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WO2018202910A1 - Combinaison d'un antibiotique et d'un inhibiteur de bcl-2 et utilisations correspondantes - Google Patents

Combinaison d'un antibiotique et d'un inhibiteur de bcl-2 et utilisations correspondantes Download PDF

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Publication number
WO2018202910A1
WO2018202910A1 PCT/EP2018/061694 EP2018061694W WO2018202910A1 WO 2018202910 A1 WO2018202910 A1 WO 2018202910A1 EP 2018061694 W EP2018061694 W EP 2018061694W WO 2018202910 A1 WO2018202910 A1 WO 2018202910A1
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combination
bcl
mitochondrially
inhibitor
tigecycline
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Inventor
Micol RAVA'
Aleco D'ANDREA
Bruno Amati
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Fondazione Istituto Italiano di Tecnologia
Istituto Europeo di Oncologia SRL IEO
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Fondazione Istituto Italiano di Tecnologia
Istituto Europeo di Oncologia SRL IEO
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • 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

Definitions

  • the present invention relates to the therapeutic use of a combination of at least one mitochondrially- targeted antibiotic and at least one inhibitor of BCL-2 for use in the treatment of MYC/BCL2 double positive B-cell lymphomas and relative compositions.
  • High-grade B cell lymphomas with MYC and BCL2 or BCL6 translocations constitute a subset of diffuse large B cell lymphoma (DLBCL) that was recently re-classified as a separate entity (1-4). Additional cases of DLBCL, commonly referred to as double-expressors, show positivity for the MYC and BCL2 proteins in the absence of the corresponding translocations.
  • activation of MYC and BCL2 correlates with poor prognosis in the face of current front-line treatments, including combined immuno- and chemotherapy (for example rituximab and CHOP, or R-CHOP) (1-7), calling for the development of new therapeutic regimens.
  • a most promising prospect in this regard is the emergence of selective BCL2 inhibitors, such as venetoclax (also called ABT- 199) (3, 8-10).
  • the inventors present preclinical data showing that a BCL2 inhibitor (preferably venetoclax) and a mitochondrially targeted antibiotic (preferably tigecycline) synergize in the treatment of MYC/BCL2 double-hit lymphomas, allowing tumor eradication in xenografted mice.
  • a BCL2 inhibitor preferably venetoclax
  • a mitochondrially targeted antibiotic preferably tigecycline
  • High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes also known as double-hit lymphomas (DHL) show dismal prognosis with current therapies.
  • MYC activation sensitizes cells to inhibition of mitochondrial translation by a tetracycline derivative antibiotic, tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma.
  • the inventors now addressed the utility of a mitochondrially- targeted antibiotic fortreatment of DHL.
  • BCL2 activation in mouse ⁇ -myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax.
  • tigecycline and two related antibiotics tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells.
  • Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft (PDX) revealed strong anti-tumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines.
  • This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens.
  • Venetoclax and tigecycline are currently in the clinic with distinct indications: the inventors' preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.
  • the present invention provides a combination of at least one mitochondrially-targeted antibiotic and at least one inhibitor of BCL-2 for use in the treatment of a MYC/BCL2 double positive B-cell lymphoma.
  • the at least one mitochondrially-targeted antibiotic is selected from the group consisting of: erythromycin and derivatives thereof, tetracycline and derivatives thereof, glycylcycline and derivatives thereof, an anti-parasitic drug and derivatives thereof, and chloramphenicol and derivatives thereof.
  • the erythromycin derivative is selected from the group consisting of: Azithromycin, Carbomycin, Cethromycin, Clarithromycin, Dirithromycin, Mitemcinal, Oleandomycin, flurithromycin, Roxithromycin, Spiramycin, Telithromycin and Tylosin.
  • the tetracycline and/or glycylcycline derivative is selected from the group consisting of: Tigecycline, Tetracycline, Doxycycline, Chlortetracycline, Oxytetracycline, Demeclocycline, Lymecycline, Meclocycline, Methacycline, Minocycline and Rolitetracycline.
  • the anti-parasitic drug is pyrvinium pamoate.
  • the mitochondrially-targeted antibiotic is administered intravenously.
  • the mitochondrially-targeted antibiotic is administered every two days.
  • the inhibitor of BCL-2 is selected from the group consisting of: ABT-737, ABT-263, ABT-199 (Venetoclax).
  • the inhibitor of BCL-2 is administered for at least one cycle of 5 days.
  • the mitochondrially-targeted antibiotic is Tigecycline. In a preferred embodiment, the mitochondrially-targeted antibiotic is doxycycline. In a preferred embodiment, the mitochondrially-targeted antibiotic is tetracycline.
  • the inhibitor of BCL-2 is ABT-199.
  • the mitochondrially-targeted antibiotic is Tigecycline and the inhibitor of BCL-2 is ABT-199. In another preferred embodiment, the mitochondrially-targeted antibiotic is doxycycline and the inhibitor of BCL-2 is ABT-199. In another preferred embodiment, the mitochondrially-targeted antibiotic is tetracycline and the inhibitor of BCL-2 is ABT-199.
  • the MYC/BCL2 double positive B-cell lymphoma is a double-hit lymphoma or a double- expressor lymphoma.
  • the combination as defined above further comprises at least one additional therapeutic agent.
  • the additional therapeutic agent is selected from the group consisting of: an anti-CD 20 antibody, an anti-CD22 antibody, an anti-VEGF antibody, an anti-CD52 antibody, Cyclophosphamide, Doxorubicin (Hydroxydaunomycin), Vincristine (Oncovin ®), Prednisolone and a combination thereof.
  • the anti-CD 20 antibody is Rituximab.
  • the anti-CD22 antibody is Epratuzumab.
  • the anti-VEGF antibody is Bevacizumab.
  • the anti-CD52 antibody is Alemtuzumab.
  • the additional therapeutic agent is rituximab.
  • the mitochondrially-targeted antibiotic is Tigecycline and the inhibitor of BCL-2 is ABT-199.
  • the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and optionally the least one additional therapeutic agent are administered simultaneously or sequentially.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one mitochondrially-targeted antibiotic as defined above, at least one inhibitor of BCL-2 as defined above, a pharmaceutically acceptable vehicle and optionally at least a further therapeutic agent as defined above for use in the treatment of MYC/BCL2 double positive B-cell lymphomas.
  • the MYC/BCL2 double positive B-cell lymphoma is a double-hit lymphoma or a double-expressor lymphoma.
  • the present invention provides a kit comprising at least one mitochondrially- targeted antibiotic as defined above, at least one inhibitor of BCL-2 as defined above and optionally at least a further therapeutic agent as defined above for use in the treatment of MYC/BCL2 double positive B-cell lymphomas.
