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NZ733726B2 - Combined preparations for the treatment of cancer or infection - Google Patents

Combined preparations for the treatment of cancer or infection Download PDF

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Publication number
NZ733726B2
NZ733726B2 NZ733726A NZ73372616A NZ733726B2 NZ 733726 B2 NZ733726 B2 NZ 733726B2 NZ 733726 A NZ733726 A NZ 733726A NZ 73372616 A NZ73372616 A NZ 73372616A NZ 733726 B2 NZ733726 B2 NZ 733726B2
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NZ
New Zealand
Prior art keywords
virus
lag
protein
derivative
cancer
Prior art date
Application number
NZ733726A
Other versions
NZ733726A9 (en
NZ733726A (en
Inventor
Chrystelle Brignone
Frederic Triebel
Original Assignee
Immutep Sas
Filing date
Publication date
Publication of NZ733726A9 publication Critical patent/NZ733726A9/en
Priority claimed from GBGB1500374.2A external-priority patent/GB201500374D0/en
Application filed by Immutep Sas filed Critical Immutep Sas
Priority to NZ771781A priority Critical patent/NZ771781B2/en
Publication of NZ733726A publication Critical patent/NZ733726A/en
Publication of NZ733726B2 publication Critical patent/NZ733726B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Combined preparations, and pharmaceutical compositions, comprising: (a) LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; and (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, are described. The PD-1 pathway inhibitor, such as an anti-PD-1 antibody or an anti-PD-L1 antibody, and a soluble derivative of LAG- 3, acting as an APC activator, together synergistically activate T cells (in particular, CD8+ T cells). Use of the combined preparations and compositions as medicaments, in particular for the treatment of cancer or infection, and to methods for the treatment of cancer or infection, is described.

Claims (48)

What I (or we) claim is: 63
1. A combined preparation, which comprises: (a) LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of LAG-3 protein, and wherein the LAG-3 protein or the derivative of LAG-3 protein is an antigen presenting cell (APC) activator; and (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2, or wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1.
2. A pharmaceutical composition, which comprises: (a) LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of LAG-3 protein, and wherein the LAG-3 protein or the derivative of LAG-3 protein is an APC activator; (b) a PD-1 pathway inhibitor, wherein the PD-1 pathway inhibitor comprises an anti PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD 1 to PD-L1 and/or PD-L2, or wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1; and (c) a pharmaceutically acceptable carrier, excipient, or diluent.
3. A combined preparation according to claim 1, or a pharmaceutical composition according to claim 2, for co-administration or sequential administration of the LAG-3 protein, or derivative thereof, and the PD-1 pathway inhibitor.
4. 64 A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the LAG-3 protein, or derivative thereof, is present at a dose which is a molar equivalent of 0.25-30 mg of LAG-3Ig fusion protein IMP321.
5. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, which comprises a plurality of doses of the LAG-3 protein, or derivative thereof and/or a plurality of doses of the PD-1 pathway inhibitor.
6. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the PD-1 pathway inhibitor is pembrolizumab or nivolumab or pidilizumab.
7. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the PD-1 pathway inhibitor is BMS-936559, MEDI4736, MPDL3280A, or MSB0010718C.
8. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the PD-1 pathway inhibitor is present at a dose that is up to 50%, 1-50%, 1-25%, or 1-10%, of a typically prescribed dose of the PD-1 pathway inhibitor as a monotherapy, or wherein the PD-1 pathway inhibitor is present at a dose that is 0.1-50%, 0.1-25%, 0.1-20%, 0.1-10%, <20%, <10%, 0.1-<20%, 0.1-<10%, 0.01-<20%, or 0.01-<10% of a typically prescribed dose of the PD-1 pathway inhibitor as a monotherapy.
9. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the LAG-3 protein or derivative thereof, and the PD-1 pathway inhibitor, are present in any of the combinations of dosage amounts shown in the following Table: Type of PD-1 pathway inhibitor Dose of PD-1 pathway inhibitor: mg/kg [mg dose for 70kg human] Human dose of LAG-3 protein or derivative thereof (given as a mg dose of IMP321, or a molar equivalent thereof) 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] Anti-PD-1 antibody or anti PD-L1 antibody 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 65 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg Anti-PD-1 antibody or anti PD-L1 antibody 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg Anti-PD-1 antibody or anti PD-L1 antibody 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg Pembrolizumab 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 66 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg Pembrolizumab 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg Pembrolizumab 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg Nivolumab 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg 67 Nivolumab 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg Nivolumab 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg BMS-936559 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg BMS-936559 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 68 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg BMS-936559 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg MPDL3280A 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg MPDL3280A 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 69 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg MPDL3280A 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg
10. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the derivative of LAG-3 protein comprises: the 30 amino acid extra-loop sequence GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO:2) of domain D1 of human LAG-3 protein; or a variant of the 30 amino acid extra-loop sequence GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO:2) of domain D1 of human LAG-3 protein, wherein the variant comprises one or more conservative amino acid substitutions, and has at least 70% amino acid identity with the 30 amino acid extra-loop sequence.
11. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the derivative of LAG-3 protein is fused to Immunoglobulin Fc sequence.
12. A combined preparation or a pharmaceutical composition according to any one of the preceding claims, wherein the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321.
13. 70 A combined preparation or a pharmaceutical composition according to any one of claims 1 to 12 for use in preventing, treating, or ameliorating cancer.
14. Use of a combined preparation or a pharmaceutical composition according to any one of claims 1 to 12 in the manufacture of a medicament for preventing, treating, or ameliorating cancer.
15. A combined preparation or a pharmaceutical composition for use according to claim 13, or use according to claim 14, wherein the cancer is a PD-L1-positive or a PD-L2-positive cancer.
16. A combined preparation or a pharmaceutical composition for use according to claim 13 or 15, or use according to claim 14 or 15, wherein the cancer is skin, lung (especially squamous or nonsquamous non-small-cell lung carcinoma, NSCLC), ovarian, renal, colon, colorectal, breast, gastric, esophageal, pancreatic, bladder, urothelial, or liver cancer, or a melanoma (for example, metastatic malignant melanoma), a prostate cancer (for example hormone refractory prostate adenocarcinoma), a head and neck cancer (for example, squamous cell carcinoma of the head and neck), a cervical cancer, a thyroid cancer, a glioblastoma, a glioma, leukemia, a lymphoma (for example, a B cell lymphoma), an adrenal gland cancer, an AIDS-associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a carotid body tumor, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, a gestational trophoblastic disease, a germ cell tumor, a haematological malignancy, hepatocellular carcinoma, an islet cell tumor, a Kaposi's sarcoma, a kidney cancer, a lipoma/benign lipomatous tumor, a liposarcoma/malignant lipomatous tumor, a medulloblastoma, a meningioma, a Merkel cell carcinoma, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplasia syndrome, a neuroblastoma, a neuroendocrine tumor, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterior uveal melanoma, a rare hematologic disorder, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a soft-tissue sarcoma, a squamous cell cancer, a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid metastatic cancer, or a uterine cancer.
17. 71 A combined preparation or a pharmaceutical composition according to any one of claims 1 to 12 for use in preventing, treating, or ameliorating an infection.
18. Use of a combined preparation or a pharmaceutical composition according to any one of claims 1 to 12 in the manufacture of a medicament for preventing, treating, or ameliorating an infection.
19. A combined preparation or a pharmaceutical composition for use according to claim 17, or use according to claim 18, wherein the infection is a chronic or persistent infection.
20. A combined preparation or a pharmaceutical composition for use according to claim 17 or 19, or use according to claim 18 or 19, wherein the infection is a viral, bacterial, fungal, or protozoan infection.
21. A combined preparation or a pharmaceutical composition for use according to claim 20, or use according to claim 20, wherein the viral infection is caused by an adenovirus, an adeno-associated virus, a B virus (macacine herpesvirus I), a BK virus, a bunyavirus, a chikungunya virus, a cocksackie virus, a coronavirus, a cytomegalovirus, an eastern equine encephalitis virus, an ebola virus, an enterovirus, an Epstein-Barr virus, a hantavirus, a hepatitis A virus, a hepatitis B virus, a hepatitis C virus, a hepatitis D virus, a hepatitis E virus, a herpes virus, a herpes simplex virus 1, a herpes simplex virus 2, a human foamy virus, a human herpes virus 3, a human herpes virus 5, a human herpes virus 6, a human herpes virus 7, a human immunodeficiency virus, a human papillomavirus, a human ß-lymphotropic virus, a human T-cell leukemia virus I, a human T-cell leukemia virus II, an influenza virus, a JC virus, a JEV, a Kaposi's sarcoma-associated herpesvirus, a Lassa virus, a lymphocytic choriomeningitis virus, a Marburg virus, a measles virus, a mumps virus, a Nipah virus, a norovirus, a Norwalk virus, an orthoreovirus, a parainfluenza virus, a parvovirus, a poliovirus, a rabies virus, a reovirus, a respiratory syncytial virus, rhinovirus, a Rift Valley fever virus, a rotavirus, rubella virus, a smallpox virus, a St Louis encephalitis virus, a variola major virus, a variola minor virus, a vericella-zoster virus, a West Nile virus, a western equine encephalitis virus, or a yellow fever virus.
