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WO2025125652A1 - Polythérapie destinée à être utilisée dans le traitement du cancer - Google Patents

Polythérapie destinée à être utilisée dans le traitement du cancer Download PDF

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WO2025125652A1
WO2025125652A1 PCT/EP2024/086405 EP2024086405W WO2025125652A1 WO 2025125652 A1 WO2025125652 A1 WO 2025125652A1 EP 2024086405 W EP2024086405 W EP 2024086405W WO 2025125652 A1 WO2025125652 A1 WO 2025125652A1
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cancer
agents
inhibit
acceptable salt
pharmaceutically acceptable
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Johanna Lahdenranta
Nicholas Keen
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BicycleTx Ltd
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BicycleTx Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Cyclic peptides are able to bind with high affinity and target specificity to protein targets and hence are an attractive molecule class for the development of therapeutics.
  • several cyclic peptides are already successfully used in the clinic, as for example the antibacterial peptide vancomycin, the immunosuppressant drug cyclosporine or the anticancer drug octreotide (Driggers et al. (2008), Nat Rev Drug Discov 7 (7), 608-24).
  • Good binding properties result from a relatively large interaction surface formed between the peptide and the target as well as the reduced conformational flexibility of the cyclic structures.
  • Phage display-based combinatorial approaches have been developed to generate and screen large libraries of bicyclic peptides to targets of interest (Heinis et al. (2009), Nat Chem Biol 5 (7), 502-7 and WO 2009/098450). Briefly, combinatorial libraries of linear peptides containing three cysteine residues and two regions of six random amino acids (Cys-(Xaa)e- Cys-(Xaa)e-Cys) were displayed on phage and cyclised by covalently linking the cysteine side chains to a small molecule (tris-(bromomethyl)benzene).
  • a combination therapy of BT7480 BCY11863
  • an anti-PD-Ll antibody and an anti-CTLA4 antibody in Example 1 leads to more complete responses compared to the treatment with each single agent or with each combination of two agents.
  • a combination therapy of BT7480 BCY11863
  • an anti-PD-1 antibody and an anti -LAG-3 antibody in Example 2 leads to more complete responses compared to the treatment with each single agent or with each combination of two agents.
  • a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the examples show that the combination therapies of the invention are particularly effective for maintaining or reducing the volume of solid tumors.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-L1 and one agent that inhibits LAG3.
  • one agent is an anti-PD-Ll antibody and one agent is an anti-LAG3 antibody.
  • Such combinations are expected to be particularly effective, in view of the interaction between PD-1 and PD-L1 and the effects shown in the examples for agents that inhibit PD-1 and LAG3.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-L1 and one agent that inhibits CTLA4.
  • one agent is an anti-PD-Ll antibody and one agent is an anti-CTLA4 antibody.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-1 and one agent that inhibits CTLA4.
  • one agent is an anti-PD-1 antibody and one agent is an anti-CTLA4 antibody.
  • Such combinations are expected to be particularly effective, in view of the interaction between PD-1 and PD-L1 and the effects shown in the examples for agents that inhibit PD-L1 and CTLA4.
  • BT7480 or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • a combination of BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators for use in a method of treating a cancer in a patient wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • a combination of BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • BT7480 or a pharmaceutical acceptable salt thereof in the manufacture of a medicament for use in a method of treating a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • BT7480 or a pharmaceutical acceptable salt thereof in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • an eleventh aspect of the invention there is provided use of one or more agents that inhibit at least two checkpoint regulators in the manufacture of a medicament for use in a method of treating a cancer, wherein the method comprises administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • a twelfth aspect of the invention there is provided use of one or more agents that inhibit at least two checkpoint regulators in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • BT7480 or a pharmaceutically acceptable salt thereof, for use in method of treating a cancer in a patient that has previously received or is scheduled to receive one or more agents that inhibit at least two checkpoint regulators.
  • one or more agents that inhibit at least two checkpoint regulators for use in method of treating a cancer in a patient that has previously received or is scheduled to receive BT7480 or a pharmaceutically acceptable salt thereof.
  • FIG. 1 depicts that the combination of BT7480 (BCY11863), an anti-PD-1 antibody (pembrolizumab) and an anti-LAG3 antibody (clone C9B7W) results in the highest complete response rate tested (6/7) and the highest probability of survival.
  • MC38-Nectin-4 (#26) tumor bearing huCD137/huPDl-C57Bl/6 mice were treated with vehicles (either 10 mM histidine, 10% sucrose, pH7 (as a BT7480 vehicle) or PBS (as an antibody vehicle)), BT7480, an anti-PD-1 antibody (pembrolizumab), an anti-LAG3 antibody (anti -mouse LAG3 antibody; clone C9B7W), a combination of BT7480 and the anti-PD-1 antibody, a combination of BT7480 and the anti-LAG3 antibody, a combination of the anti-PD-1 antibody and the anti-LAG3 antibody, or a combination of BT7480, the anti-PD-1 antibody and the anti-LAG3 antibody.
  • vehicles either 10 mM histidine, 10% sucrose, pH7 (as a BT7480 vehicle) or PBS (as an antibody vehicle)
  • BT7480 an anti-PD-1 antibody (pe
  • BT7480 was dosed at 5 mg/kg (Oh & 24h). (An extra dose is given at 24hr to more closely match the human exposure profile as BT7480 has a shorter circulating Tl/2 in mouse than in human.)
  • the anti-PD-1 antibody was dosed at 6 mg/kg.
  • the anti-LAG3 antibody was dosed at 10 mg/kg.
  • PD Progressive disease
  • SD Stable disease
  • PR Partial response
  • CR Complete response
  • FIG. 2 depicts that the combination of BT7480 (BCY11863), an anti-PD-Ll antibody (anti-mouse-PD-Ll antibody; clone 10F.9G2) and an anti-CTLA4 antibody (anti-mouse- CTLA4 antibody; clone 9H10) resulted in the highest complete response rate tested (7/7) and 100% probability of survival.
  • MC38-Nectin-4 (#26) tumor bearing huCD137-C57Bl/6 mice were treated with vehicles (either 10 mM histidine, 10% sucrose, pH7 (as a BT7480 vehicle) or PBS (as an antibody vehicle)), BT7480, the anti-PD-Ll antibody, the anti-CTLA4 antibody, a combination of BT7480 and the anti-PD-Ll antibody, a combination of BT7480 and the anti-CTLA4 antibody, a combination of the anti-PD-Ll antibody and the anti-CTLA4 antibody, or a combination of BT7480, the anti-PD-Ll antibody and the anti-mCTLA4 antibody.
  • vehicles either 10 mM histidine, 10% sucrose, pH7 (as a BT7480 vehicle) or PBS (as an antibody vehicle)
  • BT7480 was dosed at 5 mg/kg (Oh & 24h). (An extra dose is given at 24hr to more closely match the human exposure profile as BT7480 has a shorter circulating Tl/2 in mouse than in human.)
  • the anti-PD-Ll antibody was dosed at 10 mg/kg.
  • the anti-CTLA4 antibody was dosed at 2.5 mg/kg.
