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WO2019088176A1 - Amplificateur de l'effet d'un conjugué anticorps-médicament - Google Patents

Amplificateur de l'effet d'un conjugué anticorps-médicament Download PDF

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WO2019088176A1
WO2019088176A1 PCT/JP2018/040536 JP2018040536W WO2019088176A1 WO 2019088176 A1 WO2019088176 A1 WO 2019088176A1 JP 2018040536 W JP2018040536 W JP 2018040536W WO 2019088176 A1 WO2019088176 A1 WO 2019088176A1
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antibody
drug
drug complex
linker
effect
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広 松岡
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Kobe University NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to means etc. for enhancing the effect of antibody drug complex.
  • the results of chemotherapy for acute myeloid leukemia (AML) are not satisfactory, and the 5-year survival rate remains at less than 40%.
  • the molecular target drug Gemtuzumab ozogamicin (Gemtuzumab Ozogamicin (GO)) is an antibody-drug complex (Antibody-Drug Conjugates: ADC) in which an anti-CD33 monoclonal antibody and calicheamicin having a potent cell-killing effect are combined. Since expression was observed in about 90% of AML cases, it was hoped to be a breakthrough molecular targeting drug for AML.
  • An object of the present invention is to provide a method for enhancing the effect of GO (gemtuzumab ozogamicin).
  • the present inventors activate lysosomes by activating lysosomes (in particular, increasing the number of intracellular lysosomes) to effectively cleave the linker (hydrazone linker) that links GO gemtuzumab and ozogamicin. It has been found that mTOR inhibitors can be suitably used to convert (especially to increase the number of intracellular lysosomes). Then, after the antibody drug complex (Antibody-Drug Conjugate: ADC) is bound to the cells recognized by the antibody, it is usually taken up into the cell by endocytosis, and in lysosome, the linker that binds the antibody and the drug is cleaved. It is recognized that activating the lysosome can enhance the effect of not only GO, but also the antibody drug complex, since the separated drug exerts its drug effect in cells, and further improvement is completed to complete the present invention. It reached.
  • ADC Antibody-Drug Conjugate
  • the present invention includes, for example, the subject matters described in the following sections.
  • Item A-1 An antibody drug complex effect enhancer comprising a lysosomal activator.
  • Item A-2 The enhancer according to Item A-1, wherein the lysosomal activator is an mTOR inhibitor.
  • Item A-3 The enhancer according to item A-1, wherein the lysosomal activator is at least one selected from the group consisting of rapamycin, temsirolimus, everolimus, PP242, Torin1, AZD2014, and MLN0128.
  • Item A-4 The enhancer according to item A-1, wherein the lysosomal activator is at least one selected from the group consisting of rapamycin, temsirolimus, everolimus, PP242, Torin1, AZD2014, and MLN0128.
  • the drug of the antibody-drug complex is an anticancer drug (eg, calicheamicin, esperamycin, emtansine, auristatin F-HPA (F-hydroxypropylamide), a derivative of DX-8951 (DXd), and monomethyl auristatin E (The enhancer according to any one of Items A-1 to A-3, which is at least one selected from the group consisting of MMAE). Item A-5.
  • an anticancer drug eg, calicheamicin, esperamycin, emtansine, auristatin F-HPA (F-hydroxypropylamide), a derivative of DX-8951 (DXd), and monomethyl auristatin E
  • the enhancer according to any one of Items A-1 to A-3, which is at least one selected from the group consisting of MMAE). Item A-5.
  • the antibody of the antibody-drug complex and the drug are linked by a linker that is cleaved in lysosome (preferably, a linker that is cleaved by an acidic cleavable linker or a linker that is cleaved by an intralysosomal enzyme)
  • a linker that is cleaved in lysosome preferably, a linker that is cleaved by an acidic cleavable linker or a linker that is cleaved by an intralysosomal enzyme
  • the enhancer according to any one of Items A-1 to A-4.
  • Item A-6 Item A-1 to A, wherein the antibody of the antibody-drug complex and the drug are linked by at least one selected from the group consisting of a hydrazone linker, a maleimide linker, a thioether linker, a peptide linker, and a combination thereof
  • the antibody of the antibody drug complex is at least one selected from the group consisting of gemtuzumab, trastuzumab, brentuximab, inotuzumab, rituximab, ofatumumab, mogamulizumab, and alemtuzumab, at least one of items A-1 to A-4.
  • Item B-1 An antibody-drug complex composition used to be administered to a patient in a state where a lysosomal activator is or has been administered.
  • Item B-2 The antibody / drug conjugate composition according to Item B-1 wherein the lysosomal activator is an mTOR inhibitor.
  • Item B-3 The antibody-drug complex composition according to Item B-1, wherein the lysosomal activating agent is at least one selected from the group consisting of rapamycin, temsirolimus, everolimus, PP242, Torin1, AZD2014, and MLN0128.
  • Item B-4 The antibody-drug complex composition according to Item B-1, wherein the lysosomal activating agent is at least one selected from the group consisting of rapamycin, temsirolimus, everolimus, PP242, Torin1, AZD2014, and MLN0128.
