutyric acid), SMPPPGTRV (SEQ ID No 6), IMIGHLVGV (SEQ ID No 7), KVAEIVHFL (SEQ ID No 8), YLSGADLNL (SEQ ID No 9) and aKXVAAWTLKAAa (SEQ ID No 10, with X and a respectively indicating cyclohexylalanine and d-alanine).
  • RLLQETELV SEQ ID No 1
  • YLQLVFGIEV SEQ ID No 2
  • LLTFWNPPV SEQ ID No 3
  • KVFGSLAFV SEQ ID No 4
  • Peptides in accordance with the invention can be prepared synthetically, by recombinant DNA technology or chemical synthesis, Epitopes may be synthesised individually or joined directly or indirectly in a peptide.
  • the peptide will preferably be substantially free of other naturally occurring host cell proteins and fragments thereof, in some embodiments the peptides may be synthetically conjugated to be joined to native fragments or particles.
  • the peptides can be synthesised using standard Boc or Fmoc chemistry for solid phase peptide synthesis starting with the appropriate resin, and purified by standard methods.
  • the peptide may be produced by genetic engineering with recombinant cells or by RNA, for instance by in vitro translation system.
  • Peptides may comprise carriers such as those well known in the art, e.g., thyroglobulin, albumins such as human serum albumin, tetanus toxoid, polyamino acid residues such as poly L-lysine, poly L-glutamic acid, influenza virus proteins, hepatitis B virus core protein, and the like.
  • carriers such as those well known in the art, e.g., thyroglobulin, albumins such as human serum albumin, tetanus toxoid, polyamino acid residues such as poly L-lysine, poly L-glutamic acid, influenza virus proteins, hepatitis B virus core protein, and the like.
  • the peptide may be modified by terminal -NH2 acylation, e.g., by alkanoyl (C1-C20) or thioglycolyl acetylation, terminal-carboxyl amidation, e.g., ammonia, methylamine, etc. In some instances these modifications may provide sites for linking to a support or other molecule.
  • the peptides in accordance with the invention can contain modifications such as but not limited to glycosylation, side chain oxidation, biotinylation, phosphorylation, addition of a surface active material, e.g. a lipid, or can be chemically modified, e.g., acetylation, etc.
  • bonds in the peptide can be other than peptide bonds, e.g, covalent bonds, ester or ether bonds, disulfide bonds, hydrogen bonds, ionic bonds, etc.
  • Peptides in accordance with the invention can be prepared synthetically, by recombinant DNA technology or chemical synthesis, or can be isolated from natural sources such as native tumours or pathogenic organisms. Epitopes may be synthesised individually or joined directly or indirectly in a peptide. Although the peptide will preferably be substantially free of other naturally occurring host cell proteins and fragments thereof, in some embodiments the peptides may be synthetically conjugated to be joined to native fragments or particles.
  • the peptides of the invention can be prepared in a wide variety of ways, for example such as described in W02004094454.
  • the peptides can be synthesised in solution or on a solid support in accordance with conventional techniques.
  • Various automatic synthesizers are commercially available and can be used in accordance with known protocols. (See, for example, Stewart & Young, SOLID PHASE PEPTIDE SYNTHESIS, 2D. ED., Pierce Chemical Co., 1984).
  • individual peptides can be joined using chemical ligation to produce larger peptides that are still within the bounds of the invention.
  • recombinant DNA technology can be employed wherein a nucleotide sequence which encodes a peptide inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression.
  • the anticancer vaccine is a nucleotide vaccine, preferably a TAA nucleotide vaccine specific for HLA class I, such as HLA-A, B or C.
  • nucleotide vaccine As used herein, the terms “nucleotide vaccine,” “nucleic acid vaccine,” “nucleic acid-based vaccine,” and “genetic vaccine” can be used interchangeably and refer to a vaccine in which the antigenic component comprises a nucleic acid.
  • Such vaccines are capable of delivering genetic materials encoding the antigen of interest (e.g., tumour antigen) into host cells, which subsequently produce the antigen and thereby, initiate an immune response that is capable of protecting the host against the disease or disorder from which the antigen was derived (e.g., cancer).
  • a nucleotide vaccine comprises both DNA vaccine and RNA (e.g., mRNA) vaccine.
  • a nucleotide vaccine is a DNA vaccine (i.e., the antigenic component is a DNA sequence).
  • a nucleotide vaccine is a RNA (mRNA) vaccine (i.e., the antigenic component is a RNA sequence).
  • the nucleotide molecules of the cancer vaccine encodes for TAA or fragment or epitopes thereof specific for HLA class I presentation.
  • Vaccines comprising nucleotides or polynucleotides encoding each of the peptides of OSE 2101, in particular such as described above are also part of the invention.
  • the cancer vaccine is a mRNA vaccine encoding the amino acid sequences of SEQ ID NO: 1 to 10.
  • cancer vaccine comprises one or more mRNA molecules, each encoding a different peptide of the OSE-2101 vaccine.
  • the cancer vaccine may particularly comprise a single mRNA molecule that encodes for all the OSE2101 peptides.
  • nucleotide molecules or polynucleotides encoding peptides contemplated herein can be synthesised by chemical techniques, for example, the phosphotriester method of Matteucci, et al., J. Am. Chem. Soc. 103:3185 (1981).
  • Polynucleotides encoding peptides comprising or consisting of an analogue can be made simply by substituting the appropriate and desired nucleic acid base(s) for those that encode the native epitope.
  • the polynucleotide may be produced by assembling oligonucleotides that encode the plus and minus strands of the polynucleotide. Overlapping oligonucleotides (15-100 bases long) may be synthesised, phosphorylated, purified and annealed under appropriate conditions using well known techniques. The ends of the oligonucleotides can be joined, for example, using T4 DNA ligase.