  • the present invention provides a method of treating a cancer in a patient, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the present invention also provides a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • BT7480 (also referred to as BCY11863) is a heterotandem bicyclic peptide complex that consists of a Nectin-4 specific peptide BCY8116 linked to two CD137 specific peptides (both of which are BCY8928) via a N-(acid-PEG3)-N-bis(PEG3-azide) linker, shown pictorially as:
  • the Nectin-4 specific peptide BCY8116 is CiP[lNal][dD]CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 1).
  • the CD137 specific peptide BCY8928 is Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2).
  • the CD137 specific peptide BCY8928 comprises an N- and C-terminal extension which are separated by hyphens from the left and right side of the sequence.
  • the peptides each comprise three reactive groups which form covalent bonds to a scaffold, and a sequence subtended between said reactive groups which is referred to as the loop sequence, since it forms a loop when the peptide is bound to the scaffold.
  • the reactive groups are cysteine.
  • the peptides form at least two loops on the scaffold.
  • the scaffold is l,l',l"-(l,3,5-triazinane- l,3,5-triyl)triprop-2-en-l-one (TATA). Cyclisation with TATA occurs on Ci, Cii, and Ciii.
  • Nectin-4 is a surface molecule that belongs to the nectin family of proteins, which comprises 4 members. Nectins are cell adhesion molecules that play a key role in various biological processes such as polarity, proliferation, differentiation and migration, for epithelial, endothelial, immune and neuronal cells, during development and adult life. They are involved in several pathological processes in humans. They are the main receptors for poliovirus, herpes simplex virus and measles virus. Mutations in the genes encoding Nectin- 1 (PVRL1) or Nectin-4 (PVRL4) cause ectodermal dysplasia syndromes associated with other abnormalities. Nectin-4 is expressed during foetal development.
  • PVRL1 Nectin- 1
  • PVRL4 Nectin-4
  • Nectin-4 is a tumor-associated antigen in 50%, 49% and 86% of breast, ovarian and lung carcinomas, respectively, mostly on tumors of bad prognosis. Its expression is not detected in the corresponding normal tissues. In breast tumors, Nectin-4 is expressed mainly in triple-negative and ERBB2+ carcinomas. In the serum of patients with these cancers, the detection of soluble forms of Nectin-4 is associated with a poor prognosis. Levels of serum Nectin-4 increase during metastatic progression and decrease after treatment. These results suggest that Nectin-4 could be a reliable target for the treatment of cancer.
  • Enfortumab Vedotin (ASG-22ME) is an antibody-drug conjugate (ADC) targeting Nectin- 4 and is currently clinically investigated for the treatment of patients suffering from solid tumors.
  • ADC antibody-drug conjugate
  • CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4- 1BB and induced by lymphocyte activation (ILA).
  • TNFRSF9 tumor necrosis factor receptor superfamily member 9
  • 4- 1BB 4- 1BB
  • IVA lymphocyte activation
  • CD137 can be expressed by activated T cells, but to a larger extent on CD8+ than on CD4+ T cells.
  • CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation.
  • One characterized activity of CD137 is its costimulatory activity for activated T cells.
  • Crosslinking of CD137 enhances T cell proliferation, IL-2 secretion, survival and cytolytic activity. Further, it can enhance immune activity to eliminate tumors in mice.
  • CD137 is a homotrimeric protein and the natural ligand CD137L exists as a homotrimer either expressed on immune cells or secreted.
  • the biology of CD137 is highly dependent on multimerization to induce CD137 activity in immune cells.
  • One way to generate CD137 multimerization is through cellular cross-linking of the CD137 specific agonist through interaction with a specific receptor present on another cell.
  • the advantage of BT7480 is that the presence of the two peptide ligands specific for CD137 provides a more effective clustering of CD137.
  • BT7480 demonstrated strong CD 137 activation and induces robust IL-2 and IFN-y cytokine secretion, and that BT7480 demonstrated an excellent PK profile with a terminal half-life of 4.1 hours in SD Rats and 5.3 hours in cyno.
  • the peptides which form BT7480 may be manufactured synthetically by standard techniques followed by reaction with a TATA scaffold in vitro. When this is performed, standard chemistry may be used. This enables the rapid large scale preparation of soluble material for further downstream experiments or validation. Such methods could be accomplished using conventional chemistry such as that disclosed in Timmerman et al (supra). To extend the peptide, it may simply be extended chemically at its N-terminus or C-terminus or within the loops using orthogonally protected lysines (and analogues) using standard solid phase or solution phase chemistry. Standard (bio)conjugation techniques may be used to introduce an activated or activatable N- or C-terminus.
  • additions may be made by fragment condensation or native chemical ligation e.g. as described in (Dawson et al. 1994. Synthesis of Proteins by Native Chemical Ligation. Science 266:776-779), or by enzymes, for example using subtiligase as described in (Chang et al. Proc Natl Acad Sci U S A. 1994 Dec 20; 91(26): 12544-8 or in Hikari et al Bioorganic & Medicinal Chemistry Letters Volume 18, Issue 22, 15 November 2008, Pages 6000-6003).
  • the peptides may be extended or modified by further conjugation through disulphide bonds.
  • This has the additional advantage of allowing the Nectin-4 and CD137 peptides to dissociate from each other once within the reducing environment of the cell.
  • the TATA scaffold could be added during the chemical synthesis of the Nectin-4 peptide so as to react with the three cysteine groups; a further cysteine or thiol could then be appended to the N or C-terminus of the Nectin-4 peptide, so that this cysteine or thiol only reacted with a free cysteine or thiol of the CD 137 peptides, forming a disulfide -linked bicyclic peptide-peptide conjugate.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. It will be appreciated that salt forms are within the scope of this invention, and references to peptide ligands include the salt forms of said ligands.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • references to a peptide, molecule or compound include the salt forms of said peptide, molecule or compound.
  • the pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • the pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as oxalic, citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or /?-toluenesulphonic acid.
  • the pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g.
  • the pharmaceutically acceptable salt is a salt formed with a pharmaceutically acceptable base, in particular a quaternary ammonium salt e.g. tetrabutylammonium salt, or an alkali metal salt, e.g. sodium or potassium salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt or acetate salt.
  • the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof may be (radio)isotope-labelled, wherein the (radio)isotope is a pharmaceutically acceptable (radio)isotope.
  • one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof may comprise metal chelating groups (termed “effector”) that are capable of holding relevant (radio)isotopes.
  • the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof may comprise (radio)isotopes or isotopically labelled functional groups in the place of certain functional groups.
  • isotopes suitable for inclusion in the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof comprise isotopes of hydrogen, such as 2 H (D) and 3 H (T), carbon, such as n C, 13 C and 14 C, chlorine, such as 36 C1, fluorine, such as 18 F, iodine, such as 123 I, 125 I and 131 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, sulfur, such as 35 S, copper, such as 64 Cu, gallium, such as 67 Ga or 68 Ga, yttrium, such as 90 Y and lutetium, such as 177 Lu, and Bismuth, such as 213 Bi.
  • hydrogen such as 2 H (D) and 3 H (T)
  • carbon such as n C, 13 C and 14 C
  • chlorine such as 36 C1
  • fluorine such as 18 F
  • iodine such as 123 I
  • Certain isotopically-labelled peptides used to form BT7480, or a pharmaceutically acceptable salt thereof, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies, and to clinically assess the presence and/or absence of the Nectin-4 target on diseased tissues.