  • the MYC/BCL2 double positive B-cell lymphoma is a double-hit lymphoma or a double-expressor lymphoma.
  • the present invention particularly pertains to a combination of at least one mitochondrially-targeted antibiotic, at least one inhibitor of BCL-2, and optionally at least one additional therapeutic agent useful for separate, simultaneous or sequential administration to a subject in need thereof for treating or preventing a MYC/BCL2 double positive B-cell lymphoma.
  • the present invention also pertains to said combination for use in the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disease in a subject in need thereof.
  • said combination is used for the treatment or prevention of a proliferative disease comprising administering to the subject a combination therapy, comprising an effective amount of at least one mitochondrially-targeted antibiotic, an effective amount of at least one inhibitor of BCL-2 and optionally an effective amount additional therapeutic agent.
  • a combination therapy comprising an effective amount of at least one mitochondrially-targeted antibiotic, an effective amount of at least one inhibitor of BCL-2 and optionally an effective amount additional therapeutic agent.
  • the mitochondrially-targeted antibiotic, the inhibitor of BCL-2, and the optional additional therapeutic agent are administered at therapeutically effective dosages which, when combined, provide a beneficial effect.
  • the administration may be separate (e.g. in a chronologically staggered manner, especially a sequence-specific manner), simultaneous or sequential.
  • the present invention further provides a kit, i.e.
  • a commercial package comprising as therapeutic agents a mitochondrially-targeted antibiotic, an inhibitor of BCL-2 and optionally at least one additional therapeutic agent, together with instructions for simultaneous, separate or sequential administration thereof for use in the delay of progression or treatment of a MYC/BCL2 double positive B-cell lymphoma.
  • combination may define for example a fixed combination in one dosage unit form for simultaneous administration or a kit of parts for the combined administration where the mitochondrially-targeted antibiotic, the inhibitor of BCL-2 and the optional additional therapeutic agent may be administered independently at the same time (separate administration) or separately within time intervals (sequential administration) that allow that the combination partners show a cooperative, e.g., synergistic, effect.
  • the components are not in the same dosage unit form, e.g. they are in a kit of parts, they can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously or at different time points.
  • the parts of the kit of parts can then e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the ratio of the total amounts of the mitochondrially-targeted antibiotic to the the inhibitor of BCL-2 and to the optional additional therapeutic agent can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient.
  • Therapeutically effective amounts of the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and at least one additional therapeutic agent depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co -administered.
  • the amount of the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight.
  • Single dose compositions contain these amounts or a combination of submultiples thereof.
  • an initial dose of up to 1000 mg may be used, preferably up to 500 mg, followed by up to 250 mg every 12 hours.
  • Intravenous infusion of the mitochondrially-targeted antibiotic derivative may last approximately 30 to 60 minutes and may occur every 12 hrs for days 1 -5, and every 21 days for 2 cycles.
  • the initial dose may be twice as much as the maintenance dose.
  • the components may be each independently administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.
  • combined administration or “co-administration” as used herein encompasses the administration of the selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • a "mitochondrially-targeted antibiotic” means an antibiotic acting through inhibition of mitochondrial biogenesis and/or mitochondrial translation and includes for instance the erythromycins, the tetracyclines, the glycylcyclines, anti-parasitic drugs, and chloramphenicol.
  • the antibiotic acting through inhibition of mitochondrial translation is a tetracycline.
  • IHC may be used as described in D 'Andrea et al, Oncotarget 2016 Nov 8;7(45):72415-72430 and in Skrtic M, et al Cancer Cell 201 1 Nov 15;20(5):674-88.
  • D'Andrea et al, Oncotarget 2016 Nov 8;7(45):72415-72430 refer to analysis of mitochondrial membrane with electronic microscope and the study of OCR (Oxygen consumption rate).
  • Skrtic et al, 2011 use [3H]-leucine incorporation or S- ⁇ 5 -pulse label as described in Sasarman F, et al. Methods Mol Biol 2012;837:207-17.
  • derivative refers to any known synthetic, semi-synthetic or natural derivative of a parent agent.
  • derivative refers to any agent that can be prepared, at least theoretically, from a parent agent.
  • the derivative is structurally related to the parent agent.
  • said parent agent is preferably a mitochondrially- targeted antibiotic or an inhibitor of BCL-2 or an additional therapeutic agent as defined herein.
  • erythromycin Semi-synthetic or synthetic derivatives of erythromycin have played an important role in antimicrobial chemotherapy.
  • First generation derivatives such as 2'-esters and acid-addition salts significantly improved the chemical stability and oral bioavailability of erythromycin.
  • Erythromycin derivatives according to the present invention may be for instance first generation derivatives, such as 2'-esters and acid-addition salts, or second generation erythronolide-modified derivatives, such as roxithromycin, clarithromycin, azithromycin, dirithromycin and fiurithromycin.
  • first generation derivatives such as 2'-esters and acid-addition salts
  • second generation erythronolide-modified derivatives such as roxithromycin, clarithromycin, azithromycin, dirithromycin and fiurithromycin.
  • Tetracycline derivatives are a family of broad-spectrum antibiotics. They are a subclass of polyketides. The modifications of naturally occurring tetracyclines, such as chlortetracycline and tetracycline, and the synthesis of novel compounds within the tetracycline family have generated many compounds. Semi-synthetic derivatives of tetracycline include for instance doxycycline and minocycline. The tetracyclines exert their antibiotic effect primarily by binding to the bacterial ribosome and halting protein synthesis. Bacterial ribosomes have high- affinity binding site located on the 30S subunit and multiple low-affinity binding sites located at the 30S and 50S subunits. Upon binding the ribosome, the tetracyclines allosterically inhibit binding of the amino acyl-tR A at the acceptor site (A-site) and protein synthesis ceases.
  • tetracycline derivative as used herein preferably refers to any known synthetic, semi-synthetic or natural derivative of tetracycline.
  • the tetracycline derivative according to the present invention belongs to a subclass of polyketides.
  • the expression "tetracycline derivative” as used herein means any agent that can be prepared, at least theoretically, from tetracycline.
  • Tetracycline derivatives according to the present invention may exert their effect by binding to the bacterial ribosome and halting protein synthesis, for instance by binding to the bacterial ribosome, preferably at a high-affinity binding site located on the 30S subunit or at a low- affinity binding site located at the 30S or 50S subunit, allosterically inhibiting binding of the amino acyl-tRNA at the acceptor site (A-site) and ceasing protein synthesis.