  • the drug of the antibody-drug complex is an anticancer drug (eg, calicheamicin, esperamycin, emtansine, auristatin F-HPA (F-hydroxypropylamide), a derivative of DX-8951 (DXd), and monomethyl auristatin E (The antibody-drug complex composition according to any one of Items B-1 to B-3, which is at least one selected from the group consisting of MMAE). Item B-5.
  • an anticancer drug eg, calicheamicin, esperamycin, emtansine, auristatin F-HPA (F-hydroxypropylamide), a derivative of DX-8951 (DXd), and monomethyl auristatin E
  • the antibody-drug complex composition according to any one of Items B-1 to B-3, which is at least one selected from the group consisting of MMAE). Item B-5.
  • the antibody of the antibody-drug complex and the drug are linked by a linker that is cleaved in lysosome (preferably, a linker that is cleaved by an acidic cleavable linker or a linker that is cleaved by an intralysosomal enzyme)
  • a linker that is cleaved in lysosome preferably, a linker that is cleaved by an acidic cleavable linker or a linker that is cleaved by an intralysosomal enzyme
  • the antibody of the antibody-drug complex is at least one selected from the group consisting of gemtuzumab, trastuzumab, brentuximab, inotuzumab, rituximab, ofatumumab, mogamulizumab, and alemtuzumab, any one of paragraphs B-1 to B-4
  • the antibody-drug complex composition according to any one of the above.
  • Item C An antibody-drug complex according to any one of Items A-1 to A-7, comprising: the enhancer according to any one of Items A-1 to A-7; and the antibody-drug complex composition according to any one of Items B-1 to B-7.
  • Item D-1 A leukemia therapeutic composition containing an anti-CD33 antibody-DNA cleaving anticancer drug complex, which is used to be administered to a patient in a state in which a lysosomal activator is or has been administered.
  • Item D-2 The leukemia therapeutic composition according to Item D-1, wherein the lysosomal activator is an mTOR inhibitor.
  • Item D-3 The leukemia therapeutic composition according to Item D-1 or D-2, wherein the mTOR inhibitor is at least one selected from the group consisting of rapamycin, temsirolimus, everolimus, PP242, Torin1, AZD2014, and MLN0128.
  • Item D-4 A leukemia therapeutic composition containing an anti-CD33 antibody-DNA cleaving anticancer drug complex, which is used to be administered to a patient in a state in which a lysosomal activator is or has been administered.
  • Item D-2 The leukemia therapeutic composition according to I
  • Item D-7 The leukemia therapeutic composition according to any one of Items D-1 to D-5, wherein the anti-CD33 antibody-DNA cleaving anticancer drug complex is gemtuzumab ozogamicin.
  • An anti-CD33 antibody-DNA cleavage anti-cancer agent complex effect enhancing composition comprising an anti-CD33 antibody-DNA cleavage anti-cancer agent complex and a lysosomal activator.
  • Item D-8. A kit for treating leukemia, comprising an anti-CD33 antibody-DNA cleavage anticancer drug complex and a lysosomal activator.
  • Item D-9. An anti-CD33 antibody-DNA cleavage anti-cancer drug complex effect enhancer comprising a lysosomal activator.
  • the therapeutic effect of GO (gemtuzumab ozogamicin) as well as the therapeutic effect of an antibody-drug complex other than GO can be enhanced, and there are few side effects.
  • the percentage of dead cells (specific apoptosis) when treated with cells at each concentration of PP242 is shown.
  • concentration PP242 analyzed by a western blot is shown.
  • the result of having evaluated the dead cell percentage (specific apoptosis)% is shown, when PP242 single treatment, GO (gemtuzumab ozogamicin) single treatment, or a combination treatment of PP242 and GO is performed on each AML cell line.
  • Acute myeloid leukemia cell line (SKM-1) is treated with AZD2014 alone, GO (gemtuzumab ozogamicin) alone, or combined treatment with AZD2014 and GO, and after culture for 36 hours, Annexin V-PI (propidium iodide) It shows the result of performing staining and evaluating dead cell percentage (specific apoptosis)% using flow cytometry.
  • the results of staining and analysis of the U937 cell line (without treatment, treatment with AZD2014 alone, treatment with GO alone, or treatment with AZD2014 and a combination of GOD) using the fluorescent dye LysoTracker (registered trademark) are shown.
  • Primary cultured cells were prepared from 6 patients with AML, and using these AML primary cultured cells (AML cells 1 to 6), it was examined whether the GO effect was enhanced by the combination of AZD2014 and GO. (Percentage of dead cells) is shown.
  • the mTOR inhibitor PP242 400 nM and the antibody / drug complex inotuzumab ozogamicin (IO) were used alone or in combination at 2 ng / ml. (Percentage of dead cells) is shown.
  • the present invention encompasses antibody drug complex effect enhancers containing lysosomal activators. (It may be referred to as “the enhancer of the present invention”.)
  • Antibody-Drug Conjugate (ADC) is bound to cells recognized by antibody, then taken up into the cell usually by endocytosis, and further in lysosomes.
