WO2012035131A1 - Traitement du lymphome b surexprimant abl - Google Patents

Traitement du lymphome b surexprimant abl Download PDF

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Publication number
WO2012035131A1
WO2012035131A1 PCT/EP2011/066070 EP2011066070W WO2012035131A1 WO 2012035131 A1 WO2012035131 A1 WO 2012035131A1 EP 2011066070 W EP2011066070 W EP 2011066070W WO 2012035131 A1 WO2012035131 A1 WO 2012035131A1
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Prior art keywords
abl
bcr
lymphoma
treatment
acid
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PCT/EP2011/066070
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English (en)
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Anne Mueller
Vanessa Craig
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University Of Zurich
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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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of bcr-abl inhibitors, such as imatinib, dasatinib and nilotinib, in the treatment of ABL overexpressing B-cell lymphoma, in particular mucosa- associated lymphoid tissue (MALT) lymphoma.
  • bcr-abl inhibitors such as imatinib, dasatinib and nilotinib
  • Mucosa-associated lymphoid tissue (MALT) lymphoma account for 50% of all primary gastric lymphoma.
  • MALT lymphoma The development of gastric MALT lymphoma is tightly linked to chronic infection with the human bacterial pathogen Helicobacter pylori; consequently, antibiotic eradication therapy is now the first line treatment for this malignancy.
  • lymphomagenesis is initiated by H. py/or/ ' -associated chronic inflammation and the subsequent accumulation of gastric organized lymphoid tissue ("MALT"), from which individual neoplastic clones may grow out and invade the adjacent epithelium, forming the lympho-epithelial lesions that are a hallmark of low grade MALT lymphoma (Sagaert X. et al., Nat Rev Gastroenterol Hepatol 2010, 7(6): 336-346).
  • MALT gastric organized lymphoid tissue
  • MALT lymphoma tumor immunoglobulins are clonal, somatically hypermutated and polyreactive, i.e. they bind to a variety of unrelated self- and foreign antigens (Craig V.J. et al., Blood 1 15:581-591 (2010)).
  • the same panel of antigens that are recognized by MALT lymphoma surface immunoglobulin induce proliferation of explanted tumor cells, supporting the notion that early low grade gastric MALT lymphoma is an antigen-dependent malignancy.
  • Low grade gastric MALT lymphoma are infiltrated by large numbers of T-cells, which are polarized to produce Th2 cytokines such as interleukin-4.
  • T-cells prevent the proliferation of tumor cells ex vivo and induces tumor regression in a mouse model of gastric MALT lymphoma, implying a synergistic role for T-cell-derived signals and B-cell receptor-mediated antigen recognition during early MALT lymphoma pathogenesis.
  • MALT lymphoma are a sub-group of ABL overexpressing B-cell lymphoma.
  • Other such lymphoma of the stomach are, for example, diffuse large B cell lymphoma (DLBCL).
  • DLBCL diffuse large B cell lymphoma
  • MicroRNAs are well-conserved, 18-25 nucleotide long non-coding RNAs with pivotal roles in post-transcriptional gene regulation. miRNA expression patterns correlate with particular cancer types and are predictive of clinical outcome. Over 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites. Many miRNAs are known to function as tumor suppressors, regulating the expression of oncoproteins such as RAS and c-MYC.
  • Bcr-abI fusion protein is an oncogene fusion protein consisting of BCR (breakpoint cluster region) and ABL (ABL1 , Abelson proto-oncogene 1). It is associated with Philadelphia chromosome, a reciprocal translocation between chromosome 22 and 9, and is often found in chronic myeloid leukemia patients, but also connected with acute lymphoblastic leukemia.
  • the bcr-abl fusion protein encodes an unregulated cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without regulation by cytokines. Recently efficient bcr-abl inhibitors have been developed. Imatinib, also known as
  • Imatinib is a very efficient drug for the treatment of chronic myelogenous leukemia (CML) and
  • GIST gastrointestinal stromal tumors
  • the invention relates to bcr-abl inhibitors, such as imatinib, dasatinib and nilotinib, for use in the treatment of ABL overexpressing B-cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT) lymphoma, and to compositions further comprising an antibiotic and/or proton-pump inhibitor for such use.
  • bcr-abl inhibitors such as imatinib, dasatinib and nilotinib
  • bcr-abl inhibitors such as imatinib, dasatinib and nilotinib
  • bcr-abl inhibitors for use in the preparation of a medicament for the treatment of ABL overexpressing B-cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT) lymphoma
  • MALT mucosa-associated lymphoid tissue
  • a bcr-abl inhibitor such as imatinib, dasatinib and nilotinib.
  • A LNA (locked nucleic acid) real-time RT-PCR validation of miR-203 expression in human (h) samples of tonsil (T) and MALT lymphoma (MALT-L). miR-203 levels were normalized to U6 snRNA expression.
  • C Expression levels of miR-203 in murine (m) MALT lymphoma (MALT-L) and corresponding gastritis (G) samples as determined by LNA RT-PCR.
  • the miR-203 promoter is specifically hypermethylated in MALT lymphoma.
  • T human tonsil
  • G gastritis
  • gDLBCL gastric diffuse large B-cell lymphoma
  • Black and white circles represent methylated and unmethylated CpG
  • 5'-azacytidine (Aza), alone or in combination with 3 mM 4-phenylbutyric acid (Aza + PBA), or left untreated (-).
  • Three single clones were sequenced for each treatment and the percentage of methylated CpG dinucleotides is shown. Black and white circles represent methylated and unmethylated CpG, respectively.