  • a polynucleotide, e.g. minigene, encoding the peptide(s) of the invention, can be cloned into a desired vector such as an expression vector. The coding sequence can then be provided with appropriate linkers and ligated into expression vectors commonly available in the art, and the vectors used to transform suitable hosts to produce the desired peptide such as a fusion protein.
  • sequences that can be included in a minigene include: HLA class I epitopes, HLA class II epitopes, a ubiquitination signal sequence, and/or a targeting sequence such as an endoplasmic reticulum (ER) signal sequence to facilitate movement of the resulting peptide into the endoplasmic reticulum.
  • ER endoplasmic reticulum
  • multi-epitope minigenes is also described in, e.g., copending applications U.S.S.N. 09/311,784, 09/894,018, 60/419,973, 60/415,463; Ishioka et al., J. Immunol. 162:3915-3925, 1999; An, L. and Whitton, J. L., J.
  • the pharmaceutical composition comprising an IL-7 molecule or a variant thereof and/or the anticancer vaccine may comprise a pharmaceutically acceptable carrier or excipient. More preferably, the pharmaceutically acceptable carrier is an aqueous carrier, especially a buffer.
  • a pharmaceutically acceptable form is employed which does not adversely affect the desired immune potentiating effects of pharmaceutical composition comprising an IL-7 molecule or a variant thereof and/or the anti-cancer vaccine of the invention.
  • the pharmaceutical composition comprising an IL-7 molecule or a variant thereof and/or the anticancer vaccine thereof as described herein can be made into a pharmaceutical composition for in vivo administration.
  • the means of making such a composition have been described in the art (see, for instance, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005).
  • composition of the invention may further comprise one or more pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts.
  • the IL-7 molecule or a variant thereof according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like a mixture of both or pharmaceutically acceptable oils or fats and suitable mixtures thereof.
  • a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like a mixture of both or pharmaceutically acceptable oils or fats and suitable mixtures thereof.
  • a pharmaceutical composition of the invention also may include a pharmaceutically acceptable anti-oxidant.
  • pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulphate, sodium metabisulfite, sodium sulphite and the like; oil-soluble antioxidants, such as ascorbic palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alphatocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulphate, sodium metabisulfite, sodium sulphite and the like
  • oil-soluble antioxidants such as ascorbic palmitate, butylated hydroxyanisole (BHA), but
  • compositions and/or vaccines typically must be sterile and stable under the conditions of manufacture and storage.
  • the pharmaceutical composition can be formulated as a solution, micro-emulsion, liposome, or other ordered structure suitable to high drug concentration and/or in suitable for injection.
  • compositions and/or vaccines of the invention may be isotonic with human blood that is the formulations of the invention have essentially the same osmotic pressure as human blood.
  • Such isotonic formulations generally have an osmotic pressure from about 250 mOSm to about 350 mOSm. Isotonicity can be measured by, for example, a vapor pressure or ice-freezing type osmometer.
  • Tonicity of a formulation is adjusted by the use of tonicity modifiers.
  • “Tonicity modifiers" are those pharmaceutically acceptable inert substances that can be added to the formulation to provide an isotonicity of the formulation.
  • Tonicity modifiers suitable for this invention include, but are not limited to, saccharides, salts and amino acids.
  • the anti-cancer vaccine may comprise one or several adjuvants.
  • adjuvants can be incomplete Freund’s adjuvant, mineral oil adjuvant, aluminium hydroxide, or alum, GM-CSF.
  • suitable adjuvants are well-known in the art.
  • the anti-cancer peptide vaccine may comprise peptide pulsed antigen presenting cells, such as dendritic cells.
  • Antigen presenting cells e.g., dendritic cells
  • the peptide can be bound to an HLA molecule on the antigen-resenting cell, whereby when an HLA-restricted cytotoxic T lymphocyte (CTL) is present, a receptor of the CTL binds to a complex of the HLA molecule and the peptide.
  • CTL cytotoxic T lymphocyte
  • the peptides are emulsified in incomplete Freund’s adjuvant or the like.
  • the adjuvant is a mineral oil adjuvant, similar to Incomplete Freund's Adjuvant, manufactured and supplied by Seppic SA, Paris, FRANCE.
  • adjuvants can be incomplete Freund’s adjuvant, mineral oil adjuvant, aluminium hydroxide, or alum, GM-CSF.
  • suitable adjuvants are well-known in the art.
  • the adjuvant is Montanide® ISA 51.
  • Each peptide of the composition can be present at a concentration of 0.1 mg/ml to 1 mg/ml, preferably 0.5 mg/ml. Preferably, all the peptides are present in the composition at the same concentration.
  • OSE-2101 vaccine is a sterile, preservative-free emulsion of the 10 peptides at a concentration of 0.5 mg/ml each, formulated in Montanide® ISA 51 adjuvant at a ratio of 1 : 1 (w:w) and filled into rubber-stoppered glass vials, and refrigerated at 2° to 8°C.
  • the peptide anti-cancer vaccine preferably the OSE-2101 vaccine
  • the peptide composition of the present invention may further comprise additional peptides, in particular peptide epitopes used for inducing of cytotoxic T-lymphocyte (CTL) responses and targeting TAAs.
  • CTL cytotoxic T-lymphocyte
  • the peptide composition of the present invention may further comprise a peptide as disclosed in WO2009/143843 (the disclosure of which being incorporated herein by reference), and more particularly IDO5.