  • the linker that binds the antibody and the drug is cleaved, and the separated drug exerts its drug effect in cells. Therefore, activating the lysosome can enhance the effect of the antibody-drug complex.
  • lysosome activating agent one which increases the number of lysosomes per cell (lysosome number increasing agent) is particularly preferable.
  • a lysosomal activator for example, an mTOR inhibitor is preferably mentioned.
  • mTOR is a mammalian target of rapamycin in mammals and is one of protein kinases (serine and threonine kinases) involved in intracellular signal transduction. mTOR forms a complex with multiple proteins, and the complex is called mTORC.
  • mTOR forms two functionally different complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
  • the mTOR inhibitor may be an mTORC1 inhibitor, an mTORC2 inhibitor, or an mTORC dual inhibitor (ie an inhibitor that inhibits both mTORC1 and mTORC2), with the mTORC dual inhibitor being preferred.
  • mTOR inhibitors known mTOR inhibitors can be used. More specifically, for example, rapamycin, temsirolimus, everolimus, PP242 (torquinib), Torin1, AZD2014, MLN0128, ductorisive (BEZ235), AZD8055, SF2523, CZ415, PI-103, KU-0063794, tacrolimus, ridaforolimus, Voxtalisib (SAR 245409, XL 765) Analogue, Omiparisib (GSK 2126458, GSK 458), OSI-027, PF-04691502, Apitrisive (GDC-0980, RG 7422), GSK 1059615, Gedatrisive, WYE-354, Torin 2, WYE-125132 (WYE-132) , BGT226 (NVP-BGT226), P529, PP1 1, WYE-687, WAY-600, ETP
  • mTORC1 inhibitors Can. Rapamycin, temsirolimus and everolimus are mTORC1 inhibitors, and PP242, Torin1, AZD2014 and MLN0128 are mTORC dual inhibitors. mTOR inhibitors can be purchased commercially and used.
  • the lysosomal activator can be used singly or in combination of two or more.
  • the antibody-drug conjugate ADC
  • known antibody-drug conjugates can be used.
  • the antibody and the drug are linked by a linker.
  • the linker for example, a linker that is cleaved in lysosome is preferable.
  • the linker that is cleaved in lysosome includes, for example, a linker that is linked by a linker that is cleaved in an acidic state or that is cleaved by an enzyme in lysosome.
  • a linker known in the art (particularly in the antibody drug complex field) or a linker under development can be used.
  • linkers more specifically, for example, hydrazone linker (eg, semicarbazone linker), maleimide linker, thioether linker, peptide linker (eg, valine-citrulline (vc) dipeptide linker, valine-alanine (valine) And the like) and the like, and the like) and the like) and the like.
  • the linker comprised by these combination is also preferable.
  • a peptide linker and a maleimide linker can be combined and used as one linker (for example, a maleimide linker can be disposed between an antibody and a peptide linker).
  • linkers have a structure including the structures (semicarbazone, maleimide, hydrazone, thioether, valine-citrulline dipeptide, valine-alanine dipeptide, glycyn-glycyn-phenylalanyn-glycyn (GGFG) peptide etc.) described in each of them.
  • GGFG glycyn-glycyn-phenylalanyn-glycyn
  • linker has a structure including the structures (semicarbazone, maleimide, hydrazone, thioether, valine-citrulline dipeptide, valine-alanine dipeptide, glycyn-glycyn-phenylalanyn-glycyn (GGFG) peptide etc.) described in each of them.
  • the hydrazone linker is stable in serum and, after internalization into cells, is hydrolyzed in the acidic environment within the lysosome
  • Thioether linkers are not easily cleaved, have excellent stability in serum, and are difficult to release drugs in serum, and thus are considered to be less likely to cause side effects. After being taken up by tumor cells, the whole antibody is degraded in lysosome to release toxin.
  • a linker such as Fleximer linker (Mersana Therapeutics) can also be used.
  • linkers listed in, for example, Int J Mol Sci. 2016 Apr; 17 (4): 561 or linkers that can be easily conceived from the known linkers can be used.
  • the linker contained in the antibody drug complex may be one kind alone, or two or more kinds may be combined.
  • One or more of the above linkers may be disposed in one linker.
  • all of the linkers that bind the antibody and the drug may be the same, or two or more types of linkers may be used.
  • the drug (payload) of the antibody-drug complex is not particularly limited, but an anticancer drug is preferably exemplified.
  • an anticancer drug for example, one which exerts an anticancer effect by cleaving DNA (a DNA cleaving anticancer agent) is preferably mentioned, but there is no particular limitation.
  • anticancer agents more specifically, for example, calicheamicin, esperamycin, emtansine, auristatin F-HPA (F-hydroxypropylamide), a derivative of DX-8951 (DXd), monomethyl auristatin E (MMAE) and the like can be mentioned.
  • the antibody may be a monoclonal antibody or a polyclonal antibody, preferably a monoclonal antibody.
  • the antibody is preferably a chimeric antibody, a humanized antibody or a fully humanized antibody (human antibody).