  • the peptides used to form BT7480, or a pharmaceutically acceptable salt thereof can further have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors.
  • the detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc.
  • labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc.
  • the radioactive isotopes tritium, i.e. 3 H (T), and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • One or more agents that inhibit at least two checkpoint regulators are provided.
  • the term “one or more agents that inhibit at least two checkpoint regulators” refers to one or more agents which is/are effective in reducing or blocking the activity of at least two checkpoint regulators.
  • the term “checkpoint regulator” refers to a protein which inhibits immune reactions.
  • the protein is a stimulatory ligand for a receptor which inhibits immune reactions (in other words a stimulatory ligand for an immune checkpoint receptor).
  • the protein is a receptor which inhibits immune reactions (in other words an immune checkpoint receptor).
  • the receptors are inhibitory (including co-inhibitory).
  • the receptors act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.
  • One or more of the “one or more agents that inhibit at least two checkpoint regulators” may act to inhibit or block a receptor which inhibits immune reactions.
  • one or more of the “one or more agents that inhibit at least two checkpoint regulators” may bind a receptor which inhibits immune reactions and inhibit or block its activity.
  • One or more of the “one or more agents that inhibit at least two checkpoint regulators” may act to inhibit or block a stimulatory ligand for a receptor which inhibits immune reactions.
  • one or more of the “one or more agents that inhibit at least two checkpoint regulators” may bind to a stimulatory ligand for a receptor which inhibits immune reactions and inhibit or block it from stimulating the receptor.
  • the “one or more agents that inhibit at least two checkpoint regulators” can comprise one or more small molecules, fusion proteins, biologies and/or antibodies, or antigen binding fragments thereof.
  • the or each agent is an antibody.
  • the antibody may be antagonistic or blocking.
  • the antibody may be monoclonal.
  • the antibody may be humanized or human.
  • the “one or more agents that inhibit at least two checkpoint regulators” comprises one or more antibodies.
  • one or more of the one or more antibodies are antagonistic or blocking antibodies.
  • one or more of the one or more antibodies are antagonistic antibodies.
  • one or more of the one or more antibodies are blocking antibodies.
  • one or more of the one or more antibodies are monoclonal antibodies.
  • one or more of the one or more antibodies are humanized or human.
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise an antagonist (e.g. checkpoint inhibitor) of one or more of CTLA-4, PD-1, PD- Ll, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT (T cell immunoreceptor with Ig and ITIM domains), CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, TIM-4, HVEM, KIR, CD160, CGEN-15049, CHK 1, CHK2, A2aR, CD28, CD86, B7-1, B7-2, B7-H2, B7-H3, B7-H4, B7-H6 and B7-H7.
  • an antagonist e.g. checkpoint inhibitor of one or more of CTLA-4, PD-1, PD- Ll, PD-L2, LAG-3, TIM-3, Galectin 9, CE
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise an antibody (e.g. antagonistic or blocking antibody) against one or more of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, TIM-4, HVEM, KIR, CD160, CGEN-15049, CHK 1, CHK2, A2aR, CD28, CD86, B7-1, B7-2, B7-H2, B7-H3, B7-H4, B7-H6 and B7-H7.
  • an antibody e.g. antagonistic or blocking antibody
  • CTLA-4 e.g. antagonistic or blocking antibody against one or more of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin
  • the “at least two checkpoint regulators” comprises one or more of CTLA-4, PD-1, PD-L1, LAG-3, PD-L2, TIM-3, and TIGIT.
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise an antagonist (e.g. checkpoint inhibitor) of one or more of CTLA-4, PD-1, PD-L1, LAG-3, PD-L2, TIM-3, and TIGIT.
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise an antibody (e.g. antagonistic or blocking antibody) against one or more of CTLA-4, PD-1, PD-L1, LAG-3, PD-L2, TIM-3, and TIGIT.
  • the anti-TIM-3 antibody may be TSR-022 (Tesaro), LY3321367 (Eli Lilly) or MBG453 (Novartis).
  • the anti- TIGIT antibody may be BMS-986207 (Bristol-Myers Squibb), or OMP-313M32 (Oncomed).
  • the “at least two checkpoint regulators” comprises one or more of CTLA-4, PD-1, PD-L1, and LAG-3.
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise an antagonist (e.g. checkpoint inhibitor) of one or more of CTLA-4, PD-1, PD-L1, and LAG-3.
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise an antibody (e.g. antagonistic or blocking antibody) against one or more of CTLA-4, PD-1, PD-L1, and LAG-3.
  • the anti-PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493).
  • the anti-PD-1 antibody is pembrolizumab or nivolumab.
  • One checkpoint regulator may be LAG3.
  • at least one agent may inhibit LAG3 (e.g. a LAG3 antagonist).
  • At least one agent may be an anti-LAG3 antibody (or antigen-binding portion thereof), such as an antagonistic LAG3 antibody (or antigenbinding portion thereof).
  • a LAG3 antagonist is administered by infusion.
  • the anti-LAG3 antibody is relatimab (BMS-986016), IMP-731, IMP-321, or REGN3767. In some embodiments, the anti-LAG3 antibody is relatimab (BMS-986016).
  • One checkpoint regulator may be PD-L1 (programmed cell death 1 ligand 1).
  • at least one agent may inhibit PD-L1 (e.g. a PD-L1 antagonist).
  • At least one agent may be an anti-PD-Ll antibody (or antigen-binding portion thereof), such as an antagonistic PD-L1 antibody (or antigen-binding portion thereof).
  • a PD-L1 antagonist is administered by infusion.
  • the anti-PD-Ll antibody is avelumab, durvalumab, atezolizumab, MPDL3280A (RG7446), BMS-936559, MSB0010718C, AMP224, or MDX-1105.
  • the anti-PD-Ll antibody is durvalumab or atezolizumab.
  • One checkpoint regulator may be CTLA-4.
  • at least one agent may inhibit CTLA-4 (e.g. a CTLA-4 antagonist).
  • At least one agent may be an anti -CTLA-4 antibody (or antigen-binding portion thereof), such as an antagonistic CTLA-4 antibody (or antigenbinding portion thereof).
  • a CTLA-4 antagonist is administered by infusion.
  • the anti-CTLA-4 antibody is ipilimumab, tremelimumab or AGEN-1884.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the one or more agents that inhibit at least two checkpoint regulators comprises two or more agents that each inhibit one checkpoint regulator. Accordingly, in some embodiments, the invention provides a method of treating a cancer in a patient or a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and two or more agents that each inhibit at least one checkpoint regulator.
  • the one or more agents that inhibit at least two checkpoint regulators may comprise one agent that inhibits one checkpoint regulator and one agent that inhibits another checkpoint regulator.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-1 and one agent that inhibits LAG3.
  • one agent is an anti-PD-1 antibody and one agent is an anti-LAG3 antibody.
  • one agent is pembrolizumab or nivolumab and one agent is relatimab (BMS-986016).
  • the combination of BT7480, or a pharmaceutically acceptable salt thereof, one agent that inhibits PD-1 and one agent that inhibits LAG3 is expected to be particularly effective in view of the results in Example 1.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-L1 and one agent that inhibits LAG3.