  • the pharmaceutical composition comprising IL-7 molecules and/or vaccines (e.g., peptides or mRNA) of the invention can also be administered via liposomes, which serve to target the composition and/or vaccines to a particular tissue, such as lymphoid tissue, or to target selectively to infected cells, as well as to increase the half-life of the peptide composition.
  • liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • composition and/or vaccines to be delivered is incorporated as part of a liposome, alone or in conjunction with a molecule which binds to a receptor prevalent among lymphoid cells or with other therapeutic or immunogenic compositions.
  • liposomes either filled or decorated with a desired IL-7 molecule and/or vaccines of the invention can be directed to the site of lymphoid cells, where the liposomes then deliver the IL-7 molecule and/or vaccine compositions.
  • Liposomes for use in accordance with the invention are formed from standard vesicle-forming lipids, which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol.
  • lipids are generally guided by consideration of, e.g., liposome size, acid lability and stability of the liposomes in the blood stream.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980), and U.S. Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.
  • compositions and vaccines of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired. Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the pharmaceutical composition comprising the IL-7 molecule or variant thereof and/or the anti-cancer vaccine disclosed herein to the subject, depending upon the type of cancer to be treated or the site of the cancer.
  • the pharmaceutical composition comprising the IL-7 molecule or variant thereof and/or the anti-cancer vaccine can be administered via conventional routes, e.g., administered orally, parenterally, enterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenterally as used herein includes subcutaneous, intra-cutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intra- synovial, intra-stemal, intra-thecal, intra-lesion, intra-tumour, and intracranial injection or infusion techniques.
  • the pharmaceutical composition according to the invention is preferably administered by intravenous route of administration.
  • the pharmaceutical composition according to the invention is preferably administered by oral route of administration. This composition can also be administered locally.
  • the method or uses disclosed herein particularly comprises administering a therapeutically effective amount of the anti-cancer vaccine and/or IL-7 molecule or variant thereof.
  • therapeutically effective amount or “effective amount” it is meant the quantity of the compound of interest of the pharmaceutical composition, kit, combination, product or combined preparation of the invention which prevents, removes or reduces the deleterious effects of cancer in mammals. It is understood that the administered dose may be lower for each compound in the combination to the “therapeutically effective amount” define for each compound used alone or in combination with other treatments than the combination.
  • the “therapeutically effective amount” of the composition will be adapted by those skilled in the art according to the patient, the pathology, the mode of administration, etc.
  • therapeutically efficient amount is intended the amount which is sufficient to increase Human Leukocyte Antigen (HLA) class I molecules presentation of tumour associated antigen (TAA) by immune cells and/or tumour cells of a patient suffering from cancer.
  • therapeutically efficient amount is intended the amount which is sufficient to reverse, delay or prevent immune suppression by cancer cells
  • peptide vaccine in particular OSE-2101
  • OSE-2101 can be administered by any appropriate route, in particular by parenteral route such as subcutaneous, intradermal or intramuscular route or by aerosol, transmucosal, intrapleural, or intrathecal routes.
  • the peptides composition is administered subcutaneously.
  • OSE-2101 is designed/formulated for subcutaneous injection.
  • the doses of each peptide are ranging from 0.1 to 10 mg of peptide per injection dose.
  • the total peptide dose for each injection or administration is 5.0 mg (1 mL of drug product containing 0.5 mg of each peptide).
  • the anti-cancer vaccine preferably the OSE 2101 vaccine
  • the anti-cancer vaccine preferably the OSE 2101 vaccine
  • the anti-cancer vaccine preferably the OSE 2101 vaccine
  • the T specific immune therapy is administered every three weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses.
  • the pharmaceutical composition comprising IL-7 or a variant thereof is administered at a dosing frequency of about once a week, about once in two weeks, about once in three weeks, about once in four weeks, about once in five weeks, about once in six weeks, about once in seven weeks, about once in eight weeks, about once in nine weeks, about once in 10 weeks, about once in 11 weeks, or about once in 12 weeks.
  • the dosing interval between the dosing pharmaceutical composition comprising IL-7 or a variant thereof and the anti-cancer vaccine, preferably the OSE-2101 vaccine can be adjusted by the man skilled in the art according to the type and severity of the infection, and to the patient, in particular its age, weight, sex, and general physical condition.
  • dosing frequency refers to the number of times a therapeutic agent (e.g., a cancer vaccine and/or IL-7) is administered to a subject within a specific time period. Dosing frequency can be indicated as the number of doses per a given time, for example, once per day, once a week, or once in two weeks. As used herein, “dosing frequency” is applicable where a subject receives multiple (or repeated) administrations of a therapeutic agent.
  • methods and uses provided herein comprise administering to a subject (i) one to three doses of an anti-cancer vaccine (e.g., OSE-2101) at a dosing frequency of once every week or month, and (ii) one to six doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof, wherein the pharmaceutical composition comprising an IL-7 molecule or a variant thereof is administered within about one to seven days after the administration of the dose of the anti-cancer vaccine.
  • an anti-cancer vaccine e.g., OSE-2101
  • methods and uses provided herein comprise administering to a subject (i) one to three doses of an anti-cancer vaccine (e.g., OSE-2101) at a dosing frequency of once every week or month, and (ii) one to six doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof, wherein the pharmaceutical composition comprising an IL-7 molecule or a variant thereof is administered within about one to seven days before the administration of the dose of the anti-cancer vaccine.
  • an anti-cancer vaccine e.g., OSE-2101
  • methods and uses provided herein comprise administering to a subject (i) one to three doses of an anti-cancer vaccine (e.g., OSE-2101) at a dosing frequency of once every week or month, and (ii) one to six doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof, wherein the pharmaceutical composition comprising an IL-7 molecule or a variant thereof is administered concurrently with at least one of the doses of the nucleotide vaccine.