  • These antibodies can be produced by known methods or methods easily conceived from known methods. Although not particularly limited, the contents described in, for example, WO2008 / 026603, WO2009 / 041643 and the like can be referred to.
  • the antibody and the drug that make up the antibody drug complex are related to each other. That is, it is preferable that the antibody recognizes a site where the drug effect is particularly required.
  • the drug of the antibody drug complex is an anticancer drug
  • the antibody of the antibody drug complex is preferably an antibody that recognizes a cancer cell, and more preferably an antibody that specifically binds to a cancer cell.
  • An antibody that recognizes such cancer cells can be appropriately prepared using known cancer cell markers as antigens.
  • anti-CD33 antibody, anti-CD30 antibody, anti-CD22 antibody, anti-Her2 antibody and the like can be mentioned.
  • anti-Her2 antibody and the like are particularly preferable.
  • gemtuzumab trastuzumab, brentuximab, inotuzumab, rituximab, ofatumumab, mogamulizumab, alemtuzumab and the like are preferably mentioned.
  • the antibody-drug complex more specifically, for example, Gemtuzumab ozogamicin (product name Myrotag (registered trademark)), Trastuzumab emtansine (product name Kadthyra (registered trademark)), XMT-1522, DS-8201a, Brentuximab bedotin (product name: Adcetris (registered trademark)), inotuzumab ozogamicin (product name: Besponsa), and the like.
  • a known antibody drug conjugate can be searched, and a known antibody drug conjugate obtained as a search result can also be preferably used in the present invention.
  • the known antibody-drug conjugates are grouped together, and these can also be preferably used in the present invention.
  • the potentiator of the present invention may consist of only the lysosomal activator, or may contain other components other than the lysosomal activator.
  • the other ingredients are not particularly limited, and pharmaceutically acceptable bases, carriers, additives (eg, excipients, binders, disintegrants, lubricants, solvents, sweeteners, coloring agents, flavoring agents, odorants) Agents, surfactants, moisturizers, preservatives, pH adjusters, thickening agents, and the like.
  • bases, carriers, additives eg, excipients, binders, disintegrants, lubricants, solvents, sweeteners, coloring agents, flavoring agents, odorants
  • surfactants e.g, surfactants, moisturizers, preservatives, pH adjusters, thickening agents, and the like.
  • the form of the preparation is also not particularly limited, and the active ingredient and other ingredients are mixed in a conventional manner, for example, tablets, coated tablets, powders, granules, fine granules, capsules, pills, solutions, suspensions, emulsions It can be prepared into a formulation such as a jelly, a chewable, a soft tablet and the like.
  • a route of administration of the enhancer of the present invention for example, oral administration or intravenous administration is preferable.
  • the enhancer of the present invention is preferably administered to a patient in an amount capable of activating (particularly increasing the number of lysosomes) to the patient by the lysosomal activator contained, and various lysosomal activators based on the degree of activation.
  • the dose and route of administration can be set as appropriate. And according to this, the dose and administration route of the enhancer of this invention can also be set suitably.
  • the dose and administration route used in the administration studies can also be appropriately set by reference.
  • AZD2014 is an orally administrable drug in clinical trials by AstraZeneca, and Phase 1 test results including PK results have already been published in the literature (above-mentioned non-patent document 2).
  • the recommended dose (recommended dose, RD) is 50 mg twice a day, which can be used as a reference. For example, it can be about 50 to 200 mg, 60 to 180 mg, 70 to 160 mg, 80 to 140 mg, or 90 to 120 mg per day for adults.
  • the daily dose may be administered at once, or may be divided into two, three, or four times a day.
  • the present invention also relates to an antibody-drug complex composition (composition containing an antibody-drug complex), which is used to be administered to a patient to which a lysosomal activating agent has been or has been administered.
  • the antibody drug complex composition may be a composition consisting only of the antibody drug complex, or may further contain other components.
  • the other components are not particularly limited, and, for example, the same components as the other components in the lysosomal activator described above can be used.
  • a pharmaceutically acceptable carrier for example, sterile water, physiological saline, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, binder Etc.
  • sterile compositions for injection can be formulated according to the usual formulation practices using vehicles such as distilled water for injection.
  • the aqueous solution for injection includes, for example, physiological saline, glucose, and isotonic solutions containing other adjuvants (eg, D-sorbitol, D-mannose, D-mannitol, sodium chloride).
  • Suitable solubilizers may be used in combination with, for example, alcohols (ethanol etc.), polyalcohols (propylene glycol, polyethylene glycol etc.), nonionic surfactants (polysorbate 80 (TM), HCO-50 etc.).
  • oily liquid examples include sesame oil, soybean oil and the like, and benzyl benzoate and / or benzyl alcohol may be used in combination as a solubilizing agent. They may also be formulated with buffers (eg, phosphate buffer and sodium acetate buffer), soothing agents (eg, procaine hydrochloride), stabilizers (eg, benzyl alcohol and phenol), and antioxidants.