  • Glycylcycline derivatives are semi-synthetic or synthetic derivatives of any tetracycline as defined above which comprise a glycyl moiety, preferably attached to the 9-position of the tetracycline ring.
  • glycosylcycline derivative as used herein preferably refers to any known synthetic, semi-synthetic or natural derivative of glycylcycline.
  • the expression “glycylcycline derivative” as used herein means any agent that can be prepared, at least theoretically, from glycylcycline or from a tetracycline or from a tetracycline derivative.
  • the expression “glycylcycline derivative” refers to an agent that can be prepared, at least theoretically, from glycylcycline or from a tetracycline or from a tetracycline derivative and that comprises a glycyl moiety.
  • an "anti-parasitic drug” refers anthelmintic drugs, vermifuges, vermicides and the like, which preferably expel parasites from the body by stunning or killing them without causing significant damage to the host.
  • anti-parasitic drugs include for instance: Benzimidazoles, Albendazole, Mebendazole, Thiabendazole, Fenbendazole, Triclabendazole, Flubendazole, Abamectin, Diethylcarbamazine, Ivermectin, Suramin, Pyrantel pamoate, Levamisole, Salicylanilides, Niclosamide, Nitazoxanide, Oxyclozanide, Praziquantel, Octadepsipeptides (e.g.: Emodepside), Aminoacetonitrile derivatives e.g., Monepantel, Spiroindoles (e.g., derquantel), Pelletierine sulphate and
  • an "anti-parasitic drug” also refers to any known agent useful for preventing and/or treating any parasitic infestation or disease, including for instance malaria, toxoplasmosis, trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, thricomoniasis and cestodiasis.
  • malaria toxoplasmosis, trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, thricomoniasis and cestodiasis.
  • existing therapies for malaria include, but are not limited to cloroquine, proguanil, mefloquine, quinine, pyrimethamine-sulphadoxine, doxocycline, berberine, halofantrine, primaquine, atovaquone, pyrimethamine -dapsone, artemisinin and quinhaosu.
  • Existing therapies for leishmaniasis include, but are not limited to meglumine antimonite, sodium stibogluconate and amphotericin B.
  • the mitochondrially-targeted antibiotic is administered intravenously.
  • the mitochondrially-targeted antibiotic derivative is administered every two days.
  • the duration of treatment with the mitochondrially-targeted antibiotic derivative may be 5 to 15 days.
  • the "inhibitor of BCL-2” refers to a potent and highly selective BH3 mimetic antagonist of BCL2 that blocks the anti-apoptotic activity of BCL-2.
  • the BCL2 family proteins share several conserved "BH" domains termed BH1, BH2, BH3 and BH4, as in the inhibitors (BCL-2, BCL-XL, BCL-2 MCL-1 , BFL/A1 , BCL-B), instead the activators (BIM, BID, PUMA) and the sensitizers (BAD, BMF, NOXA) possess only the BH3 domain, and hence are often referred to as "BH3-only" proteins.
  • BH3 mimetics can occupy the inhibitors (anti-apoptotic proteins), preventing them from binding the activators and can induce apoptosis through the intrinsic apoptosis pathway.
  • Preferred BH3 mimetic antagonists are as described in C. Billard, Mol. Cancer Ther., 2013, 9, 1691 -700, incorporated by reference.
  • Examples of BH3 mimetic antagonists according to the present invention include: ABT-199 (also known as venetoclax), ABT-737 and ABT-263 (also known as navitoclax).
  • Preferred inhibitor of BCL-2 is as described in WO 201 1/149492, incorporated by reference.
  • the inhibitor of BCL-2 is administered for at least one cycle of 5 days.
  • the inhibitor of BCL-2 may be used according to the following dosage/schedule: dosages of 150— 1200 mg given once on days 3 or 7 followed by once daily; continuous daily dosing of 200-900 mg; dosages beginning at 20 mg titrated weekly to 200-600 mg.; 50 to 600 mg daily; Dosing schedules may be as follows: 3, 7, and 28 days/cycle in each 28-day cycle in the dose-escalation portion of the study (see S. Cang et al., Journal of Hematology & Oncology (2015), 8 :129 incorporated by reference).
  • the mitochondrially-targeted antibiotic, the inhibitor of BCL-2 and/or the additional therapeutic agent may also be present in the combination of the invention as prodrugs, isomers, salts, or solvates.
  • the term "derivative" as used herein comprises prodrugs, isomers, salts, or solvates of the components of the composition.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • such prodrugs may be functional derivatives of the mitochondrially-targeted antibiotic, the inhibitor of BCL-2 and/or the additional therapeutic agent which are readily convertible in vivo into the required agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the components of the combination of the present invention may exist in different isomeric forms, all of which may be used in the combination and are thus encompassed within the scope of the present invention.
  • the components of the combination of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 11 19-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the components of the combination disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention.
  • the components may be included in the combination as a free base, as well as a pharmaceutically acceptable salt or stereoisomer thereof, all of which are encompassed within the scope of the present invention.
  • Some of the components are the protonated salts of amines.
  • components containing one or more N atoms may be protonated on any one, some or all of the N atoms.
  • the term "free base" refers to the amine compounds in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific agents described herein, but also all the typical pharmaceutically acceptable salts of the free form of the respective component.
  • the free form of the specific salt component described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the components of the instant combination can be synthesized from the individual components which contain a basic or acidic moiety by conventional chemical methods.
  • the salts of the basic components are prepared either by ion exchange chromatography or by reaction of the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the salts of the acidic components are formed by reactions with the appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the components of the composition of the invention include the conventional non-toxic salts of the components as formed by reaction of a basic instant compound with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. More particularly, pharmaceutically acceptable salts of this invention are
  • suitable “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine, be
  • the components of the combination of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • compositions for treating diseases during which are expressed anti-apoptotic Bcl-2 proteins comprising an excipient and a therapeutically effective mitochondrially-targeted antibiotic, preferably a tetracycline derivative, and a therapeutically effective amount of the inhibitor of BCL-2 and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 may be administered in a single composition/formulation or as separate compositions.
  • the at least one additional therapeutic agent may be administered in a single composition/formulation (with the mitochondrially-targeted antibiotic and/or the inhibitor of BCL-2) or as a separate composition.
  • the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and at least one additional therapeutic agent may be administered each independently with or without an excipient.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • Excipients for preparation of compositions comprising the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and at least one additional therapeutic agent to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1 ,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts
  • Excipients for preparation of compositions comprising the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and at least one additional therapeutic agent to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3- butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof.
  • Excipients for preparation of compositions comprising the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and at least one additional therapeutic agent to be administered osmotically include, for example, chlorofiuorohydrocarbons, ethanol, water and mixtures thereof.