  • an anti-cancer vaccine e.g., OSE-2101
  • methods and uses provided herein comprise administering to a subject (i) two doses of an anti-cancer vaccine (e.g., OSE-2101) at a dosing frequency of once every 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 days, and (ii) three to six doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof, wherein the pharmaceutical composition comprising an IL-7 molecule or a variant thereof is administered within about one to five days after the administration of the dose of the anti-cancer vaccine.
  • an anti-cancer vaccine e.g., OSE-2101
  • methods and uses provided herein comprise administering sequentially to a subject (i) a first dose of an anti-cancer vaccine (e.g., OSE-2101) and (ii) four to six, preferably 5 doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof, preferably within about one to ten days, preferably five days, after the administration of the dose of the anti-cancer vaccine (iii) a second dose of the anti-cancer vaccine (e.g., OSE-2101), preferably within 20 to 30 days after the last administration of the pharmaceutical composition comprising IL-7 molecule or variant thereof and (iv) two to four, preferably 3 doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof preferably within about one to five days, preferably one day, after the administration of the second dose of the anticancer vaccine.
  • an anti-cancer vaccine e.g., OSE-2101
  • four to six preferably 5 doses of a pharmaceutical composition comprising an IL-7
  • methods and uses provided herein comprise administering sequentially to a subject (i) a first dose of an anti-cancer vaccine (e.g., OSE-2101) and (ii) 5 doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof within five days after the administration of the dose of the anti-cancer vaccine (iii) a second dose of the anti-cancer vaccine (e.g., OSE-2101) within 20 days after the last administration of the pharmaceutical composition comprising IL-7 molecule or variant thereof and (iv) 3 doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof within one day after the administration of the second dose of the anti-cancer vaccine.
  • an anti-cancer vaccine e.g., OSE-2101
  • 5 doses of a pharmaceutical composition comprising an IL-7 molecule or a variant thereof within five days after the administration of the dose of the anti-cancer vaccine
  • a second dose of the anti-cancer vaccine e.g., OSE-
  • the combination of the invention is administered or to be administered sequentially, the pharmaceutical composition comprising an IL-7 molecule or a variant thereof being administered first or prior to the anti-cancer vaccine, preferably the OSE-2101 peptide vaccine.
  • IL7 IL7 identified in the present application : thanks to this increasing action on the expression of type I HLA (in particular HLA A, B and C) molecule at the surface of cells, notably tumour cells or immune cells, an IL7 compound can be used advantageously before the administration of the cancer vaccine, for a so- called early/primary activation effect linked to an increase in antigen presentation.
  • the pharmaceutical composition comprising an IL-7 molecule or a variant thereof is administered or to be administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days after the anti-cancer vaccine, preferably the OSE-2101 peptide vaccine.
  • the pharmaceutical composition comprising an IL-7 molecule or a variant thereof is administered or to be administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days before the anti-cancer vaccine, preferably the OSE-2101 peptide vaccine.
  • an anti-cancer vaccine especially a peptide vaccine such as OSE-2101 in accordance with the invention
  • injection e.g., SC, ID, IM
  • aerosol e.g., oral, transdermal, transmucosal, intrapleural, intrathecal, or other suitable routes
  • the immune system of the host responds to the vaccine by producing antibodies, CTLs and/or HTLs specific for the desired antigen. Consequently, the host becomes at least partially immune to subsequent exposure to the TAA, or at least partially resistant to further development of TAA-bearing cells and thereby derives a prophylactic or therapeutic benefit.
  • administration of the anti-cancer vaccine should generally begin at the first diagnosis of TAA-related disease such as cancer. This is followed by boosting doses at least until symptoms are substantially abated and for a period thereafter. In chronic disease states, loading doses followed by boosting doses may be required.
  • the methods and uses disclosed herein may further comprise a preliminary step of determining the HLA status of the patient, selecting the HLA class I positive patients, preferably HLA-A2 positive patients and administering a therapeutic effective amount of combination as disclosed herein to the HLA class I positive patients, preferably HLA-A2 positive patients.
  • the invention relates to a combination of an anti-cancer vaccine and an IL-7 molecule or variant thereof for the treatment of cancer.
  • cancer as used herein is defined as disease characterised by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.
  • treatment of cancer denotes curative, symptomatic, preventive treatment as well as maintenance treatment.
  • Pharmaceutical compositions, kits, products and combined preparations of the invention can be used in subjects with existing cancer or tumour, including at early or late stages of progression of the cancer.
  • the pharmaceutical compositions, kits, combinations and combined preparations of the invention reduce the development of tumours, reduce tumours burden, produce tumours regression in the subject and/or prevent metastasis occurrence, cancer relapse and/or cancer resistance.
  • the pharmaceutical compositions, kits, combinations and combined preparations according to the present invention may advantageously prevent, delay the emergence or the development of, decrease or remove the tumour cells and/or drug-tolerant or drug resistant tumour cells.
  • Treatments according to the present invention do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • compositions, products, kits, combinations or combined preparations described in the invention may be useful for inhibiting the growth of solid tumours, decreasing the tumours volume, preventing the metastatic spread of tumours and the growth or development of metastasis, preventing the tumours recurrence, preventing the tumours relapse and/or preventing tumour resistance.
  • the cancer is a solid tumour.
  • the cancer can be of the colon, non-small cell lung cancer ("NSCLC”), the breast, the ovary, the kidney, the rectum, head and neck (including but not limited to the nasal and oral cavities), the prostate, the pancreas, small cell lung cancer, the uterus, the bladder, the thyroid, the skin (including, but not limited to, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, and metastatic melanoma), breast, brain, cervical carcinomas, testicular carcinomas, etc.