  • buffers eg, phosphate buffer and sodium acetate buffer
  • soothing agents eg, procaine hydrochloride
  • stabilizers eg, benzyl alcohol and phenol
  • the lysosomal active agent and antibody-drug complex used in the antibody-drug complex composition are the same as described above.
  • a composition containing an anti-CD33 antibody-DNA cleaving anticancer drug complex (that is, a complex in which an anti-CD33 antibody and a DNA cleaving anticancer drug are bound) is particularly preferable as the antibody drug complex composition.
  • an anti-CD33 antibody-DNA cleaving anticancer drug complex that is, a complex in which an anti-CD33 antibody and a DNA cleaving anticancer drug are bound
  • the antibody drug complex composition is particularly preferable as the antibody drug complex composition.
  • a composition having a leukemia cell recognition antibody (preferably a leukemia cell specific antibody) -anticancer drug complex is useful as a leukemia treatment composition.
  • a composition having a leukemia cell recognition antibody (preferably a leukemia cell specific antibody) -anticancer drug complex is useful as a leukemia treatment composition.
  • the leukemia therapeutic composition of the present invention such a composition may be referred to as "the leukemia therapeutic composition of the present invention”.
  • a composition containing an anti-CD33 antibody-DNA cleaving anticancer drug complex is particularly useful as a leukemia therapeutic composition.
  • the leukemia composition of the present invention is not limited thereto, and those skilled in the art are not For example, it can be understood that the applicable portion of the antibody-drug complex composition using different antibodies and / or drugs is also applicable to the antibody-drug complex composition using different antibodies and / or drugs.
  • anti-CD33 antibody-DNA cleavage anticancer drug complex means “cancer cell recognition antibody (preferably cancer cell specific antibody) -anticancer drug complex”, “leukemic cell recognition” It can be read as an antibody (preferably leukemia cell specific antibody) -anticancer drug complex "," leukemia cell recognition antibody (preferably leukemia cell specific antibody) -DNA cleavage anticancer drug complex "and the like.
  • the anti-CD33 antibody may be any antibody that recognizes the CD33 antigen, and is preferably an antibody that specifically recognizes the CD33 antigen.
  • the antibody may be a polyclonal antibody or a monoclonal antibody, preferably a monoclonal antibody.
  • the antibody is preferably a chimeric antibody, a humanized antibody or a fully humanized antibody (human antibody).
  • These antibodies can be produced by known methods or methods easily conceived from known methods. Although not particularly limited, the contents described in, for example, WO2008 / 026603, WO2009 / 041643 and the like can be referred to.
  • DNA cleaving anticancer agents are anticancer agents that exhibit an anticancer effect by cleaving DNA.
  • an anticancer agent a known one can be preferably used. Among them, calicheamicin or esperamycin is preferred, and calicheamicin (especially ozogamicin) is more preferred.
  • the anti-CD33 antibody and the DNA cleaving anticancer agent are preferably linked by a linker that is cleaved (hydrolyzed) in an acidic state, or linked by a linker that is cleaved by an enzyme in lysosome.
  • a linker examples include a maleimide linker, a hydrazone linker (for example, a semicarbazone linker), a thioether linker and the like, and among them, a hydrazone bond is preferable.
  • the anti-CD33 antibody-DNA cleaving anticancer drug complex for example, a complex having a structure in which the anti-CD33 antibody is bound to the DNA cleaving anticancer drug by the binding can be preferably used.
  • Gemtuzumab ozogamicin GO: trade name “Mylotag” (registered trademark) is preferable.
  • the leukemia to be treated with the composition for treating leukemia of the present invention is preferably leukemia (CD33 positive leukemia) in which leukemia cells expressing anti-CD33 antigen are present (CD33 positive leukemia in acute myeloid leukemia (AML)). It is particularly preferred for treatment because of the high proportion of cells.
  • the anti-CD33 antibody-DNA cleaving anticancer drug complex can be used singly or in combination of two or more.
  • the leukemia therapeutic composition of the present invention is used to be administered to a patient in a (i) state or (ii) a state in which a lysosomal activator is administered. That is, the leukemia therapeutic composition of the present invention may be used to (i) be administered to a patient to which a lysosomal activator has already been administered, or (ii) a lysosomal activator has not been administered yet. May be used to be administered to a patient scheduled to be administered. In any case, the administration interval between the lysosomal activator and the leukemia therapeutic composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired.
  • the administration interval may be about two weeks, 1.5 weeks, one week, 6, 5, 4, 3, 2, or 1 day.
  • the interval may be such that the body can reach leukemia cells.
  • the administration interval between the lysosomal activator and the leukemia therapeutic composition of the present invention is preferably within 6, 5, 4, 3, 2, or 1 hour, and more preferably within 30 minutes. It is further preferred that it be within 15 minutes, and even more preferred that it be administered sequentially or simultaneously within 3 minutes.
  • the use of (ii) above includes co-administration with a lysosomal activator.