  • one agent is an anti-PD-Ll antibody and one agent is an anti-LAG3 antibody.
  • one agent is durvalumab or atezolizumab and one agent is relatimab (BMS-986016).
  • one agent that inhibits PD-L1 and one agent that inhibits LAG3 is expected to be particularly effective in view of the results in Example 1 involving one agent that inhibits PD-1 and one agent that inhibits LAG3.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-L1 and one agent that inhibits CTLA4.
  • one agent is an anti-PD-Ll antibody and one agent is an anti-CTLA4 antibody.
  • one agent is durvalumab or atezolizumab and one agent is ipilimumab or tremelimumab.
  • the combination of BT7480, or a pharmaceutically acceptable salt thereof, one agent that inhibits PD-L1 and one agent that inhibits CTLA4 is expected to be particularly effective in view of the results in Example 2.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits PD-1 and one agent that inhibits CTLA4.
  • one agent is an anti-PD-1 antibody and one agent is an anti-CTLA4 antibody.
  • one agent is pembrolizumab or nivolumab and one agent is ipilimumab or tremelimumab.
  • one agent that inhibits PD-1 and one agent that inhibits CTLA4 is expected to be particularly effective in view of the results in Example 2 involving one agent that inhibits PD-L1 and one agent that inhibits CTLA4.
  • the one or more agents that inhibit at least two checkpoint regulators comprises at least one agent that inhibits at least two checkpoint regulators.
  • the invention provides a method of treating a cancer in a patient or a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and an agent that inhibits at least two checkpoint regulators.
  • the one or more agents that inhibit at least two checkpoint regulators comprises one agent that inhibits at least two checkpoint regulators.
  • the one agent that inhibits at least two checkpoint regulators may antagonize one or two checkpoint regulators.
  • the one agent that inhibits at least two checkpoint regulators may block one or two checkpoint regulators.
  • the one agent that inhibits at least two checkpoint regulators may antagonize one checkpoint regulator and block one checkpoint regulator.
  • the one agent that inhibits at least two checkpoint regulators may antagonize two checkpoint regulators.
  • the one agent that inhibits at least two checkpoint regulators may block two checkpoint regulators.
  • the one agent that inhibits at least two checkpoint regulators may inhibit (e.g. antagonize) two of CTLA-4, PD-1, PD-L1, and LAG-3.
  • the one agent that inhibits at least two checkpoint regulators may inhibit (e.g. antagonize) PD-1 and LAG-3.
  • the one agent that inhibits at least two checkpoint regulators may inhibit (e.g.
  • the one agent that inhibits at least two checkpoint regulators may inhibit (e.g. antagonize) PD-1 and CTLA-4.
  • the one agent that inhibits at least two checkpoint regulators may inhibit (e.g. antagonize) PD-L1 and CTLA-4.
  • the one agent that inhibits at least two checkpoint regulators may be a bispecific molecule.
  • a “bispecific molecule” refers to molecule that is engineered to bind to two different epitopes, antigens or receptors.
  • the one or more agents that inhibit at least two checkpoint regulators comprises at least one agent that inhibits at least two checkpoint regulators.
  • the at least one agent that inhibits at least two checkpoint regulators is a bispecific antibody.
  • the term “bispecific antibody” refers to an antibody that is engineered to bind to two different epitopes or antigens. According to the present invention, the bispecific antibody inhibits at least two checkpoint regulators.
  • the bispecific antibody may be antagonistic to one or two checkpoint regulators.
  • the bispecific antibody may be blocking to one or two checkpoint regulators.
  • the bi specific antibody may antagonize one checkpoint regulator and block one checkpoint regulator.
  • the bispecific antibody may antagonize two checkpoint regulators.
  • the bispecific antibody may block two checkpoint regulators.
  • the bispecific antibody may target two of CTLA-4, PD-1, PD-L1, and LAG-3.
  • the bispecific antibody may target PD-1 and LAG-3.
  • the bispecific antibody is tobemstomig (RG6139).
  • the bispecific antibody may target PD-L1 and LAG-3.
  • the bispecific antibody may target PD-1 and CTLA-4.
  • the bispecific antibody is volrustomig (MEDI5752).
  • the bispecific antibody may target PD-L1 and CTLA-4.
  • an agent which inhibits a checkpoint regulator may be referred to as a checkpoint inhibitor.
  • an agent described herein that inhibits a checkpoint regulator can be referred to as a checkpoint inhibitor.
  • a checkpoint inhibitor may bind to and inhibit or block an immune checkpoint receptor or a stimulatory ligand for an immune checkpoint receptor.
  • the “one or more agents that inhibit at least two checkpoint regulators” may comprise two or more checkpoint inhibitors.
  • the present invention provides a method of treating a cancer in a patient, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and two or more checkpoint inhibitors.
  • the present invention also provides a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and two or more checkpoint inhibitors.
  • one checkpoint inhibitor can be an anti -PD-1 antibody and one checkpoint inhibitor can be an anti-LAG3 antibody.
  • one checkpoint inhibitor can be an pembrolizumab or nivolumab and one checkpoint inhibitor can be an relatimab (BMS-986016).
  • one checkpoint inhibitor can be an anti- PD-L1 antibody and one checkpoint inhibitor can be an anti-LAG3 antibody.
  • one checkpoint inhibitor can be durvalumab or atezolizumab and one checkpoint inhibitor can be relatimab (BMS-986016).
  • one checkpoint inhibitor can be an anti-PD-Ll antibody and one checkpoint inhibitor can be an anti-CTLA4 antibody.
  • one checkpoint inhibitor can be durvalumab or atezolizumab and one checkpoint inhibitor can be ipilimumab or tremelimumab.
  • one checkpoint inhibitor can be an anti-PD-1 antibody and one checkpoint inhibitor can be an anti-CTLA4 antibody.
  • one checkpoint inhibitor can be pembrolizumab or nivolumab and one checkpoint inhibitor can be ipilimumab or tremelimumab.
  • the cancer may be any cancer described herein.
  • the cancer is a solid tumor.
  • the solid tumor is sarcoma, carcinoma, or lymphoma.
  • the cancer is associated with Nectin-4 expression. In some embodiments, the cancer is high Nectin-4 expressing. In some embodiments, the cancer is malignant. In some embodiments, the cancer is metastatic.
  • the cancer is associated with CD137 expression. In some embodiments, the cancer is associated with Nectin-4 expression and the cancer is associated with CD137 expression. In some embodiments, the cancer (e.g. solid tumor) comprises CD137 positive cells (in other words, cells that express CD137).
  • the cancer (e.g. solid tumor) that is “associated with Nectin- 4 expression” is positive for Nectin-4 protein expression.
  • a skilled person can readily determine whether a cancer (e.g. solid tumor) is positive for Nectin-4 protein expression.
  • Nectin-4 protein expression may be determined by multiplex immunofluorescence assay, such as MultiOmyxTM hyperplexed immunofluorescence assay.
  • MultiOmyxTM hyperplexed immunofluorescence assay A skilled person would readily be able to perform a multiplex immunofluorescence assay to determine Nectin-4 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of Nectin-4).
  • Nectin-4 expression may be scored using the Combined Positive Score (CPS).