  • NSCLC non-small cell lung cancer
  • patient’s cancer are due to one of the following cancers: lung cancer such as NSCLC (non-small cell lung cancer) and small cell lung cancer, melanoma, mesothelioma, breast cancers, primary brain cancers, ovarian, uterine carcinoma, especially uterine corpus and/or uterine cervix carcinoma, head and neck, colon, gastro-intestinal, renal cancers, sarcoma, germ cell tumours, leukaemia, lymphoma, testicular cancers and bladder cancers, preferably NSCLC, colon cancer, breast cancer, ovarian cancer, and a cancer of the head and/or neck, more preferably NSCLC.
  • NSCLC non-small cell lung cancer
  • small cell lung cancer melanoma
  • mesothelioma breast cancers
  • primary brain cancers ovarian
  • uterine carcinoma especially uterine corpus and/or uterine cervix carcinoma
  • head and neck colon
  • gastro-intestinal renal cancers
  • the patient’s cancer are advanced cancer.
  • advanced cancer or “advanced stage cancer” refers to a cancer at an advanced stage of development, i.e. a cancer that has spread in the body (metastasis).
  • the patient suffers from brain metastases.
  • the staging of a cancer describes the severity of a person’s cancer based on the size and/or extent (reach) of the original (primary) tumour and whether or not cancer has spread in the body (metastasis). Cancer stages are numbered from 0 to IV. Stages III and IV are the most advanced stages.
  • the cancer cells have a decreased expression of HLA class I molecules, preferably a decreased expression of HLA- A, HLA-B and/or HLA-C.
  • the cancer vaccine can be administered either to patients exhibiting a lower HLA expression level of cells (tumour and/or immune cells) that a reference HLA level, and/or to patients exhibiting a normal/ standard HLA expression level but for which the IL7 compound will boost the immune response.
  • the reference HLA level is a HLA level in a patient or group of patients that are healthy or cancer-free. It is mentioned that the combined use of the IL7 compound and of the cancer vaccine is or can be particularly advantageous in patients where cells (tumoral and/or immune cells) have a decreased expression of HLA class I molecules, but such combination is or can be also useful for patients who do not have such decreased expression.
  • the cancer cells express or overexpress a least one of the following TAA: HER2/neu, CEA, MAGE2, MAGE3 and p53.
  • the cancer is resistant or non-responsive to the anti-cancer vaccine.
  • the cancer is resistant or non-responsive to the TAA epitope peptide vaccine.
  • the subject has a primary or secondary resistance to a first line of anticancer treatment.
  • Resistance to anti-cancer treatment can either primary, meaning that the patients do not respond at all to treatment (in particular immediately after treatment initiation) or secondary, meaning that patients respond to treatment at the beginning but develop resistance later on, especially weeks or months after evidence of initial clinical benefit.
  • a "subject”, “host” or “patient” includes any human or nonhuman animal.
  • the term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs.
  • the subject to treat is preferably a human, particularly a human at the prenatal stage, a new-born, a child, an infant, an adolescent or an adult, in particular an adult of at least 30 years old, 40 years old, preferably an adult of at least 50 years old, still more preferably an adult of at least 60 years old, even more preferably an adult of at least 70 years old.
  • the patient suffering from cancer is a HLA-A positive patient, even more preferably a HLA-A2 positive patient.
  • HLA-A2 positive patients bear at least one allele of HLA-A2 and/or HLA-A2 supertype, such as described in WO 2004/094454.
  • the patient has a positive CTL and/or an HTL response.
  • a "CTL and/or an HTL response” is a protective or therapeutic immune response to an antigen derived from a pathogenic antigen (e.g., an antigen from an infectious agent or a tumour antigen), which in some way prevents or at least partially arrests disease symptoms, side effects or progression.
  • the immune response may also include an antibody response which has been facilitated by the stimulation of helper T cells.
  • the patient has already received several lines of treatment prior to the vaccination with the claimed anti-cancer vaccine, the IL7 molecule or variant thereof, or prior to the administration of the combination of the invention.
  • the combinations of the invention are administered to a patient who has a malignancy associated with expression of one or more TAAs, or to an individual susceptible to, or otherwise at risk for developing TAA-related disease. Upon administration an immune response is elicited against the TAAs, thereby enhancing the patient's own immune response capabilities.
  • peptide and/or nucleic acid compositions are administered to a patient in an amount sufficient to elicit an effective immune response to the TAA-expressing cells and to thereby cure, arrest or slow symptoms and/or complications.
  • kits for use in enhancing immune responses, in increasing antigen presentation, reversing immune suppression and/or treating cancer are included in kits provided by the present invention.
  • the present disclosure particularly provides kits for use in enhancing immune responses, in increasing antigen presentation, reversing immune suppression and/or treating cancer.
  • kit means two or more components (one of which corresponding to the bifunctional molecule, the nucleic acid molecule, the vector or the cell of the invention) packaged in a container, recipient or otherwise.
  • a kit can hence be described as a set of products and/or utensils that are sufficient to achieve a certain goal, which can be marketed as a single unit.
  • the kits of this invention are in suitable packaging.
  • kits according to the invention may comprise: a) a anti-cancer vaccine as described herein; and b) a composition comprising an IL-7 molecule or a variant thereof such as described herein.
  • compositions comprised in the kit according to the invention may particularly be formulated into a syringe compatible composition.
  • the kit may be tailored to a particular cancer for an individual, especially individual having a primary or secondary resistance to an anticancer treatment.
  • the invention also concerns the use of such kit in the treatment of cancer.
  • the invention also relates to the use of the kit to increase Human Leukocyte Antigen (HLA) class I molecules presentation of tumour associated antigen (TAA) by immune cells and/or tumour cells of a patient suffering from cancer.