  • the dosage of the leukemia therapeutic composition of the present invention can be appropriately set based on the amount of the anti-CD33 antibody-DNA cleavage anticancer drug complex contained. That is, the dose of the leukemia therapeutic composition of the present invention may be adjusted so that the dose of the anti-CD33 antibody-DNA cleaving anticancer drug complex contained can exert an anticancer effect.
  • intravenous administration is preferred as the administration route.
  • the dose of GO is preferably 1 to 20 mg / m 2 per adult day, 2, 3, 4, 5 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / m 2 is more preferable.
  • multiple administrations for example, 2, 3, 4 or 5 administrations
  • lysosomal activating agent it is preferable to administer to the patient an amount capable of activating lysosome (in particular, increase the number of lysosomes) to the lysosomal activating agent, and the dosage and administration route of various lysosomal activating agents are appropriately determined It can be set.
  • the dose and administration route used in the administration studies can also be appropriately set by reference.
  • AZD2014 is an orally administrable drug in clinical trials by AstraZeneca, and Phase 1 test results including PK results have already been published in the literature (above-mentioned non-patent document 2).
  • the recommended dose (recommended dose, RD) is 50 mg twice a day, which can be used as a reference. For example, it can be about 50 to 200 mg, 60 to 180 mg, 70 to 160 mg, 80 to 140 mg, or 90 to 120 mg per day for adults.
  • the daily dose may be administered at once, or may be divided into two, three, or four times a day.
  • oral administration or intravenous administration is preferred.
  • a composition containing GO which is used to be administered to a patient to which AZD 2014 has been administered or to be administered, is given as a particularly preferred embodiment of the leukemia therapeutic composition of the present invention.
  • the dose of AZD 2014 be the above dose and the number of doses
  • the dose of GO be also the above dose and the number of doses.
  • a preferred example is a dosing schedule in which GOD is administered 2 or 3 times in 2 weeks (9 to 10 mg in a single dose), and AZD 2014 is dosed twice daily at around 50 mg twice daily. Can.
  • the leukemia therapeutic composition of the present invention may contain, in addition to the anti-CD33 antibody-DNA cleavage anticancer drug complex, a pharmaceutically acceptable carrier and the like.
  • a pharmaceutically acceptable carrier include sterile water and physiological saline, vegetable oils, emulsifiers, suspensions, surfactants, stabilizers, flavors, excipients, vehicles, preservatives, binders, and the like.
  • sterile compositions for injection can be formulated according to the usual formulation practices using vehicles such as distilled water for injection.
  • the aqueous solution for injection includes, for example, physiological saline, glucose, and isotonic solutions containing other adjuvants (eg, D-sorbitol, D-mannose, D-mannitol, sodium chloride).
  • Suitable solubilizers may be used in combination with, for example, alcohols (ethanol etc.), polyalcohols (propylene glycol, polyethylene glycol etc.), nonionic surfactants (polysorbate 80 (TM), HCO-50 etc.).
  • examples of the oily liquid include sesame oil, soybean oil and the like, and benzyl benzoate and / or benzyl alcohol may be used in combination as a solubilizing agent. They may also be formulated with buffers (eg, phosphate buffer and sodium acetate buffer), soothing agents (eg, procaine hydrochloride), stabilizers (eg, benzyl alcohol and phenol), and antioxidants.
  • the present invention provides an anti-CD33 antibody-DNA cleavage anticancer drug complex effect enhancing composition
  • an anti-CD33 antibody-DNA cleavage anticancer drug complex and a lysosomal activator ie, an anti-CD33 antibody—
  • compositions that have an enhanced effect compared to administration of a DNA cleaving anticancer drug complex alone.
  • the anti-CD33 antibody-DNA cleavage anticancer drug complex and the lysosomal activator included in the effect enhancing composition are the same as described above.
  • the effect-enhancing composition may contain other components other than the anti-CD33 antibody-DNA cleavage anticancer drug complex and the lysosomal activator.
  • the same pharmaceutically acceptable carrier in the above-mentioned leukemia therapeutic composition can be used.
  • the administration route of the effect enhancing composition is preferably intravenous administration.
  • the description is also valid for antibody-drug complex compositions using different antibodies and / or drugs. That is, the present invention also encompasses the antibody drug conjugate effect enhancing composition, which comprises an antibody drug conjugate and a lysosomal activator.
  • the present invention also encompasses a kit for treating leukemia, which comprises an anti-CD33 antibody-DNA cleavage anticancer drug complex and a lysosomal activator.
  • the anti-CD33 antibody-DNA cleaving anticancer drug complex and the lysosomal activator provided in the kit are the same as described above.
  • the kit may also contain equipment other than the anti-CD33 antibody-DNA cleavage anticancer drug complex and the lysosomal activator. Such equipment is not particularly limited, and examples thereof include a drip needle and a disinfectant (for example, ethanol).
  • the description is also valid for antibody-drug complex compositions using different antibodies and / or drugs. That is, the present invention also encompasses a kit for treating a disease to be treated by a drug of antibody drug complex, comprising an antibody drug complex and a lysosomal activator.
  • the present invention also encompasses an anti-CD33 antibody-DNA cleavage anti-cancer drug complex effect enhancer comprising a lysosomal activator.