22. A combined preparation or a pharmaceutical composition for use according to claim 20, or use according to claim 20, wherein the bacterial infection is caused by Escherichia coli, Clostridium difficile, Salmonella thyphimurium, Pseudomonas aeruginosa, Vibrio cholerae, Neisseria gonorrhoeae, Helicobacter pylori, Hemophilus influenzae, Shigella dysenteriae, Staphylococcus aureus, Mycobacterium tuberculosis, Streptococcus pneumonia, or Chlamydia trachomatis.
23. 72 A combined preparation or pharmaceutical composition for use according to claim 20, or use according to claim 20, wherein the fungal infection is caused by Candida, Aspergillus, Cryptococcus, Coccidioides, Histoplasma, Pneumocystis, or Stachybotrys.
24. A combined preparation or pharmaceutical composition for use according to claim 20, or use according to claim 20, wherein the protozoan infection is caused by Amoebozoa, Excavata, Chromalveolata, Entamoeba, Plasmodium, Giardia, Trypanosoma, Coccidia, Besnoitia, Dicrocoelium, or Leishmania.
25. Use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the LAG-3 protein or the derivative of LAG-3 protein is an antigen presenting cell (APC) activator, and a programmed cell death protein-1 (PD-1) pathway inhibitor, for the manufacture of a medicament for the treatment of a cancer in a subject, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of LAG-3 protein, and wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2, or wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1.
26. Use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the LAG-3 protein or the derivative of LAG-3 protein is an antigen presenting cell (APC) activator, for the manufacture of a medicament for treating a cancer in a subject, wherein the treating comprises co-administration or sequential administration of the medicament with a programmed cell death protein (PD-1) pathway inhibitor, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of LAG-3 protein, and wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2, or wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1.
27. Use according to claim 25 or 26, wherein the cancer is a PD-L1-positive or a PD-L2 positive cancer.
28. 73 Use according to any one of claims 25 to 27, wherein the cancer is skin, lung (especially squamous or nonsquamous non-small-cell lung carcinoma, NSCLC), ovarian, renal, colon, colorectal, breast, gastric, esophageal, pancreatic, bladder, urothelial, or liver cancer, or a melanoma (for example, metastatic malignant melanoma), a prostate cancer (for example hormone refractory prostate adenocarcinoma), a head and neck cancer (for example, squamous cell carcinoma of the head and neck), a cervical cancer, a thyroid cancer, a glioblastoma, a glioma, leukemia, a lymphoma (for example, a B cell lymphoma), an adrenal gland cancer, an AIDS-associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a carotid body tumor, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, a gestational trophoblastic disease, a germ cell tumor, a haematological malignancy, hepatocellular carcinoma, an islet cell tumor, a Kaposi's sarcoma, a kidney cancer, a lipoma/benign lipomatous tumor, a liposarcoma/malignant lipomatous tumor, a medulloblastoma, a meningioma, a Merkel cell carcinoma, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplasia syndrome, a neuroblastoma, a neuroendocrine tumor, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterior uveal melanoma, a rare hematologic disorder, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a soft-tissue sarcoma, a squamous cell cancer, a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid metastatic cancer, or a uterine cancer.
29. Use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the LAG-3 protein or the derivative of LAG-3 protein is an antigen presenting cell (APC) activator, and a programmed cell death protein-1 (PD-1) pathway inhibitor, for the manufacture of a medicament for the treatment of an infection in a subject, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of LAG-3 protein, and wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2, or wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1.
30. 74 Use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the LAG-3 protein or the derivative of LAG-3 protein is an antigen presenting cell (APC) activator, for the manufacture of a medicament for treating an infection in a subject, wherein the treating comprises co-administration or sequential administration of the medicament with a programmed cell death protein (PD-1) pathway inhibitor, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of LAG-3 protein, and wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2, or wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1.
31. Use according to claim 29 or 30, wherein the infection is a chronic or persistent infection.
32. Use according to any one of claims 29 to 31, wherein the infection is a viral, bacterial, fungal, or protozoan infection.