  • HLA Human Leukocyte Antigen
  • TAA tumour associated antigen
  • the invention also relates to the use of the kit for use to stimulate T cell response against cancer or to reverse, delay or prevent immune suppression by cancer cells.
  • IL-7 induces an upregulation of pan HLA-A ,B and C surface expression at proteins levels.
  • Cell lines and Fresh human tumour cells were incubated in culture medium with IL-7 overnight and collected cells were performed for pan HLA-A, B, C staining analysed by flow cytometry.
  • Fig 1A/B Expression of pan HLA-A, B, C at protein level in HPB-ALL and THP-1 cells. Staining with FITC anti-human pan HLA A, B, C was quantified after incubation by flow cytometry using Cytoflex.
  • Fig 1C Whole Human Kidney tumour was digested and cultivated in complete medium alone or with IL-7 in a 24-well plate during 24h at 37°C. Expression of pan HLA-A, B, C at protein level was quantified by flow cytometry using Cytoflex.
  • FIG. 2 IL-7 treatment enhances T cell response elicited by QSE2101 HLA-A2 specific vaccine.
  • Eight-weeks-old female HLA-A2/HLA-DR1 transgenic mice were subcutaneously immunised with OSE2101 on day 0 and 35 with lOOpL (15pg/mouse). On day 5/8/11/13/15 and day 36/39/41, mice were intraperitoneally injected with IL-7 at 4 mg/kg. On Day 49, Lung resident T cells isolated from lung Bronchoalveolar lavage were restimulated ex vivo to assess IFN-y response using ELISpot assay.
  • Example 1 IL-7 treatment induces an upregulation of HLA-A, B, C protein surface expression
  • IL-7 surprisingly induced an upregulation of HLA type I protein on cell surface of HPB-ALL and THP-1 cell lines as illustrated in Figure 1 A and B.
  • a higher Median fluorescence is obtained in IL-7 treated group versus untreated group.
  • an upregulation of HLA cell surface expression was confirmed after treatment of whole human fresh kidney tumour.
  • HLA type I molecule was overexpressed (Median fluorescence analysis) in myeloid infiltrating cells and more specifically in CDl lb+ myeloid cells (CD45+ CDl lb+), monocytes derived macrophages population (CD 145+CD 14+), resident macrophages (CD45+ CD163+) after incubation with IL-7 at 270nM compared to cells incubated with medium only ( Figure 1C).
  • Example 2 IL-7 boosts cytotoxic T lymphocyte (CTL) response induced by OSE2101 HLA type I epitope vaccine
  • the inventors next evaluated whether IL-7 can enhance CD8 T cell response induced by type I HLA based epitope vaccine.
  • Fc- IL-7 is a IgGl N297A isotype antibody fused to a flexible linker (G4S)3 and to IL7. This Fc IL-7 molecule was used to improved pharmacokinetic profile compared to a naked cytokine that shows generally limited half-life.
  • OSE2101 (or Tedopi®) is HLA-A2 T-cell epitope-based cancer vaccine composed of 9 epitopes of 5 tumour-associated antigens (TAA): Carcinoembryonic Antigen (CEA) (CEA.24V9, CEA.605D6, CEA691H5), Human epidermal growth factor receptor 2 (HER-2) (HER2.369V2V9, HER2.689), Melanoma-Associated Antigen 2 (MAGE-A2) (MAGE2.157), Melanoma- Associated Antigen 3 (MAGE- A3) (MAGE3.11215), P53 (p53.139L2B3, p53149M2) plus a Pan DR T helper cell epitope (PADRE).
  • OSE2101 peptides are as described in Table 1.
  • OSE2101 peptides are emulsified in Montanide ISA51 adjuvant prior injection.
  • mice Immunization of mice was performed with subcutaneous OSE2101 vaccine (prime Day 0 + boost Day 35) containing 9 peptides + CTL Pan DR peptide adjuvanted in Montanide ISA51 alone or in combination with IL-7 (Fc-IL7).
  • T cell immunogenicity was evaluated using IFNy Elispot after ex vivo OSE2101 peptide restimulation of T cells isolated from BAL. No peptide stimulation (Medium) was used as basal IFN-y non-specific secretion.
  • OSE2101 epitope vaccine is composed by 5 Tumour-Associated Antigens (TAAs) Carcinoembryonic Antigen
  • CEA Human epidermal growth factor receptor 2
  • HER- 2 Human epidermal growth factor receptor 2
  • HER- 2 Human epidermal growth factor receptor 2
  • MAGE-A2 Melanoma- Associated Antigen 2
  • MAGE-A3 Melanoma-Associated Antigen 3
  • P53 p53.139L2B3,p53149M2
  • PADRE Pan DR T helper cell epitope
  • OSE2101 epitopes are as described in Table 1. Epitopes were emulsified in Montanide ISA51 adjuvant prior injection. Each mouse was injected subcutaneously in the upper back on the right for the first injection and in the in the upper back on the left for the second injection with lOOul.
  • mice were treated on days 5/8/11/13/15 and 36/39/41 with Fc-IL-7 molecules (4 mg/kg). Intraperitoneal injections were realised for each injection. On day 49, mice were sacrificed, BAL (bronchoalveolar lavage), perfused lungs were harvested and processed to isolate T cells. Immunogenicity was evaluated after ex vivo restimulation using IFN-y Elispot.
  • IFN-y Elispot was performed to assess T cell activation following ex vivo restimulation.
  • Total BAL T cells were used for stimulation with OSE2101 (5ug/mL of each individual peptide resuspended in DMSO) or media (negative control) or for 18 hours at 37°c on an IFN-y precoated Elispot plate (Merck Millipore, Plate MSIPS4510).