  • the lysosomal activator is the same as described above.
  • the anti-CD33 antibody-DNA cleaving anticancer drug complex to be enhanced is the same as described above.
  • the effect enhancer may include other components other than the lysosomal activator. As such other components, for example, the same pharmaceutically acceptable carrier in the above-mentioned leukemia therapeutic composition can be used.
  • the description is also valid for antibody-drug complex compositions using different antibodies and / or drugs. That is, the present invention also encompasses antibody drug complex effect enhancers, including lysosomal activators.
  • the term “comprising” also includes “consisting essentially of” and “consisting of” (The term “comprising” includes “consisting essentially of” and “consisting of.”). Also, the contents described in the documents and web pages listed in the present specification are incorporated herein by reference. In addition, various characteristics (properties, structures, functions, etc.) described for each embodiment of the present invention described above may be combined in any way in specifying the subject matter included in the present invention. That is, the present invention includes all the subject matter consisting of all combinations of the combinable features described in the present specification.
  • SKNO-1 JCRB Cell Bank, Tokyo, Japan
  • U937 ATCC, Manassas, VA, USA
  • THP-1 ECACC, PD, UK
  • SKM-1 established by the inventor
  • Non-Patent Document 3 Investigation of mTOR Inhibitor Use Concentration It is suggested in the above-mentioned Non-Patent Document 3 that some mTOR inhibitors have the effect of increasing the number of lysosomes per cell.
  • the mTOR inhibitor PP242 used in the literature was selected as the mTOR inhibitor used in the present invention, etc., and the PP242 concentration that did not cause cell damage and exhibits the mTOR inhibitory action was examined.
  • PP242 purchased and used a commercial item. The cells were cultured at 37 ° C., 5% CO 2 and passaged every 48 hours using RPMI 1640 as a culture medium, and used for examination.
  • 100-600 nM of PP242 is added to culture medium of acute myeloid leukemia cell line (U937), and culture is performed for 24 hours, and the concentration which does not cause cell damage as compared with the case of not adding PP242 (control) investigated.
  • the degree of cell damage was determined by comparing the% specific apoptosis.
  • the Annexin V-FITC Apoptosis Detection Kit (Nacalai Tesque, Inc., Japan) was used to examine the percentage of dead cells.
  • Specific apoptosis is the percentage of dead cells calculated by subtracting the natural cell death in the control (normally 4 to 5% of cell death is usually observed naturally in cell line culture) from the cell death measurement value by flow cytometry. It is.
  • Annexin V-FITC PI Propidium Iodide
  • dead cells were determined by flow cytometry.
  • the examination was performed using a kit: Annexin V-FITC Apoptosis Detection Kit (Nacalai Tesque, Inc., Japan).
  • the degree of phosphorylation of AKT protein and S6K protein was analyzed by Western blot. It is well known that inhibition of mTOR reduces phosphorylation of AKT protein and S6K protein, and the phosphorylation is widely used for mTOR inhibition studies. A decrease in phosphorylated S6K indicates mTORC1 inhibition and a decrease in phosphorylated AKT indicates mTORC2 inhibition.
  • the source of the antibody used for Western blot analysis is described below.
  • FIG. 1 shows the specific apoptosis% (FIG. 1a) and the result of Western blot analysis (FIG. 1b) in the examination.
  • FIG. 1a “Ctr” indicates a control
  • P100 indicates PP242 100 nM
  • FIG. 1 b “p-AKT” indicates phosphorylated AKT protein
  • FIG. 1b “(p-) 70S6k” indicates (phosphorylated) S6K protein. From the results, it was confirmed that almost no cell damage occurred at 100 to 500 nM of PP242 (FIG. 1a), and an mTOR inhibitory effect was obtained at 200 to 500 nM (FIG. 1b). Based on the results, PP242 treatment was performed at a concentration of 500 nM unless otherwise specified in the following study.
  • the GO treatment concentration was 0.5 ⁇ g / ml for THP-1 and SKNO-1, and 2.5 ⁇ g / ml for other cell lines. This concentration setting is based on the following circumstances.
  • the blood concentration (Pharmacokinetics, PK) under administration of an approved dose of GO (9 mg / m 2 twice a day for 14 days or more) has been reported (MIROTAGG® Interview Form).
  • PK Pharmacokinetics, PK
  • GO was administered at 0.5 ⁇ g / ml in a cell line in which the effect was strongly observed.
  • the GO treatment concentration for each AML cell line was the same in the subsequent studies unless otherwise stated.
  • Lysosomes in Acute Myeloid Leukemia (AML) Cell Line The AML cells were stained with the fluorescent dye LysoTracker (registered trademark) (Invitrogen) to examine lysosomes.
  • the fluorescent dye functions to stain an acidic structure in cells and is considered to stain normal acidic lysosome.
  • lysosomes of U937 and THP-1 were stained by the fluorescence expression. The results are shown in FIG. In the left panel of FIG. 3, cell corners are blue and lysosomes are red. Further, the right side of FIG. 3 is a graph of the intensity of red fluorescence.