33. Use according to claim 32, wherein the viral infection is caused by an adenovirus, an adeno-associated virus, a B virus (macacine herpesvirus I), a BK virus, a bunyavirus, a chikungunya virus, a cocksackie virus, a coronavirus, a cytomegalovirus, an eastern equine encephalitis virus, an ebola virus, an enterovirus, an Epstein-Barr virus, a hantavirus, a hepatitis A virus, a hepatitis B virus, a hepatitis C virus, a hepatitis D virus, a hepatitis E virus, a herpes virus, a herpes simplex virus 1, a herpes simplex virus 2, a human foamy virus, a human herpes virus 3, a human herpes virus 5, a human herpes virus 6, a human herpes virus 7, a human immunodeficiency virus, a human papillomavirus, a human ß-lymphotropic virus, a human T-cell leukemia virus I, a human T-cell leukemia virus II, an influenza virus, a JC virus, a JEV, a Kaposi's sarcoma-associated herpesvirus, a Lassa virus, a lymphocytic choriomeningitis virus, a Marburg virus, a measles virus, a mumps virus, a Nipah virus, a norovirus, a Norwalk virus, an orthoreovirus, a parainfluenza virus, a parvovirus, a poliovirus, a rabies virus, a reovirus, a respiratory syncytial virus, rhinovirus, a Rift Valley fever virus, a rotavirus, rubella virus, a smallpox virus, a St Louis encephalitis virus, a variola major virus, a variola minor virus, a vericella-zoster virus, a West Nile virus, a western equine encephalitis virus, or a yellow fever virus.
34. 75 Use according to claim 32, wherein the bacterial infection is caused by Escherichia coli, Clostridium difficile, Salmonella thyphimurium, Pseudomonas aeruginosa, Vibrio cholerae, Neisseria gonorrhoeae, Helicobacter pylori, Hemophilus influenzae, Shigella dysenteriae, Staphylococcus aureus, Mycobacterium tuberculosis, Streptococcus pneumonia, or Chlamydia trachomatis.
35. Use according to claim 32, wherein the fungal infection is caused by Candida, Aspergillus, Cryptococcus, Coccidioides, Histoplasma, Pneumocystis, or Stachybotrys.
36. Use according to claim 32, wherein the protozoan infection is caused by Amoebozoa, Excavata, Chromalveolata, Entamoeba, Plasmodium, Giardia, Trypanosoma, Coccidia, Besnoitia, Dicrocoelium, or Leishmania.
37. Use according to any one of claims 25 to 36, wherein the LAG-3 protein, or derivative thereof, is present at a dose which is a molar equivalent of 0.25-30 mg of LAG-3Ig fusion protein IMP321.
38. Use according to any one of claims 25 to 37, which comprises a plurality of doses of the LAG-3 protein, or derivative thereof and/or a plurality of doses of the PD-1 pathway inhibitor.
39. Use according to any one of claims 25 to 38, wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-1 to PD-L1 and/or PD-L2.
40. Use according to any one of claims 25 to 39, wherein the PD-1 pathway inhibitor is pembrolizumab or nivolumab or pidilizumab.
41. Use according to any one of claims 25 to 38, wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody, or a derivative or fragment thereof that retains ability to inhibit binding of PD-L1 to PD-1.
42. Use according to any one of claims 25 to 38, or 41, wherein the PD-1 pathway inhibitor is BMS-936559, MEDI4736, MPDL3280A, or MSB0010718C.
43. Use according to any one of claims 25 to 42, wherein the PD-1 pathway inhibitor is present at a dose that is up to 50%, 1-50%, 1-25%, or 1-10%, of a typically prescribed dose of the PD-1 pathway inhibitor as a monotherapy, or wherein the PD-1 pathway inhibitor is present at a dose that is 0.1-50%, 0.1-25%, 0.1-20%, 0.1-10%, <20%, <10%, 0.1-<20%, 0.1 76 <10%, 0.01-<20%, or 0.01-<10% of a typically prescribed dose of the PD-1 pathway inhibitor as a monotherapy.