  • OSE2101 phosphatipore, Plate MSIPS4510
  • IFN-y precoated Elispot plate Merck Millipore, Plate MSIPS4510
  • Ipg/mL lonomycin
  • IFN-y Elispot was performed using a Diaclone kit as per as manufacturer instructions (# 862.031.020P). Spots were counted following manufacturer instructions using Mabtech-ELISpot system. One spot corresponds to one cell secreting IFN-y. A minimal threshold of 10 spots per well was applied for the experiment.
  • HPB-ALL and THP-1 cells were incubated in a 96-well plate at 2,5xlO A 6 cell/mL in a 2% Bovine Serum Albumin (BSA) RPMI media with or without IL-7 (130nM, Miltenyi, #130-095-364) during 24h. Cells were washed and stained with Live dead yellow (Fisher,# L34959) during 15 min at 4°. Human Fc Block (BD, #564220) containing 5% BSA were added after one wash with PBS IX BSA 2% EDTA 2mM during 20 min at RT.
  • BSA Bovine Serum Albumin
  • Kidney Tumours were freshly collected after surgery and directly processed. We used ex vivo organoid culture system to generate tumour organoids after cutting whole tumour fragment into small pieces and digestion using human dissociation miltenyi kit (#130-095-929). After 70pm filtration, all cells were incubated in a 24 well plate at lxlO A 6 cell/mL in 10% Bovine Serum Albumin (BSA) RPMI w/o IL-7 (270 nM, Miltenyi, #130-095-364) during 24h, washed and stained with Live dead Blue ( ThermoFisher, #L34962) during 15 min at 4°c.
  • BSA Bovine Serum Albumin
  • Human Fc Block (BD, #564220) were added after one wash with PBS IX BSA 2% EDTA 2mM during 20 min at RT. After one wash, cells were stained with BUV395 anti-human CD45 antibody (BD, #563792), BUV563 anti-human CDl lb antibody (BD, #741357), BV510 anti-human CD163 antibody (Biolegend, #333627), BV421 anti-human CD66b antibody (BD, #562940), BUV805 anti-human CDl lc antibody (BD, #742005), APC-H7 anti-human CD14 antibody (BD, #560270), Pe-Cy7 anti-human CD3 antibody (BD, #557749), BV785 anti-human CD31 antibody (BD, Biolegend, #303147), PE anti-human CD127 antibody (BD, #351304), APC anti-human CD19 antibody (BD, #555415), FITC anti-Pan HLA antibody (Biolegend, #311404) during

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Abstract

La présente invention concerne une combinaison de i) une composition pharmaceutique comprenant une molécule d'interleukine -7 (IL-7) ou un variant de celle-ci et ii) un vaccin antigénique associé à une tumeur (TAA) spécifique de la classe I de l'antigène leucocytaire humain (HLA), et leur utilisation pour le traitement du cancer.
PCT/EP2024/080568 2023-10-31 2024-10-29 Combinaison d'interleukine 7 et de vaccin antigénique associé à une tumeur Pending WO2025093541A1 (fr)

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Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
EP0314415A2 (fr) 1987-10-26 1989-05-03 Immunex Corporation Interleukine-7
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
WO1994004678A1 (fr) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulines exemptes de chaines legeres
WO1995007707A1 (fr) 1993-09-14 1995-03-23 Cytel Corporation Alteration de la reponse immunitaire a l'aide de peptides se liant a des alleles pan dr
WO1996034103A1 (fr) 1995-04-25 1996-10-31 Vrije Universiteit Brussel Fragments variables d'immunoglobulines et leur utilisation dans un but therapeutique ou veterinaire
WO1997026784A1 (fr) 1996-01-24 1997-07-31 Cytel Corporation Induction d'une reaction immune contre des determinants souhaites
US5714141A (en) * 1993-04-01 1998-02-03 University Of Washington Use of interleukin 7 to enhance humoral immunity
WO2004018681A2 (fr) 2002-08-08 2004-03-04 Cytheris Substance de medicament a base d'il-7, composition, preparation et utilisations correspondantes
WO2004094454A2 (fr) 2003-04-18 2004-11-04 Idm Pharma, Inc. Peptides antigenes hla-a2 associes a une tumeur et compositions
WO2006061219A2 (fr) 2004-12-09 2006-06-15 Merck Patent Gmbh Variants de l'il-7 a immunogenicite reduite
EP1904635A2 (fr) 2005-07-20 2008-04-02 Cytheris Il-7 glycosylee, preparation et utilisations
WO2009036568A1 (fr) * 2007-09-19 2009-03-26 University Health Network Procédés et compositions pour traiter des tumeurs et des infections virales
WO2009143843A1 (fr) 2008-04-17 2009-12-03 Herlev Hospital Immunothérapie à base d'indoléamine 2,3-dioxygénase
US7960514B2 (en) 2003-12-30 2011-06-14 Merck Patent Gmbh IL-7 fusion proteins
WO2013074489A1 (fr) * 2011-11-14 2013-05-23 Emory University Conjugués de gm-csf et d'il-7, compositions en contenant et méthodes associées
WO2016070928A1 (fr) 2014-11-06 2016-05-12 Orphan Synergy Europe - Pharma Immunothérapie spécifique à plusieurs peptides t thérapeutiques pour le traitement de métastase cérébrale