  • LysoTracke fluorescent spot in AML cells was very small and thus the number of lysosomes was small.
  • LysoTracke fluorescent spots were enhanced about 1.5 times in the U937 cell line, and with the PP242 and GO combined treatment, the LysoTracke fluorescence remained enhanced. Similar results were obtained with the THP-1 cell line.
  • the action mechanism of GO which is an antibody-drug conjugate (ADC) is digestion of a linker in lysosome.
  • the linker of GO is a hydrazone linker which is hydrolyzed in an acidic environment, and the linker links the anti-CD33 monoclonal antibody and calicheamicin (ozogamicin).
  • ADC antibody-drug conjugate
  • the phagocytes fuse with lysosomes to become secondary phagocytes, and the linker is hydrolyzed in the acidic environment in lysosomes to release calicheamicin to become active form. Free and active calicheamicin binds to DNA in the nucleus, causing DNA double strand breaks, leading to cell death (FIG. 4). Thus, retention of lysosomal function in leukemia cells is important for GO effect expression.
  • AZD2014 is a drug under investigation by AstraZeneca, and Phase 1 test results including PK results have already been published in the literature (above Non-Patent Document 2), and can be purchased from a reagent company.
  • the recommended dose (recommended dose, RD) for humans defined in the Phase 1 study of AZD 2014 is 50 mg twice daily.
  • Acute myelogenous leukemia cell line (U937 or SKM-1) is treated with AZD2014 alone, GO (gemtuzumab ozogamicin) alone, or combined treatment with AZD2014 and GO, and cultured for 36 hours after Annexin V-PI (propidium) Iodide) staining was performed to assess the% specific apoptosis using flow cytometry.
  • the results are shown in Figure 5a (U937) and Figure 5b (SKM-1).
  • lysosomes are stained by staining each U937 cell (without treatment, treatment with AZD2014 alone, treatment with GO alone, or treatment with AZD2014 in combination with AZD2014) with the fluorescent dye LysoTracker (registered trademark) (Invitrogen) went.
  • LysoTracker registered trademark
  • FIG. 6 cell nuclei are blue and lysosomes are red.
  • the right side of FIG. 6 is a graph of the intensity of red fluorescence (a relative value with the control being 1).
  • primary cultured cells are prepared from 6 patients with AML, and using the AML primary cultured cells (AML cells 1 to 6), the GO effect is enhanced by the combination of AZD2014 and GO in the same manner as above. We examined whether it was recognized. The results (percentage of dead cells) are graphed and shown in FIG. Also from the results, it can be confirmed that the GO effect is enhanced by the combined use of the mTOR inhibitor (AZD2014) and GO.
  • the preparation of primary culture cells was performed according to the method described in the above-mentioned supplementary materials and methods of Non-Patent Document 1 (Leukemia (2013) 27, 233-235).
  • MLN 0128 also referred to as INK128 or TAK-228
  • AML acute myeloid leukemia
  • the lysosomal activator (in particular, the mTOR inhibitor) exerts an effect of enhancing the effect of the antibody-drug complex.

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Abstract

La présente invention concerne un procédé permettant d'amplifier l'effet d'un conjugué anticorps-médicament tel que GO (gemtuzumab-ozogamicine). Plus spécifiquement, l'invention concerne un amplificateur de l'effet d'un conjugué anticorps-médicament qui contient un activateur de lysosome.
PCT/JP2018/040536 2017-10-31 2018-10-31 Amplificateur de l'effet d'un conjugué anticorps-médicament Ceased WO2019088176A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
JP2015078168A (ja) * 2013-10-18 2015-04-23 ピーエスエムエー ディベロップメント カンパニー，エルエルシー Ｐｓｍａリガンドコンジュゲートによる併用療法
JP2017101041A (ja) * 2010-10-22 2017-06-08 シアトル ジェネティクス，インコーポレーテッド アウリスタチン系抗体薬物複合体とＰＩ３Ｋ−ＡＫＴ ｍＴＯＲ経路インヒビターの間の相乗効果
JP2017530983A (ja) * 2014-10-10 2017-10-19 ファイザー・インク 相乗的オーリスタチン組合せ

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JP2017101041A (ja) * 2010-10-22 2017-06-08 シアトル ジェネティクス，インコーポレーテッド アウリスタチン系抗体薬物複合体とＰＩ３Ｋ−ＡＫＴ ｍＴＯＲ経路インヒビターの間の相乗効果
JP2015078168A (ja) * 2013-10-18 2015-04-23 ピーエスエムエー ディベロップメント カンパニー，エルエルシー Ｐｓｍａリガンドコンジュゲートによる併用療法
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MAIMAITILI, YIMAMU ET AL.: "An mTORCl/2 Kinase Inhibitor Remarkably Enhances the Cytotoxicity of Gemtuzumab Ozogamicin By Activating Lysosomal Function and Cell Cycle Promotion in AML Cells", BLOOD, vol. 130, no. 1374, December 2017 (2017-12-01), XP055613389 *
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