  • Excipients for preparation of compositions comprising the mitochondrially-targeted antibiotic derivative and the inhibitor of BCL-2 and at least one additional therapeutic agent to be administered parenterally include, for example, 1 ,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, saffiower oil, sesame oil, soybean oil, U.S. P. or isotonic sodium chloride solution, water and mixtures thereof.
  • Excipients for preparation of compositions of this invention to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
  • MYC/BCL2 double positive B-cell lymphoma refers to a diffuse large B cell lymphoma (DLBCL) and comprises double-hit lymphomas (DHL) and double-expressor lymphomas.
  • DHL double-hit lymphomas
  • double-expressor lymphoma refers to a high-grade B cell lymphoma with MYC and BCL2 translocations.
  • double-expressor lymphoma refers to a DLBCL that shows positivity for the MYC and BCL2 proteins in the absence of the corresponding translacations.
  • additional therapeutic agent refers to any agent that is useful in the prevention and/or treatment of a MYC/BCL-2 double positive B-cell lymphoma and includes for example: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other apoptosis promoters (for example, Bcl- xL, Bcl-w and Bfi-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase (CDK) inhibitors, cell cycle inhibitors, cyclooxygenase-2 (COX- 2) inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90
  • alkylating agents for example, an
  • BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
  • BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT 103) and the like.
  • cytolytic granule components which include perforin and granzyme B.
  • Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B.
  • SiRNAs are molecules having endogenous R A bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'- deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F- ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like.
  • the siR A can have varying lengths (e.g., 10- 200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing.
  • a double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1 -2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'- and/ or the 3 '-ends of a given strand.
  • siR As targeting Mcl-1 have been shown to enhance the activity of ABT-263, (i.e., N-(4-(4-((2-(4-chlorophenyl)-5 ,5 -dimethyl- 1 - cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3 -(morpholin-4-y 1)- 1 - ((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide) or ABT- 737 (i.e., N-(4-(4-((4'-chloro(l,r-biphenyl)-2-yl)methyl)piperazin-l-yl)benzoyl)-4- ((( 1 R)-3 - (dimethylamino)- 1 -((phenyls),
  • Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies.
  • the term "multispecific binding protein” means a binding protein capable of binding two or more related or unrelated targets.
  • Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's.
  • Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites.
  • Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
  • Preferred further combinations include the mitochondrially-targeted antibiotic and the inhibitor of BCL-2 and the combination of CHOP (Cyclophosphamide, doxorubicin (Hydroxydaunomycin), vincristine (Oncovin ®) and Prednisolone) or R-CHOP (the combination of CHOP with the anti- CD20 monoclonal antibody Rituximab).
  • Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE®(laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA®(bendamustine), treosulfan, rofosfamide and the like.
  • Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie -2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
  • Tie -2 endothelial-specific receptor tyrosine kinase
  • EGFR epidermal growth factor receptor
  • IGFR-2 insulin growth factor-2 receptor
  • MMP-2 matrix metalloproteinase-2
  • MMP-9 matrix metalloproteinase-9
  • PDGFR platelet-derived growth factor receptor
  • VEGFR vascular endothelial growth factor receptor ty
  • Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT®(cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifiuridine, efiornithine, EICAR (5- ethynyl-l-P -D-ribofuranosylimidazole-4- carboxamide), enocitabine, ethnylcytidine, fiudarabine, 5- fluorouracil alone or in combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid
  • Aurora kinase inhibitors include ABT-348, AZD-1 152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan- Aurora kinase inhibitors and the like.
  • Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE® (G3139 or oblimersen (Bcl- 2 -targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro( 1 , 1 '-biphenyl)-2- yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3 -(dimethylamino)- 1 ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2- (4- chlorophenyl)-5 ,5 -dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4- ((( 1 R)
  • Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC® (imatinib) and the like.
  • CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK- 304709 and the like.
  • COX-2 inhibitors include ABT-963 , ARCOXI A® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3 ,4-dimethylphenyl)-l-(4- sulfamoylphenyl-lH- pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067,
  • EGFR inhibitors include ABX-EGF, anti-EGFR immuno liposomes, EGF-vaccine, EMD-7200, ERBrrUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA ® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB ® (lapatinib) and the like.
  • ErbB2 receptor inhibitors include CP-724-714, CI- 1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNrTARG® (2C4, petuzumab), TAK- 165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI- 166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti- HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR- 209, mAB 2B-1 and the like.
  • Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS- 275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
  • HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody to HSP-90), NCS- 683664, PU24FC1 , PU-3, radicicol, SNX-21 12, STA-9090 VER49009 and the like.
  • Inhibitors of inhibitors of apoptosis proteins include HGS1029, GDC-0145, GDC- 0152, LCL-161, LBW-242 and the like.
  • Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22- MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 and the like
  • Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-ST01 , GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.
  • Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.
  • JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCBO 18424 and the like.
  • MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
  • mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001 , rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.
  • Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID® (difiunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.
  • PDGFR inhibitors include C-451 , CP-673, CP-868596 and the like.
  • Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL- 147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC- 0941 , BGT226, BEZ235, XL765 and the like.
  • Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
  • VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYMETM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG- 13736), AZD-2171 , CP-547,632, IM- 862, MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU- 11248), VEGF trap, ZACTEVIATM (vandetanib, ZD-6474) and the like.
  • AVASTIN® bevacizumab
  • ABT-869 AEE-788
  • ANGIOZYMETM a
  • Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.
  • Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine), difiomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafiuposide, topotecan and the like.
  • Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT- 1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGFlR-speciflc antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.
  • Hormonal therapies include ARIMIDEX®(anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX®(bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN®(trilostane), dexamethasone, DROGENIL®(flutamide), EVISTA®(raloxifene), AFEMATM (fadrozole),
  • Deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PA RETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN®(bexarotene), LGD-1550 and the like.
  • PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, AZD-2281, AG- 014699, BSI- 201, BGP-15, INO-1001, ONO-2231 and the like.
  • Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
  • Proteasome inhibitors include VELCADE®(bortezomib), MG132, NPI-0052, PR-171 and the like.
  • immunologicals include interferons and other immune-enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma- la, ACTEVIMU E® (interferon gamma- lb) or interferon gamma-nl, combinations thereof and the like.
  • agents include ALFAFERONE®,(IFN-a), BAM- 002 (oxidized glutathione), BEROMU ®(tasonermin), BEXXAR®(tositumomab), CAMPATH®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti- CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARGTM (gemtuzumab ozogamicin), NEUPOGEN®(filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFGl), PROVENGE®(sipuleucel-T), sargaramostim,
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF- 3512676 (CpG-8954), ubenimex and the like.
  • Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifiuridine, FLUDARA®(fludarabine), 5-FU (5-fluorouracil), fioxuridine, GEMZAR®(gemcitabine), TOMUDEX®(ratitrexed), TROXATYLTM (triacetyluridine troxacitabine) and the like.
  • Purine analogs include LANVIS®(thioguanine) and PURI-NETHOL® (mercaptopurine).
  • Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3 -yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE®(docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
  • Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.
  • the combination of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy.
  • radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
  • Tigecycline and the inhibitor of BCL-2 maybe combined with other chemotherapeutic agents such as ABRAXANETM (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN®(Ad5CMV-p53 vaccine), ALTOCOR®or MEVACOR®(lovastatin), AMPLIGEN®(poly Lpoly C12U, a synthetic R A), APTOSYN®(exisulind), AREDIA®(pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3,17-dione-androsta- 1,4- diene), AVAGE®(tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC®(cancer vaccine), CELEUK®(celmoleukin), CEPLENE®
  • REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE®LA (lanreotide), SORIATANE®(acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN®(bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA®(canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE®(STn- KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4- pyridylthio)quinazoline dihydrochloride), TNFERADETM (adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER®or ZAVESCA®(
  • the term "effective amount” shall mean an amount which achieves a desired effect or therapeutic effect as such effect is understood by those of ordinary skill in the art.
  • composition/formulation refers to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the mammal.
  • pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.
  • compositions containing the mitochondrially-targeted antibiotic, the inhibitor of BCL-2 and optionally at least one additional therapeutic agent of the present invention may be manufactured by processes well known in the art, e.g., using a variety of well-known mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the compositions may be formulated in conjunction with one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Parenteral routes are preferred in many aspects of the invention.
  • the pharmaceutical compositions can be chosen on the basis of the treatment requirements.
  • compositions are prepared by blending and are suitably adapted to oral or parenteral administration, and as such can be administered in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable, or infusible liquid solutions, suspensions, or suppositories.
  • Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).
  • excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).
  • the oral solid compositions can be prepared by conventional methods of blending, filling or tableting.
  • the blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of fillers. Such operations are conventional.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or with a suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents.
  • Oral formulations also include conventional slow-release formulations such as enterically coated tablets or granules.
  • composition for administration by inhalation can be delivered from an insufflator or a nebulizer pressurized pack.
  • parenteral administration fluid unit dosages can be prepared, containing the combination or the components of the combination and a sterile vehicle.
  • the combination or the components of the combination can be either suspended or dissolved, depending on the vehicle and concentration.
  • the parenteral solutions are normally prepared by dissolving the combination or the components of the combination in a vehicle, sterilising by filtration, filling suitable vials and sealing.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle.
  • the composition can be frozen after having filled the vials and removed the water under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the combination or the components of the combination can be suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the combination or the components of the combination of the invention.
  • compositions may be tablets, lozenges, pastilles, or gel.
  • the combination or the components of the combination can be pharmaceutically formulated as suppositories or retention enemas, e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • Topical formulations can contain for example ointments, creams, lotions, gels, solutions, pastes and/or can contain liposomes, micelles and/or microspheres.
  • ointments include oleaginous ointments such as vegetable oils, animal fats, semisolid hydrocarbons, emulsifiable ointments such as hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glycerol monostearate, stearic acid, water soluble ointments containing polyethylene glycols of various molecular weights.
  • Creams are viscous liquids or semisolid emulsions, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase generally contains petrolatum and an alcohol such as cetyl or stearic alcohol.
  • Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • transdermal delivery A further method of administering the combination or the components of the combination of the invention regards transdermal delivery.
  • Typical transdermal formulations comprise conventional aqueous and non-aqueous vectors, such as creams, oils, lotions or pastes or can be in the form of membranes or medicated patches.
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • the treatment will be given for one or more cycles until the desired clinical and biological result is obtained.
  • the exact amount, frequency and period of administration of the combination of the present invention will vary, of course, depending upon the sex, age and medical condition of the patient as well as the severity and type of the disease as determined by the attending clinician.
  • Still further aspects include combining the therapy described herein with other anticancer therapies, such as radiotherapy, for synergistic or additive benefit.
  • the schedule of treatment with the combinations can foresee that mitochondrially-targeted antibiotic is administered concomitantly, before and/or after the inhibitor of BCL-2 identified above and optionally before and/or after the at least one additional agent as above indicated.
  • Fig. 1 Blockade of tigecycline-induced cell death by BCL2 in ⁇ -myc lymphomas and its restoration by venetoclax.
  • Two mouse ⁇ -myc lymphoma cell lines, one wild-type (p53-wt) and one null (p53-null) for the Trp53 locus were infected with a recombinant retrovirus encoding human BCL2 or with the corresponding empty vector (EV). After selection, the infected cells were treated with tigecycline and/or venetoclax at the indicated concentrations. Total and viable cell counts were determined by Trypan blue exclusion 48 hours after addition of the drugs to the culture medium.
  • A The viability of cells expressing BCL2 or empty vector is presented as the % of live relative to total cells (live + dead) in each culture.
  • B The proliferative index of cells expressing BCL2 or empty vector is presented as the increase in viable cell counts over 48 hours, normalized to the corresponding increase in parallel untreated cultures (4 population doublings for the p53-wt cells with either EV or BCL2; 3.5 and 2 doublings for the p53-null cells with EV and BCL2, respectively).
  • C Cell viability of ⁇ i-myc/BCL2 lymphomas in the presence or absence of venetoclax.
  • D Cell viability of ⁇ i-myc/BCL2 lymphomas in the presence or absence of tigecycline and/or venetoclax. All data points represent the average ⁇ s.d. from 3 independent experiments.
  • Fig. 2 Induction of cell death by tigecycline and venetoclax in human MYC/BCL2 double-hit lymphomas.
  • A or immunoblotting (B) in the indicated cell lines (Karpas-442, SU-DHL-6, DOHH-2, SU-DHL-4, OCI-LY8, OCI-LY7).
  • the expression data shown here are consistent with the known status of MYC or BCL2 translocations in those cell lines, as indicated at the bottom.
  • Fig. 3 Therapeutic activity of tigecycline and venetoclax in DHL-xenografted mice.
  • A Schematic representation of the general strategy, followed in panel B
  • B The human cell lines SU- DHL-6, DOHH-2, OCI-LY8 (all with MYC and BCL2 translocations), or OCI-LY7 (MYC translocation only) were xenografted subcutaneously in CD 1 -nude mice. After about 2 weeks, tumor- bearing animals were randomized and treated with the indicated doses of tigecycline and/or venetoclax over a period of 12 days. Tumor volumes were measured at the indicated time points after treatment.