  • CPS Combined Positive Score
  • regions of interest e.g. 30 ROIs
  • FFPE Form-Fixed Paraffin-Embedded tissue section from the cancer.
  • the tissue section can then be stained for Nectin-4 protein and imaged.
  • the number of positive cells can be divided by the total number of cells and then multiplied by 100, and the median value of all ROIs per slide can be used as the final value.
  • a CPS of one or more is considered positive for Nectin-4.
  • the CPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more.
  • Nectin-4 protein expression may be determined by immunohistochemistry. A skilled person can readily perform immunohistochemistry to determine Nectin-4 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of Nectin-4). Nectin-4 protein expression may be scored using the H-score method (the sum of the products of the percent of cells x their staining intensity, on a scale of 0-3 where 0 is negative and 3 is strongly stained). A skilled person would readily be able to determine the H-score.
  • a H- score of one or more is considered positive for Nectin-4.
  • the H-score may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, about 50 or more, about 100 or more, about 150 or more, or about 200 or more.
  • the H-score may be about 100 or more.
  • Nectin- 4 protein expression may be determined by tumor proportion score (TPS). A skilled person would readily be able to determine the TPS.
  • TPS tumor proportion score
  • a TPS of about one or more is considered positive for Nectin-4.
  • the TPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more.
  • BT7480 has been shown to only require low Nectin-4 expression levels for activity. Without wishing to be bound by theory, BT7480 may mediate activity in patients expressing naturally low or heterogeneous levels of Nectin-4. Thus, in some embodiments, the cancer (e.g. solid tumor) is associated with low or heterogeneous Nectin-4 expression.
  • the cancer (e.g. solid tumor) that is “associatedwith CD 137 expression” is positive for CD137 protein expression.
  • CD 137 protein expression may be determined by multiplex immunofluorescence assay, such as MultiOmyxTM hyperplexed immunofluorescence assay.
  • multiplex immunofluorescence assay such as MultiOmyxTM hyperplexed immunofluorescence assay.
  • a skilled person would readily be able to perform a multiplex immunofluorescence assay to determine CD137 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of CD137, e.g. clone BLR051F).
  • CD137 expression may be scored using the Combined Positive Score (CPS).
  • CPS Combined Positive Score
  • regions of interest e.g. 30 ROIs
  • ROIs regions of interest
  • FFPE Form-Fixed Paraffin-Embedded tissue section
  • the tissue section can then be stained for CD137 protein and imaged.
  • the CPS for each region of interest (ROI), the number of positive cells can be divided by the total number of cells and then multiplied by 100, and the median value of all ROIs per slide can be used as the final value.
  • a CPS of one or more is considered positive for CD137.
  • the CPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more.
  • CD137 protein expression may be determined by immunohistochemistry. A skilled person can readily perform immunohistochemistry to determine CD 137 protein expression (for example using, amongst other reagents, an antibody directed to the extracellular domain of CD 137). CD 137 protein expression may be scored using the H-score method (the sum of the products of the percent of cells x their staining intensity, on a scale of 0-3 where 0 is negative and 3 is strongly stained). A skilled person would readily be able to determine the H-score.
  • a H- score of one or more is considered positive for CD137.
  • the H-score may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, about 50 or more, about 100 or more, or about 150 or more.
  • the H-score may be about 100 or more.
  • CD 137 protein expression may be determined by tumor proportion score (TPS). A skilled person would readily be able to determine the TPS. In some embodiments, a TPS of about one or more is considered positive for CD137.
  • the TPS may be about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 10 or more, about 15 or more, about 20 or more, or about 50 or more.
  • the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric/upper gastrointestinal (GI) cancer, pancreatic cancer, head and neck cancer (e.g. HNSCC), cervical cancer, bladder cancer (e.g. urothelial cancer), and melanoma.
  • the cancer is colorectal cancer.
  • the cancer is bladder cancer.
  • the bladder cancer is selected from the group consisting of basal, p53-like, and luminal.
  • the cancer is endometrial cancer.
  • the endometrial cancer is selected from the group consisting of MMR-D, POLE EDM, p53 WT, p53 abnormal, Type I, Type II, carcinoma, carcinosarcoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed or undifferentiated carcinoma, mixed serous and endometrioid, mixed serous and low-grade endometrioid, and undifferentiated.
  • the cancer is esophageal cancer.
  • the esophageal cancer is selected from the group consisting of adenocarcinoma (EAC), squamous cell carcinoma (ESCC), chromosomal instability (CIN), Epstein-Barr virus (EBV), genomically stable (GS), and microsatellite instability (MSI).
  • EAC adenocarcinoma
  • ESCC squamous cell carcinoma
  • CIN chromosomal instability
  • EBV Epstein-Barr virus
  • GS genomically stable
  • MSI microsatellite instability
  • the cancer is glioblastoma.
  • the glioblastoma is selected from the group consisting of proneural, neural, classical, and mesenchymal.
  • the cancer is mesothelioma.
  • the mesothelioma is selected from the group consisting of pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, epithelioid mesothelioma, sarcomatoid mesothelioma, biphasic mesothelioma, and malignant mesothelioma.
  • the cancer is multiple myeloma.
  • the multiple myeloma is selected from the group consisting of hyperdiploid, non-hyperdiploid, cyclin D translocation, MMSET translocation, MAF translocation, and unclassified.
  • the cancer is ovarian cancer.
  • the ovarian cancer is selected from the group consisting of clear cell, endometrioid, mucinous, high-grade serous and low-grade serous ovarian cancer.
  • the cancer is pancreatic cancer.
  • the pancreatic cancer is selected from the group consisting of squamous, pancreatic progenitor, immunogenic, and ADEX (Aberrantly Differentiated Endocrine eXocrine) pancreatic cancer.
  • the cancer is prostate cancer.
  • the prostate cancer is selected from the group consisting of AZGP1 (subtype I), MUC1 (subtype II), and MUC1 (subtype III) prostate cancer.
  • a cancer is a lung cancer.
  • a lung cancer is a met-amplified squamous NSCLC, a squamous cell NSCLC with wild type EGFR, or a T790M EGFR-expressing lung adenocarcinoma.
  • a cancer is a breast cancer.
  • a breast cancer is a triple negative breast cancer.
  • a breast cancer is a basaloid triple negative breast cancer.
  • a cancer is a colon cancer. In some embodiments, a cancer is a colorectal adenocarcinoma. In some embodiments, a colorectal adenocarcinoma is a high pgp-expressing colorectal adenocarcinoma.
  • a cancer is a gastric cancer.
  • a gastric cancer is a FGFR-amplified gastric cancer.
  • a cancer is a head and neck cancer.
  • a head and neck cancer is a nasal septum squamous cell carcinoma.
  • a cancer is a sarcoma.
  • a sarcoma is a fibrosarcoma.
  • a fibrosarcoma is an N-ras mutant/IDHl mutant soft tissue sarcoma (STS).
  • Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endo
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma
  • the cancer is acoustic neuroma, astrocytoma (e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - G
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocy
  • the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Wald
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma
  • HCC
  • the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepat
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In
  • the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T- cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papilloma virus
  • adult T-cell leukemia which is caused by human T- cell leukemia virus type I (HTLV-I) and is a highly aggressive
  • a cancer is melanoma cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is lung cancer. In some embodiments, a cancer is small cell lung cancer (SCLC). In some embodiments, a cancer is non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • a pharmaceutical composition comprising BT7480, or a pharmaceutically acceptable salt thereof, can be used in place of the BT7480, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a pharmaceutical composition comprising the one or more agents that inhibit at least two checkpoint regulators can be used in place of the one or more agents that inhibit at least two checkpoint regulators.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the pharmaceutical composition may comprise all of the one or more agents that inhibit at least two checkpoint regulators.
  • the one or more agents that inhibit at least two checkpoint regulators comprises two agents, then there may be a first pharmaceutical composition comprising a first agent (i.e. one of the two agents), and a second pharmaceutical composition comprising a second agent (i.e. the other of the two agents).
  • any of the above pharmaceutical compositions e.g. a pharmaceutical composition comprising all of the one or more agents that inhibit at least two checkpoint regulators, or a separate pharmaceutical composition for each agent of the one or more agents that inhibit at least two checkpoint regulators
  • any of the above pharmaceutical compositions can be used in place of the one or more agents that inhibit at least two checkpoint regulators.
  • a first pharmaceutical composition comprising one of the one or more agents that inhibit at least two checkpoint regulators (which can be referred to as a first agent) and a second pharmaceutical composition comprising one of the one or more agents that inhibit at least two checkpoint regulators (which can be referred to as a second agent), wherein the agent in the first pharmaceutical composition is different to the agent in the second pharmaceutical composition (in other words, the first agent and second agent are different), can be used in place of the one or more agents that inhibit at least two checkpoint regulators.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the pharmaceutical compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-
  • the treating may ameliorate one or more symptoms.
  • One or more symptoms may be completely remedied.
  • the compounds, agents, combinations and/or pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compounds, agents, combinations and/or pharmaceutical compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of compounds, agents, combinations and/or pharmaceutical compositions may be aqueous or oleaginous suspension.
  • suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di -glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the compounds, agents, combinations and/or pharmaceutical compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the compounds, agents, combinations and/or pharmaceutical compositions may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • the compounds, agents, combinations and/or pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds or agents include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation.
  • Such pharmaceutical compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions may also be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutical compositions are administered without food. In other embodiments, pharmaceutical compositions are administered with food.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound or agent described herein in the pharmaceutical composition will also depend upon the particular compound or agent in the pharmaceutical composition.
  • the present invention provides a method of treating a cancer in a patient, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the cancer may be a solid tumor.
  • the treating may result in the maintenance or reduction of the volume of the solid tumor.
  • the present invention also provides a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the maintaining or reducing the volume of the solid tumor may treat the cancer.
  • the methods of the invention can result in the maintenance or reduction of the volume of the solid tumor.
  • the maintaining or reducing of the volume of the solid tumor may treat the cancer.
  • “Maintenance” or “maintaining” the volume of the solid tumor refers to the disease not progressing. In some embodiments, “maintenance” or “maintaining” the volume of the solid tumor refers to an increase in the volume of the solid tumor of no more than 30%. In some embodiments, “maintenance” or “maintaining” the volume of the solid tumor refers to the volume of the solid tumor increasing by no more than 30% and decreasing by no more than 30%.
  • the treating results in the volume of the solid tumor being no more that 30% greater than the volume of the tumor at the first administration and the volume of the tumor being no less than 30% less than the volume of the tumor at the first administration.
  • the volume of the solid tumor is maintained or reduced when measured at at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 42 days, at least 48 days, at least 56 days, at least 63 days, or at least 70 days after first administration of BT7480, or a pharmaceutically acceptable salt thereof.
  • the volume of the solid tumor is maintained or reduced when measured at at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 42 days, at least 48 days, at least 56 days, at least 63 days, or at least 70 days after first administration of the one or more agents that inhibit at least two checkpoint regulators.
  • the volume of the solid tumor is reduced by at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, at least 95%, or 100%.
  • the volume of the tumor may be measured and compared to the volume of the tumor at the first administration.
  • the volume of the solid tumor is measured by caliper measurement.
  • the BT7480, or a pharmaceutical acceptable salt thereof is administered at a dose of up to about 10 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.002 mg/kg to about 7.5 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.02 mg/kg to about 7.5 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.05 mg/kg to about 7.5 mg/kg.
  • the BT7480, or a pharmaceutical acceptable salt thereof is administered at a dose of about 0.1 mg/kg to about 7.5 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.15 mg/kg to about 7.5 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.02 to about 6 mg/kg, about 0.05 to about 6 mg/kg, about 0.15 to about 6 mg/kg, about 0.3 to about 6 mg/kg, about 0.6 to about 6 mg/kg, about 1.3 to about 6 mg/kg, or about 2.6 to about 6 mg/kg.
  • the BT7480 is administered at a dose of about 0.002 mg/kg, about 0.006 mg/kg, about 0.02 mg/kg, about 0.05 mg/kg, about 0.15 mg/kg, about 0.3 mg/kg, about 0.6 mg/kg, about 1.3 mg/kg, about 2.0 mg/kg, about 2.6 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 3.9 mg/kg, about 4.25 mg/kg, about 5.0 mg/kg, about 5.75 mg/kg, about 6.0 mg/kg, about 6.5 mg/kg, about 7.0 mg/kg, or about 7.5 mg/kg.
  • the BT7480, or a pharmaceutical acceptable salt thereof is administered at a dose of about up to about 7.5 mg/kg, about 0.002 to about 7.5 mg/kg, about 0.01 to about 7.5 mg/kg, about 0.1 to about 7.5 mg/kg, about 0.3 to about 7.5 mg/kg, about 0.6 to about 6.0 mg/kg, about 1.3 to about 5.5 mg/kg, about 2.6 to about 5.75 mg/kg, or about 2.6 to about 5.0 mg/kg, or about 3.0 to about 4.0 mg/kg.
  • the BT7480, or a pharmaceutical acceptable salt thereof is administered at a dose of about 0.3 mg/kg to about 5.0 mg/kg, about 0.3 to about 3.5 mg/kg, about 0.3 to about 2.6 mg/kg, about 0.6 mg/kg to about 5.0 mg/kg, about 0.6 to about 3.5 mg/kg, about 0.6 to about 2.6 mg/kg, about 1.3 mg/kg to about 5.0 mg/kg, about 1.3 to about 3.5 mg/kg, or about 1.3 to about 2.6 mg/kg.
  • the BT7480, or a pharmaceutical acceptable salt thereof is administered at a dose of about 0.3 to about 3.5 mg/kg, about 0.6 to about 3.5 mg/kg, about 1.3 to about 3.5 mg/kg, or about 2.6 to about 3.5 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 0.3 mg/kg, about 0.6 mg/kg, about 1.3 mg/kg, about 2.6 mg/kg, or about 3.5 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 2.6 mg/kg. In some embodiments, the BT7480, or a pharmaceutical acceptable salt thereof, is administered at a dose of about 3.5 mg/kg.
  • the BT7480, or a pharmaceutically acceptable salt thereof is administered at a frequency of once a week. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once every 1.5 weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once every 2 weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once every 2.5 weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once every 3 weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once every 4 weeks. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered at a frequency of once a month.