44. Use according to any one of claims 25 to 43, wherein the LAG-3 protein or derivative thereof, and the PD-1 pathway inhibitor, are present in any of the combinations of dosage amounts shown in the following Table: Type of PD-1 pathway inhibitor Dose of PD-1 pathway inhibitor: mg/kg [mg dose for 70kg human] Human dose of LAG-3 protein or derivative thereof (given as a mg dose of IMP321, or a molar equivalent thereof) Anti-PD-1 antibody or anti PD-L1 antibody 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg Anti-PD-1 antibody or anti PD-L1 antibody 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg Anti-PD-1 antibody or anti PD-L1 antibody 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 77 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg Pembrolizumab 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg Pembrolizumab 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg Pembrolizumab 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 78 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg Nivolumab 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg Nivolumab 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg Nivolumab 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 79 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg BMS-936559 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg BMS-936559 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg BMS-936559 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg MPDL3280A 0.001-5 mg/kg [0.07-350mg] 0.25-30mg 80 0.001-2.5 mg/kg [0.07-175mg] 0.25-30mg 0.001-1 mg/kg [0.07-70mg] 0.25-30mg 0.001-<1 mg/kg [0.07-<70mg] 0.25-30mg 0.001-0.5 mg/kg [0.07-35mg] 0.25-30mg 0.001-0.1 mg/kg [0.07-7mg] 0.25-30mg 0.002-5 mg/kg [0.14-350mg] 0.25-30mg 0.002-2.5 mg/kg [0.14-175mg] 0.25-30mg 0.002-1 mg/kg [0.14-70mg] 0.25-30mg 0.002-<1 mg/kg [0.14-<70mg] 0.25-30mg 0.002-0.5 mg/kg [0.14-35mg] 0.25-30mg 0.002-0.1 mg/kg [0.14-7mg] 0.25-30mg MPDL3280A 0.001-5 mg/kg [0.07-350mg] 1-30mg 0.001-2.5 mg/kg [0.07-175mg] 1-30mg 0.001-1 mg/kg [0.07-70mg] 1-30mg 0.001-<1 mg/kg [0.07-<70mg] 1-30mg 0.001-0.5 mg/kg [0.07-35mg] 1-30mg 0.001-0.1 mg/kg [0.07-7mg] 1-30mg 0.002-5 mg/kg [0.14-350mg] 1-30mg 0.002-2.5 mg/kg [0.14-175mg] 1-30mg 0.002-1 mg/kg [0.14-70mg] 1-30mg 0.002-<1 mg/kg [0.14-<70mg] 1-30mg 0.002-0.5 mg/kg [0.14-35mg] 1-30mg 0.002-0.1 mg/kg [0.14-7mg] 1-30mg MPDL3280A 0.001-5 mg/kg [0.07-350mg] 6-30mg 0.001-2.5 mg/kg [0.07-175mg] 6-30mg 0.001-1 mg/kg [0.07-70mg] 6-30mg 0.001-<1 mg/kg [0.07-<70mg] 6-30mg 0.001-0.5 mg/kg [0.07-35mg] 6-30mg 0.001-0.1 mg/kg [0.07-7mg] 6-30mg 0.002-5 mg/kg [0.14-350mg] 6-30mg 0.002-2.5 mg/kg [0.14-175mg] 6-30mg 0.002-1 mg/kg [0.14-70mg] 6-30mg 0.002-<1 mg/kg [0.14-<70mg] 6-30mg 0.002-0.5 mg/kg [0.14-35mg] 6-30mg 0.002-0.1 mg/kg [0.14-7mg] 6-30mg
45. Use according to any one of claims 25 to 44, wherein the derivative of LAG-3 protein comprises: the 30 amino 81 acid extra-loop sequence GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO:2) of domain D1 of human LAG-3 protein; or a variant of the 30 amino acid extra-loop sequence GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO:2) of domain D1 of human LAG-3 protein, wherein the variant comprises one or more conservative amino acid substitutions, and has at least 70% amino acid identity with the 30 amino acid extra-loop sequence.
46. Use according to any one of claims 25 to 45, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of human LAG-3 protein, or wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2, D3, and optionally D4, of human LAG-3 protein.
47. Use according to any one of claims 25 to 46, wherein the derivative of LAG-3 protein is fused to Immunoglobulin Fc sequence.
48. Use according to any one of claims 25 to 47, wherein the derivative of LAG-3 protein is the recombinant soluble human LAG-3Ig fusion protein IMP321.
NZ733726A 2016-01-08 Combined preparations for the treatment of cancer or infection NZ733726B2 (en)

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GBGB1500374.2A GB201500374D0 (en) 2015-01-09 2015-01-09 Combined preparations for the treatment of cancer
PCT/EP2016/050321 WO2016110593A1 (en) 2015-01-09 2016-01-08 Combined preparations for the treatment of cancer or infection

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