  • Fig. 4 Therapeutic activity of tigecycline and venetoclax in a DHL patient-derived xenograft.
  • Fig. 5 Response of mouse Li-myclBCL2 lymphomas to tigecycline and venetoclax.
  • A DNA- content histograms and
  • B RT-PCR measurement of Cdknla mR A expression (normalized to the RplpO mRNA) after treatment of lymphoma lines with 100 ⁇ tigecycline for 72 hours. The RT-PCR results are shown as mean ⁇ s.d. of technical triplicates.
  • (C) Senescence- associated beta-galactosidase (SA-Bgal) staining after a 5 -day treatment with 100 ⁇ tigecycline or 100 nM doxorubicin, the latter serving as a positive control for the induction of senescence in ⁇ - myc/BCL2 lymphomas (20). Data are shown as % of positive cells (mean ⁇ s.d.) from counts in 4 different fields.
  • (D) Drug interaction landscapes and delta scores for synergy, based on the ZIP model in SynergyFinder (64), derived from the data of Fig. ID. The landscapes identify the specific dose regions where there is a synergistic (red) or antagonistic (green) drug interaction.
  • Fig. 6 Synergistic effects of tigecycline and venetoclax against human DHL cell lines. Drug interaction landscapes and delta scores (as defined in fig. 5D) were derived from the data of Fig. 2D. Fig. 7. Similar effects of tigecycline, doxycycline, and tetracycline in DHL cells.
  • A Immunoblot analysis of the mitochondrial proteins COX1 , COX2 (encoded by the mitochondrial genome), and SDHA (encoded in the nucleus) in SU-DHL-6 cells after 48 hours of treatment with 5 ⁇ of tigecycline (tig), doxycycline (doxy), or tetracycline (tet).
  • OCR Oxygen consumption rate
  • C-D Cell viability (C, determined as in Fig. 1) and drug interaction landscapes (D, as defined in fig. 5D) after treatment of SU-DHL-6 cells with tigecycline, doxycycline, or tetracycline in combination with venetoclax, as indicated. The experiments were performed and analyzed as described in Figures 2D and 5D.
  • Fig. 8 Short-term effects of tigecycline and venetoclax in SU-DHL-6 tumors. Immunohistochemical analysis of subcutaneous SU-DHL-6 tumors collected 24 hours after a single treatment with the indicated drugs, stained with primary antibodies against cleaved caspase 3 (CC3) or Ki67. H&E: hematoxylin-eosin staining. Scale bars: 100 ⁇ .
  • Fig. 9 Kaplan-Meier representation of disease-free survival in PDX recipient mice. Animals bearing PDX-derived tumors and exposed to the indicated treatments (the same shown in Fig. 4) were sacrificed at the first observable signs of disease, including hind-limb paralysis and hunched posture.
  • Fig. 10 Reactive liver lesions caused by intraperitoneal delivery of tigecycline.
  • CD 1 -nude mice bearing subcutaneous SU-DHL-6 tumors were treated with repeated doses of tigecycline delivered by either intraperitoneal (LP., bi-daily) or intravenous injection (I.V., every three days) for two weeks.
  • LP. intraperitoneal
  • I.V. intravenous injection
  • A Liver morphology in mice sacrificed after the indicated treatments. Compacted liver lobes were observed in animals treated with tigecycline alone or in combination with venetoclax.
  • B Hematoxylin-eosin stained sections show marked changes in the structure of the peritoneal membrane and liver tissue in mice after IP- but not IV-based delivery of tigecycline.
  • the inventors observed a diffuse hyperplasia of mesothelial cells that were organized in irregular buds and papillae in the peritoneal membrane and a thickening of the liver capsule with areas of neutrophilic infiltration.
  • the lobular architecture was maintained, with diffuse centrilobular hepatocellular hypertrophy and hyperplastic foci.
  • typical signs of liver toxicity hepatocellular necrosis, periportal inflammatory infiltrates, or fibrosis
  • were absent indicating that the observed lesions were reactive in nature.
  • Scale bars 100 ⁇ .
  • Fig. 11 Toxicology of tigecycline and venetoclax drug combination studies in vivo. Gross organ histology of nude mice treated with tigecycline (75 mg/kg twice a day by LP. injection) and/or venetoclax (50 mg/kg daily by oral gavage) or vehicle control.
  • the organs are normal with neither neoplastic nor inflammatory infiltrates, with the exception of animals treated with tigecycline (alone or in combination with venetoclax), in which the inventors observed changes in the liver and spleen.
  • capsular fibrosis with subcapsular diffuse minimal inflammatory neutrophilic infiltrates, with a diffuse hydropic degeneration of hepatocyte cytoplasm and increased mitoses.
  • the white pulp was expanded by increased numbers of periarteriolar lymph sheath (PALS) lymphocytes.
  • PALS periarteriolar lymph sheath lymphocytes.
  • the inventors also observed marginal zone atrophy, with a marked spleen hyperplasia in red pulp with diffuse neutrophilic inflammatory infiltrate.
  • Fig. 12 Whole-body imaging of PDX-derived tumors treated with tigecycline and/or venetoclax.
  • a cohort of PDX-bearing mice was randomized and subjected to treatment with tigecycline and/or venetoclax, as indicated.
  • IVIS images are shown here for all mice and time -points in the experiment. Note that the animals in the untreated and tigecycline + venetoclax groups are also shown in Fig. 4B at day 1 1. * Indicates that the animal died following anesthesia. Other missing animals succumbed to excessive tumor burden. Surviving animals were sacrificed upon disease manifestation.
  • FIG. 3 For SU-DHL-6 and DOHH-2 tumors
  • Fig. 4 for PDX tumors
  • the IVIS images shown in (D) include all mice in the rituximab-only, as well as in the triple combination groups, shown at day 11. Other groups and time -points are shown in fig. 14.
  • Fig. 14 Whole-body imaging of PDX-derived tumors treated with rituximab, tigecycline and/or venetoclax.
  • the groups of mice shown here belong to the same cohort as in fig. 12 and were treated with rituximab in addition to tigecycline and/ or venetoclax, as indicated. Note that the animals in the rituximab and in the triple combination groups are also shown in fig. 13B at day 1 1.
  • Fig. 15 (A). Schematic summary of the nucleus-mitochondrial interaction. Oncogenic activation of Myc sensitizes to inhibition of the mitochondrial ribosome by tigecycline. (B). Kapan-Meier survival curve of Eu-Myc lymphoma-transplanted mice treated with tigecycline or vehicle (saline solution) (16).