  • the BT7480, or a pharmaceutically acceptable salt thereof is administered at a frequency of once a week or once every two weeks.
  • the BT7480, or a pharmaceutically acceptable salt thereof is administered by an intravenous bolus injection. In some embodiments, the BT7480, or a pharmaceutically acceptable salt thereof, is administered by an intravenous infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 5-10 minute infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 10-20 minute infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 20-40 minute infusion.
  • an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof is an about 45, or about 50, or about 55 minute infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 55-75 minute infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 1 hour infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 1-1.5 hr infusion. In some embodiments, an intravenous infusion of the BT7480, or a pharmaceutically acceptable salt thereof, is an about 1.5-2 hr infusion.
  • one or more of the one or more agents that inhibit at least two checkpoint regulators is administered at a dose of about 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/kg. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered at a dose of about 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.
  • one or more of the one or more agents that inhibit at least two checkpoint regulators is administered at a frequency of 1, 2, 3, or 4 times a week. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered once daily. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered once every 2 days. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered once every 3 days. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered once every 4 days. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered once every 5 days.
  • one or more of the one or more agents that inhibit at least two checkpoint regulators is administered at a frequency of once every 4 weeks. In some embodiments, one or more of the one or more agents that inhibit at least two checkpoint regulators is administered at a frequency of once a month.
  • the term “combination” refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • the BT7480, or a pharmaceutically acceptable salt thereof may be administered with the one or more agents that inhibit at least two checkpoint regulators simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • each of the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators may be administered in separate unit dosage forms.
  • the amount of the BT7480, or a pharmaceutically acceptable salt thereof, for example, as described herein, and/or the one or more agents that inhibit at least two checkpoint regulators that may be combined with the carrier materials to produce a single unit dosage form will vary depending upon the host treated and the particular mode of administration.
  • the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators may act synergistically. Therefore, the amount of the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators may be less than that required in a monotherapy utilizing only that therapeutic agent.
  • the amount administered of the one or more agents that inhibit at least two checkpoint regulators present in the compositions of this invention may be no more than the amount that would normally be administered if it was the only active agent (i.e. monotherapy).
  • the amount administered of the one or more agents that inhibit at least two checkpoint regulators in the presently disclosed compositions will range from about 50% to 100% of the amount that would normally be administered if it was the only active agent (i.e. monotherapy).
  • the one or more agents that inhibit at least two checkpoint regulators is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered as monotherapy.
  • the phrase “the amount that would normally be administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • the amount administered of the one or more agents that inhibit at least two checkpoint regulators may be no more than the amount that would normally be administered if it was the only active agent (i.e. monotherapy).
  • the amount administered of the one or more agents that inhibit at least two checkpoint regulators will range from about 50% to 100% of the amount that would normally be administered if it was the only active agent (i.e. monotherapy).
  • the one or more agents that inhibit at least two checkpoint regulators is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered as monotherapy.
  • the invention further provides BT7480, or a pharmaceutically acceptable salt thereof, for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the maintaining or reducing the volume of the solid tumor treats the cancer.
  • the method of maintaining or reducing may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the invention further provides one or more agents that inhibit at least two checkpoint regulators for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • the method of treating may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the invention further provides a combination of BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators for use in a method of treating a cancer in a patient, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • the method of treating may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the invention further provides a combination of BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • the maintaining or reducing the volume of the solid tumor treats the cancer.
  • the method of maintaining or reducing may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the invention further provides use of BT7480 or a pharmaceutical acceptable salt thereof, in the manufacture of a medicament for use in a method of treating a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the method of treating may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the medicament can be used in combination with the one or more agents that inhibit at least two checkpoint regulators.
  • the invention further provides use of BT7480 or a pharmaceutical acceptable salt thereof, in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient the BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators.
  • the maintaining or reducing the volume of the solid tumor treats the cancer.
  • the method of maintaining or reducing may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the medicament can be used in combination with the one or more agents that inhibit at least two checkpoint regulators.
  • the invention further provides use of one or more agents that inhibit at least two checkpoint regulators in the manufacture of a medicament for use in a method of treating a cancer, wherein the method comprises administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • the method of treating may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the medicament can be used in combination with the BT7480, or a pharmaceutically acceptable salt thereof.
  • the invention further provides use of one or more agents that inhibit at least two checkpoint regulators in the manufacture of a medicament for use in a method of maintaining or reducing the volume of a solid tumor in a patient suffering from a cancer, wherein the method comprises administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and the one or more agents that inhibit at least two checkpoint regulators.
  • the maintaining or reducing the volume of the solid tumor treats the cancer.
  • the method of maintaining or reducing may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the medicament can be used in combination with the BT7480, or a pharmaceutically acceptable salt thereof.
  • the invention also provides one or more agents that inhibit at least two checkpoint regulators for use in method of treating a cancer in a patient that has previously received or is scheduled to receive BT7480 or a pharmaceutically acceptable salt thereof.
  • the one or more agents that inhibit at least two checkpoint regulators may be any of the one or more agents that inhibit at least two checkpoint regulators described herein.
  • the method of treating may be any suitable method described herein.
  • the one or more agents that inhibit at least two checkpoint regulators comprises two or more agents that each inhibit one checkpoint regulator.
  • the methods of invention comprises administering one agent that inhibits PD-1 and one agent that inhibits LAG3, and the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric/upper gastrointestinal (GI) cancer, pancreatic cancer, head and neck cancer (e.g. HNSCC), cervical cancer, bladder cancer (e.g. urothelial cancer), and melanoma.
  • lung cancer e.g. NSCLC
  • ovarian cancer ovarian cancer
  • breast cancer e.g. TNBC
  • esophageal cancer gastric/upper gastrointestinal (GI) cancer
  • pancreatic cancer e.g. HNSCC
  • cervical cancer e.g. urothelial cancer
  • melanoma melanoma
  • one agent is an anti -PD
  • the methods of invention comprises administering one agent that inhibits PD-1 and one agent that inhibits LAG3, and the cancer is colorectal cancer.
  • one agent is an anti-PD-1 antibody (e.g. pembrolizumab or nivolumab) and one agent is an anti-LAG3 antibody (e.g. relatimab (BMS-986016)) and the cancer is colorectal cancer.
  • an anti-PD-1 antibody e.g. pembrolizumab or nivolumab
  • an anti-LAG3 antibody e.g. relatimab (BMS-986016)
  • the cancer is colorectal cancer.
  • the methods of invention comprises administering one agent that inhibits PD-L1 and one agent that inhibits CTLA4, and the cancer is selected from the group consisting of lung cancer (e.g. NSCLC), ovarian cancer, breast cancer (e.g. TNBC), esophageal cancer, gastric/upper gastrointestinal (GI) cancer, pancreatic cancer, head and neck cancer (e.g. HNSCC), cervical cancer, bladder cancer (e.g. urothelial cancer), and melanoma.
  • lung cancer e.g. NSCLC
  • ovarian cancer ovarian cancer
  • breast cancer e.g. TNBC
  • esophageal cancer gastric/upper gastrointestinal (GI) cancer
  • pancreatic cancer e.g. HNSCC
  • cervical cancer e.g. urothelial cancer
  • melanoma melanoma
  • one agent is an anti-PD-Ll antibody (e.g. durvalumab or atezolizumab)
  • the methods of invention comprises administering one agent that inhibits PD-L1 and one agent that inhibits CTLA4, and the cancer is colorectal cancer.