WO2022099022A1 (fr) * 2020-11-05 2022-05-12 Neoimmunetech, Inc. Procédé de traitement d'une tumeur au moyen d'une combinaison d'une protéine il-7 et d'un vaccin nucléotidique

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
EP0314415A2 (fr) 1987-10-26 1989-05-03 Immunex Corporation Interleukine-7
WO1994004678A1 (fr) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulines exemptes de chaines legeres
US5714141A (en) * 1993-04-01 1998-02-03 University Of Washington Use of interleukin 7 to enhance humoral immunity
EP0735893A1 (fr) 1993-09-14 1996-10-09 Cytel Corporation Alteration de la reponse immunitaire a l'aide de peptides se liant a des alleles pan dr
WO1995007707A1 (fr) 1993-09-14 1995-03-23 Cytel Corporation Alteration de la reponse immunitaire a l'aide de peptides se liant a des alleles pan dr
WO1996034103A1 (fr) 1995-04-25 1996-10-31 Vrije Universiteit Brussel Fragments variables d'immunoglobulines et leur utilisation dans un but therapeutique ou veterinaire
WO1997026784A1 (fr) 1996-01-24 1997-07-31 Cytel Corporation Induction d'une reaction immune contre des determinants souhaites
WO2004018681A2 (fr) 2002-08-08 2004-03-04 Cytheris Substance de medicament a base d'il-7, composition, preparation et utilisations correspondantes
EP1620456A2 (fr) 2003-04-18 2006-02-01 Idm Pharma, Inc. Peptides antigenes hla-a2 associes a une tumeur et compositions
WO2004094454A2 (fr) 2003-04-18 2004-11-04 Idm Pharma, Inc. Peptides antigenes hla-a2 associes a une tumeur et compositions
US7960514B2 (en) 2003-12-30 2011-06-14 Merck Patent Gmbh IL-7 fusion proteins
WO2006061219A2 (fr) 2004-12-09 2006-06-15 Merck Patent Gmbh Variants de l'il-7 a immunogenicite reduite
EP1904635A2 (fr) 2005-07-20 2008-04-02 Cytheris Il-7 glycosylee, preparation et utilisations
WO2009036568A1 (fr) * 2007-09-19 2009-03-26 University Health Network Procédés et compositions pour traiter des tumeurs et des infections virales
WO2009143843A1 (fr) 2008-04-17 2009-12-03 Herlev Hospital Immunothérapie à base d'indoléamine 2,3-dioxygénase
WO2013074489A1 (fr) * 2011-11-14 2013-05-23 Emory University Conjugués de gm-csf et d'il-7, compositions en contenant et méthodes associées
WO2016070928A1 (fr) 2014-11-06 2016-05-12 Orphan Synergy Europe - Pharma Immunothérapie spécifique à plusieurs peptides t thérapeutiques pour le traitement de métastase cérébrale
WO2022099022A1 (fr) * 2020-11-05 2022-05-12 Neoimmunetech, Inc. Procédé de traitement d'une tumeur au moyen d'une combinaison d'une protéine il-7 et d'un vaccin nucléotidique

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
AN, L.WHITTON, J. L., J. VIROL., vol. 71, 1997, pages 2292
APTSIAURI NATALIA ET AL: "The Challenges of HLA Class I Loss in Cancer Immunotherapy: Facts and Hopes", vol. 28, no. 23, 1 December 2022 (2022-12-01), US, pages 5021 - 5029, XP093148056, ISSN: 1078-0432, Retrieved from the Internet <URL:https://watermark.silverchair.com/5021.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA14wggNaBgkqhkiG9w0BBwagggNLMIIDRwIBADCCA0AGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMG815BTdBxV_Qfh_wAgEQgIIDEQZfY_SJ0MioLNhIC9UcVZtsoIgeL-HFEkYZw9Y8QKq1NCtThvNUf6Lh7j3lHvlzVHUBLJBUlzvC32lg2yTfc6M0K9ksoM2> DOI: 10.1158/1078-0432.CCR-21-3501 *
BITAR ET AL., FRONT. IMMUNOL., vol. 10, 2019
CAI ET AL., CANCER IMMUNOL IMMUNOTHER., vol. 67, no. 6, June 2018 (2018-06-01), pages 999 - 1009
CHOI YOUNG WOO ET AL: "Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells", CLINICAL CANCER RESEARCH, vol. 22, no. 23, 1 December 2016 (2016-12-01), US, pages 5898 - 5908, XP055887937, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-16-0423 *
HANKE, R. ET AL., VACCINE, vol. 16, 1998, pages 426
HU ET AL., PLOS ONE., vol. 15, no. 2, 27 February 2020 (2020-02-27), pages 0229327
ISHIOKA ET AL., J. IMMUNOL., vol. 162, 1999, pages 3915 - 3925
KRUL, K.G., DECISION RESOURCES, vol. 10, no. 25, 1998, pages 1 - 10
MATTEUCCI ET AL., J. AM. CHEM. SOC., vol. 103, 1981, pages 3185
PARDOLL, D. M., NATURE MEDICINE (VACCINE SUPPLEMENT, vol. 4, 1998, pages 525 - 531
SAMBROOK ET AL.: "MOLECULAR CLONING, A LABORATORY MANUAL", 1989, COLD SPRING HARBOR PRESS
SCHEFF ET AL., PHARM RES., vol. 28, 2011, pages 1081 - 9
STEWARTYOUNG: "SOLID PHASE PEPTIDE SYNTHESIS", 1984, PIERCE CHEMICAL CO.
STITES ET AL.: "IMMUNOLOGY", 1994, LANGE PUBLISHING
SZOKA ET AL., ANN. REV. BIOPHYS. BIOENG., vol. 9, 1980, pages 467
THOMSON, S. A. ET AL., J. IMMUNOL., vol. 157, 1996, pages 822
WHITTON, J. L. ET AL., J. VIROL., vol. 67, 1993, pages 348

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