  • Fig. 16 The human cell lines SU-DHL-6 (with MYC and BCL2 translocations), or OCI-LY7 (MYC translocation only) were xenografted subcutaneously in CD 1 -nude mice. After about 2 weeks, tumor- bearing animals were randomized and treated with the indicated doses of tigecycline and/or venetoclax over a period of 12 days. Tumor volumes were measured at the indicated time points after treatment. For OCI-LY7, tumor growth is shown at every time point until termination.
  • the objective of the inventors' study was to address the therapeutic interaction between at least one mitochondrially-targeted antibiotic and at least one inhibitor of BCL-2, for instance tigecycline and venetoclax, against MYC/BCL2 double-hit B-cell lymphoma (DHL) in a preclinical setting.
  • BCL-2 for instance tigecycline and venetoclax
  • human DHL cell lines SUDHL6 (ATCC CRL-2959), DOHH2 (D5M2 ACC-47), OCI-LY8 (CVCL-8803), OCI-LY7 (DSMZ ACC-688) and PDX (PDX are Patient Derived Xenografts: DFBL-69487 acquired from Proxe) were xeno-transplanted in female CD1- nude (086-CD1-Foxnl nu Charles River Laboratories) and NSG mice (005557-NOD.Cg- Prkdc scld I12rg Tmlwjl /SzJ Charles River Lab), respectively.
  • Tumors were allowed to develop to measurable sizes (about 2 weeks), followed by exclusion of outliers, blinded randomization of the experimental groups (day 0), and treatment (days 1 -12), as described in detail below. Although the number of biological replicates achieved depended upon the efficiency of engraftment and tumor growth, no fewer than 4-5 animals were included in any experimental group (with the exception of fig. IOC), to ensure statistical power.
  • the endpoint of the experiment for subcutaneous tumors was either a tumor size of 20 mm in any one dimension, or ulceration at any tumor size.
  • the endpoint was the first signs of disease manifestation (hind- limb paralysis, hunched posture).
  • mice monoclonal anti-vinculin Abeam, cat. #abl 8058
  • mouse monoclonal anti-COXl Abeam, cat. # abl4705
  • mouse monoclonal anti-COX2 Invitrogen, cat. #12C4F12
  • mouse monoclonal anti-SDHA Invitrogen, cat. #459200
  • rabbit monoclonal anti-MYC Y69 Abeam, cat. #GR144732-28
  • rabbit monoclonal anti-BCL2 E17 Abeam, cat. #ab32124
  • mouse monoclonal anti-BCL2 [OP60] Calbiochem
  • CTAGATGGCATCATTCTTCC (Seq. ID No. 1) and GAAACTGGGCAAACAACAC (Seq. ID No. 2)
  • TTCATTGTGGGAGCAGAC (Seq. ID No. 7) and CAGCAGTTTCTCCAGAGC (Seq. ID No. 8)
  • RNAse A For DNA content analysis, cells were fixed with 70% EtOH, resuspended in PBS with 50 ⁇ g/ml propidium iodide (PI) and 40 ⁇ g/ml RNAse A, and stained overnight at 4°C in the dark. Samples were acquired on a FACSCalibur flow cytometer (Becton Dickinson).
  • peripheral blood analysis 50 ⁇ of blood were collected by tail vein bleeding, and 10 ⁇ 0.5 M EDTA was immediately added to prevent coagulation.
  • Whole blood was analyzed using a Hematological Analyzer (Beckman Dickinson). Alanine aminotransferase activity was assayed with a specific kit (Sigma, MAK052).
  • rituximab 10 mg/kg on day 0 of the 12-days treatment scheme was used for the experiment in fig. 13.
  • tigecycline was delivered with a single intravenous injection every 3 days, for a total of 12 days.
  • Tigecycline was dissolved in saline solution (0.9% NaCl); venetoclax was dissolved in 60% Phosal 50 PG (Lipoid), 30% polyethylene glycol (Aldrich), 10% ethanol. Solutions were freshly prepared from dry powder just before each injection.
  • the DHL PDX line DFBL-69487-V3-mCLP (33) was acquired from the Public Repository of Xenografts (www.proxe.org). 10 6 cells were xenografted via tail vein injection into 6- to 8-week-old female NSG mice. The animals were monitored once a week by whole body imaging on an rVTS Lumina III platform after intraperitoneal injection of 150 mg/kg XenoLight D-Luciferin (PerkinElmer #122799) and anesthesia with isoflurane. The data were analyzed with the Living Image Software, version 4.2 (Caliper Life Sciences). Radiant efficiency was calculated based on the epifiuorescence signal, as indicated in the user manual.
  • tigecycline and related antibiotics have been associated with their inhibitory effect on mitochondrial translation and, hence, on respiratory activity (16, 18, 21-31). Consistent with this notion, treatment of SU-DHL-6 cells with tigecycline, doxy eye line, or tetracycline suppressed expression of the mitochondrion-encoded electron transport chain complex (ETC) IV subunits COX1 (or MTCOl) and COX2 (or MTC02), but not of the nucleus-encoded ETC II subunit SDHA (fig. 7A), and lowered oxygen consumption (fig. 7B).
  • ETC electron transport chain complex
  • doxy eye line and tetracycline also synergized with venetoclax in killing SU-DHL-6 cells (fig. 7C, fig, 7D).
  • doxy eye line and tetracycline also synergized with venetoclax in killing SU-DHL-6 cells (fig. 7C, fig, 7D).
  • the inventors xenografted the human DHL cell lines SU-DHL-6, DOHH-2, OCI-LY8 and OCI-LY7 in CDl-nude mice, let tumors develop for 2 weeks, and initiated treatment. Either drug alone partially slowed down tumor progression, but their combination showed strong anti-tumoral activity, causing either full regression (8/8 for SU-DHL-6; 3/9 for OCI-LY8) or stasis within the 12 days of treatment (Fig. 3B). The contribution of venetoclax was again on-target, as BCL2-negative OCI-LY7 tumors were resistant to the combination.
  • mice (died ⁇ lw) is the total numbers of mice treated and, in parentheses, those that died within the first week. The causes for these early deaths remain unclear and may be due to the overall experimental burden imposed on the animals; surviving animals showed no signs of distress.
  • Regression percentages of animals scored as showing tumor regression at the indicated time points, with the scored/total numbers in parentheses. At day 19, partial and complete regressions were defined as residual tumor volumes ⁇ 50% and ⁇ 10% of the initial volume, respectively. Animals showing complete regression at day 19 were followed until day 120 and sacrificed when tumors reached a diameter of 1.5 cm. Animals reaching the endpoint of 120 days had no detectable residual tumor.