  • one agent is an anti-PD-Ll antibody (e.g. durvalumab or atezolizumab) and one agent is an anti-CTLA4 antibody (e.g. ipilimumab or tremelimumab) and the cancer is colorectal cancer.
  • amino acid is intended to be represented as a D-amino acid then the amino acid will be prefaced with a lower case d within square parentheses, for example [dA], [dD], [dE], [dK], [dlNal], [dNle], etc.
  • the term “comprising” is intended to mean including but not limited to.
  • the phrase “a method of treating a cancer in a patient, comprising administering to the patient BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators ” should be interpreted to mean that the method involves administering BT7480, or a pharmaceutically acceptable salt thereof, and one or more agents that inhibit at least two checkpoint regulators, but the method may also involve, e.g., administering further agents.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds described herein are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the term “about” indicates that the given value includes the given value plus or minus 10%, more particularly plus or minus 5%, or more particularly plus or minus 1%.
  • mg/kg refers to the milligram of medication per kilogram of the body weight of the subject taking the medication.
  • the term “comprising” is replaced with the term “consisting essentially of”.
  • the term “consisting essentially of” means that specific further components can be present, namely those not materially affecting the essential characteristics of the subject matter.
  • the term “comprising” is replaced with the term “consisting of” .
  • the term “consisting of” is intended to be limiting.
  • the term “have ” can be replaced with the term “comprise ” or the term “consist of” .
  • the term “has ” can be replaced with the term “compr ises ” or the term “consists of” .
  • mice were randomized into treatment groups when average tumor volumes reached around 104 mm 3 and were treated intravenously (IV) with 25 mM histidine, 10% sucrose, pH7 (BT7480 vehicle) and intraperitoneally (IP) with PBS (antibody vehicle), BT7480, an anti-PD-1 antibody (pembrolizumab), an anti-LAG3 antibody (anti -mouse LAG3 antibody; clone C9B7W), a combination of BT7480 and the anti-PD-1 antibody, a combination of BT7480 and the anti-LAG3 antibody, a combination of the anti-PD-1 antibody and the anti-LAG3 antibody, or a combination of BT7480, the anti-PD-1 antibody and the anti-LAG3 antibody.
  • IV intravenously
  • IP intraperitoneally
  • BT7480 was dosed IV at 5 mg/kg (Oh & 24h).
  • the anti-PD-1 antibody was dosed IP at 6 mg/kg.
  • the anti-LAG3 antibody was dosed IP at 10 mg/kg.
  • the mice were treated weekly (QW) for 4 dosing cycles. Therefore, the mice were treated on DO, DI (BT7480 only), D7, D8 (BT7480 only), D14, D15 (BT7480 only), D21 and D22 (BT7480 only). Tumor growth has been monitored by caliper measurements. Data until Day 108 from treatment initiation is shown in Figure 1.
  • Figure 1 (A) tumor volume data is shown for each treatment cohort until less than half of the animals survive. Animals with >2000 mm 3 tumors were sacrificed as they had reached the Humane Endpoint.
  • Figure 1A shows the tumor volumes over time.
  • the triple combination of BT7480, the anti-PD-1 antibody and the anti-LAG3 antibody resulted in the most complete responses (CRs) in 6 out of the 7 treated animals (6/7) (see Figure 1C). This is more than the number of CRs for the monotherapies of BT7480 (3/7), the anti-PD-1 antibody (0/7) and the anti-LAG3 antibody (0/7), and for the dual combination therapies of BT7480/anti-PD-l antibody (4/7), BT7480/anti-LAG3 antibody (3/7), and anti-PD-1 antib ody/anti-LAG3 antibody (1/7) by Day 108 from treatment initiation.
  • the triple combination of BT7480, the anti-PD-1 antibody and the anti-LAG3 antibody also resulted in the highest probably of survival (see Figure IB).
  • Example 2 Efficacy Study with BT7480, anti-PD-Ll and anti-CTLA4 in combination
  • 6-8 week old female huCD137-C57Bl/6 mice were implanted subcutaneously with lxlO+e6 MC38#26 cells (MC38 cells engineered to overexpress Nectin-4).
  • mice were randomized into treatment groups when average tumor volumes reached around 94 mm 3 and were treated intravenously (IV) with 25 mM histidine, 10% sucrose, pH7 (BT7480 vehicle) and intraperitoneally (IP) with PBS (antibody vehicle), BT7480, an anti-PD-Ll antibody (anti-mouse-PD-Ll antibody; clone 10F.9G2), an anti-CTLA4 antibody (anti-mouse-CTLA4 antibody; clone 9H10), a combination of BT7480 and the anti-PD-Ll antibody, a combination of BT7480 and the anti-CTLA4 antibody, a combination of the anti-PD-Ll antibody and the anti-CTLA4 antibody, or a combination of BT7480, the anti-PD-Ll antibody and the anti-CTLA4 antibody.
  • IV intravenously
  • IP intraperitoneally
  • BT7480 an anti-PD-Ll antibody
  • an anti-CTLA4 antibody anti-mouse-CT
  • BT7480 was dosed IV at 5 mg/kg (Oh & 24h).
  • the anti-PD-Ll antibody was dosed IP at 10 mg/kg.
  • the anti-CTLA4 antibody was dosed IP at 2.5 mg/kg.
  • the anti- CTLA4 antibody dose was suboptimal to evaluate the combination effect of a reduced dose.
  • the mice were treated weekly (QW) for 4 dosing cycles. Therefore, the mice were treated on DO, DI (BT7480 only), D7, D8 (BT7480 only), D14, D15 (BT7480 only), D21 and D22 (BT7480 only). Tumor growth has been monitored by caliper measurements. Data until Day 72 from treatment initiation is shown in Figure 2. For Figure 2 (A), tumor volume data is shown for each treatment cohort until less than half of the animals survive. Animals with >2000 mm 3 tumors were sacrificed as they had reached the Humane Endpoint.

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Abstract

La présente invention concerne l'utilisation du complexe peptidique bicyclique hétérotandem BT7480, ou d'un sel pharmaceutiquement acceptable de celui-ci, en combinaison avec un ou plusieurs agents qui inhibent au moins deux régulateurs de point de contrôle pour le traitement du cancer.
PCT/EP2024/086405 2023-12-13 2024-12-13 Polythérapie destinée à être utilisée dans le traitement du cancer Pending WO2025125652A1 (fr)

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WO2004077062A2 (fr) 2003-02-27 2004-09-10 Pepscan Systems B.V. Procede pour selectionner un compose medicamenteux d’interet potentiel
WO2006078161A1 (fr) 2005-01-24 2006-07-27 Pepscan Systems B.V. Composes liants, composes immunogenes et composes peptidomimetiques
WO2009098450A2 (fr) 2008-02-05 2009-08-13 Medical Research Council Procédés et compositions
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WO2022038158A1 (fr) * 2020-08-17 2022-02-24 Bicycletx Limited Conjugués "bicycle" spécifiques de la nectine-4 et leurs utilisations
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