  • Compacted liver "yes” indicates that post-mortem examination revealed a compacted liver lobule morphology.
  • Treated animals were overall in good health, histopathological analysis showing no alterations in major organs, with the exception of inflammatory infiltrates in the liver and spleen in the presence of tigecycline (alone or in combination) (fig. 1 1). Finally, the inventors note that a fraction of the mice treated with high doses of the combined drugs died within one week (Table 1). Although the causes underlying this effect remain to be addressed, lower dosage (75 mg/kg tigecycline and 50 mg/kg venetoclax) showed no toxicity yet retained substantial anti -tumoral effects.
  • DLBCL patient-derived xenografts (PDXs), some of which were classified as DHL (33).
  • the inventors expanded one of these PDX lines (DFBL-69487- V3-mCLP, expressing luciferase) in NSG mice, and assessed its response to treatment.
  • Cell suspensions (lxlO 6 ) were transferred intravenously into recipient mice, and tumor development was monitored by whole -body imaging. Groups were randomized after two weeks (day 0) and treatment applied as above (days 1-12). Although they slowed down tumor progression, either tigecycline or venetoclax alone were insufficient to reverse the course of disease.
  • Tigecycline cooperates with rituximab
  • the anti-CD20 monoclonal antibody rituximab is a component of R-CHOP, the front-line immuno- chemotherapeutic regimen used to treat patients with DLBCL.
  • those tumors that show MYC and BCL2 translocations, thus qualifying as DHL show poor primary responses and high rates of relapse (2-7).
  • rituximab showed cooperation with either tigecycline or venetoclax in slowing tumor growth (fig. 13A, Table 2; compare with Fig. 3 for tigecycline or venetoclax alone).
  • rituximab showed moderate cooperation with either tigecycline or venetoclax (fig. 13B, C and fig. 14).
  • tigecycline and venetoclax have the potential to reinforce rituximab-containing therapies in the clinic.
  • DHL double -hit lymphomas
  • HGBL high-grade B-cell lymphomas
  • the inventors first showed that over-expression of BCL2 in mouse ⁇ -myc lymphomas blocked tigecycline-induced cell death, which was restored upon co-exposure to venetoclax. Consistent with this finding, the two drugs synergized in killing human DHL cells in vitro and showed strong anti-tumoral activity in vivo in mice xenografted with DHL cell lines or a PDX. With one line in particular (SU-DHL-6), the combined treatment achieved full disease eradication.
  • tigecycline in either mouse or human cells is attributed to its inhibitory activity on mitochondrial translation and, as a consequence, on oxidative phosphorylation (16, 18, 25-31). Indeed, other antibiotics with similar properties were also toxic toward a variety of tumor cells ((21-25) and, as shown here for doxy- and tetracycline, cooperated with venetoclax in killing DHL cells. Tigecycline was also reported to inhibit WNT/B-Catenin (34) and PBK-Akt-mTOR signaling (30, 35, 36) and to induce AMPK signaling and autophagy (36, 37), but these effects may conceivably follow from mitochondrial dysfunction.
  • tigecycline and related antibiotics may inhibit other activities in eukaryotic cells
  • a comprehensive body of evidence points to the mitochondrial ribosome as their direct and critical target. The reciprocal is true as well, since compounds isolated as mitochondrial ribosome inhibitors also showed anti-bacterial activity (38).
  • a recent study suggested that the sensitivity of several DLBCL cell lines to tigecycline was determined by their classification within the OxPhos as opposed to the BCR subtype (39), as defined by gene expression profiling (40).
  • one of the OxPhos lines was resistant to tigecycline alone in the inventors' experiments (and was also the least sensitive of the OxPhos lines in the previous study).
  • OxPhos BCR are secondary to the alternative cell-of-origin based signatures in the clinic (ABC and GCB, for Activated and Germinal Center B cell-like, respectively) and that, regardless of these expression-based classifications, DLBCL cases show heterogeneous mutational landscapes (41, 42).
  • tigecycline is among the antibiotics indicated for treatment of opportunistic, multi-drug resistant infections in cancer patients, with promising anti -bacterial responses and safety profiles (43- 47). In this setting, however, tigecycline's possible contribution to anti-tumoral responses was not considered. Based on the pre-clinical effect of tigecycline against acute myeloid leukemia (AML) (26, 48), a phase I study was undertaken in patients with relapsed AML (32), but no clinical response was reached so far, highlighting the need to reconsider the formulation and dosage of the antibiotic (32, 49), as well as its possible activity in combination regimens.
  • AML acute myeloid leukemia
  • tigecycline cooperates with chemotherapeutic drugs in hepatocellular and renal cell carcinomas (29, 30), as well as with the BCR-ABL kinase inhibitor imatinib in chronic myelogenous leukemia (CML), where it contributed to the eradication of stem/progenitor cells (31), a feature that was independently reported for venetoclax (50, 51).
  • CML chronic myelogenous leukemia
  • Tigecycline also targeted cancer stem cells (CSCs) in AML (26), breast, and other tumor types (25, 28), pointing to a critical function of mitochondrial translation in CSCs.
  • Venetoclax Compared with other subtypes of lymphoma, venetoclax appears to be relatively ineffective against DLBCL (3, 10), although the impact of the MYC/BCL2 status on clinical responses was not reported. Venetoclax showed cooperativity with rituximab in patients with chronic lymphocytic leukemia (CLL) (58, 61), as well as in mice xenografted with DHL cell lines (8), as confirmed in the inventors' work. Finally, and most relevant for future clinical development, the effects of venetoclax and tigecycline in either DOHH-2 or PDX-derived tumors appeared to be reinforced by addition of rituximab in the inventors' study.
  • CLL chronic lymphocytic leukemia
  • the inventors' preclinical data have uncovered a synergy between mitochondrially- targeted antibiotic such as tigecycline and an inhibitor of BCL-2 such as venetoclax against DHL, warranting the repurposing of these drugs in combination for secondary treatment of patients with refractory or relapsed MYC/BCL2 double-hit lymphomas.
  • the addition of both compounds to R-CHOP or other rituximab-based chemo-immunotherapeutic regimens (3) may improve the primary response of patients with this particularly aggressive lymphoma subtype.

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Abstract

La présente invention concerne l'utilisation thérapeutique d'une combinaison d'au moins un antibiotique ciblant les mitochondries et d'au moins un inhibiteur de BCL-2 destiné à être utilisé dans le traitement des lymphomes B à double liaison MYC/BCL2, ainsi que des compositions associées.
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