  • the invention relates to bcr-abl inhibitors, such as imatinib, dasatinib and nilotinib, for use in the treatment of ABL overexpressing B-cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT) lymphoma.
  • Mucosa-associated lymphoid tissue (MALT) lymphoma is a well characterized form a B- cell non-Hodgkin lymphoma.
  • the stomach is the most commonly affected organ in which MALT lymphoma pathogenesis is clearly associated with Heliobacter pylori gastro- duodenitis (Sagaert X. et al., Nat Rev Gastroenterol Hepatol 2010, 7(6):336-346).
  • MALT lymphoma includes both low grade MALT lymphoma and high grade MALT lymphoma, the more aggressive form of MALT lymphoma, also termed gastric diffuse large B-cell lymphoma (gDLBCL).
  • MALT lymphoma comprises forms of the disease in any of the organs that can be inflicted, for example in the stomach, lung, thyroid gland, salivary gland and lacrimal gland, and comprises also its splenic and nodal counterparts.
  • B-cell lymphoma overexpressing ABL are, for example, nodal or extranodal diffuse large cell B-cell lymphoma (DLBCL), for example diffuse large B-cell lymphoma of the stomach.
  • DLBCL diffuse large cell B-cell lymphoma
  • Imatinib is 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)- amino]phenyl]benzamide, and is usually applied as the mesylate.
  • Dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl- 4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate.
  • Nilotinib is 4-methyl-N-[3-(4-methyl-1 H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide, applied as the hydrochloride hydrate.
  • bcr-abl inhibitors considered are, for example, those listed by Valent P., Clinical Medicine Insights: Therapeutics 2010:365-380, in particular SKI-606 (bosutinib),
  • INNO-406 (bafetinib), AZD0530 (saracatinib), AP23464, AP23848, CGP76030, PP1 ,
  • this expression is also used to designate salts, hydrates or other solvates. Salts are, in particular, pharmaceutically acceptable salts.
  • Acid addition salts may comprise more than one acid molecule, depending on the number of basic nitrogen atoms of the free base.
  • Such acid additions salts may be formed with organic or inorganic acids, especially with pharmaceutically acceptable acids. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, oleic acid, glycolic acid, lactic acid, oxalic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane- sulfonic acid, 2-hydroxyethanes
  • salts with alkali or earth alkali cations are considered, e.g. sodium, potassium, calcium or magnesium salts.
  • salts with ammonia, or primary, secondary or tertiary amines are considered, for example with ethanolamine, di(2-hydroxyethyl)amine, tri(2-hydroxyethyl)amine or dimethyl-
  • 2-hydroxyethyl-amine also quaternary salts, such as tetramethylammonium, or salts with the basic amino acids lysine or arginine.
  • the active ingredient is preferably in the form of a pharmaceutical preparation comprising a bcr-abl inhibitor as active ingredient in chemically pure form, and optionally a pharmaceutically acceptable carrier and optionally adjuvants.
  • the bcr-abl inhibitor is used in an amount effective against the bacterial infectious disease in humans.
  • the dosage of the active ingredient depends upon the age, weight, and individual condition of the human being, the individual pharmacokinetic data, and the mode of administration.
  • the daily dose administered of an bcr-abl inhibitor is from 0.01 mg/kg bodyweight to 100 mg/kg bodyweight, preferably from 0.1 mg/kg bodyweight to 50 mg/kg bodyweight, more preferably from 1 mg/kg to 20 mg/kg bodyweight administered as a single dose or as several doses.
  • the bcr-abl inhibitor can be used alone or in combinations with other drugs.
  • compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as subcutaneous, intravenous, intrahepatic or intramuscular administration, are especially preferred.
  • the pharmaceutical compositions comprise from approximately 1 % to approximately 95% active ingredient, preferably from approximately 20% to approximately 90% active ingredient.
  • compositions of the bcr-abl inhibitor may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, viscosity-increasing agents, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, and also binders, such as starches, cellulose derivatives and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, flow conditioners and lubricants, for example stearic acid or salts thereof and/or polyethylene glycol.
  • Tablet cores can be provided with suitable, optionally enteric, coatings. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules may contain the active ingredient in the form of granules, or dissolved or suspended in suitable liquid excipients, such as in oils.
  • Slow release oral pharmaceutical preparations are also considered, for example preparations containing swellable polymers, in particular compositions comprising the active ingredient, a polymeric binder, and a non-ionic, pharmaceutically acceptable surfactant.
  • Polymeric binders considered are, for example, homo- and copolymers of N-vinylpyrrolidone, cellulose esters or ethers, high molecular weight polyalkylene oxides, polyacrylates, vinyl acetate polymers, polyvinyl alcohol and polysaccharides.
  • Transdermal/intraperitoneal and intravenous applications are also considered, for example using a transdermal patch, which allows administration over an extended period of time, e.g. from one to twenty days.
  • the bcr-abl inhibitor can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations of the bcr-abl inhibitor and one or more other therapeutic agents known in the treatment of MALT lymphoma in humans, the administration being staggered or given independently of one another, or being in the form of a fixed combination.
  • antibiotics particularly those known to eradicate H. pylori, for example beta-lactams such as amoxicillin, macrolides such as clarithromycin, chinolones such as levofloxacin, metronidazole, furthermore proton pump inhibitors, such as omeprazole, pantoprazole or rabeprazole.
  • beta-lactams such as amoxicillin
  • macrolides such as clarithromycin
  • chinolones such as levofloxacin
  • metronidazole metronidazole
  • proton pump inhibitors such as omeprazole, pantoprazole or rabeprazole.
  • the invention further relates to bcr-abl inhibitors, such as imatinib, dasatinib or nilotinib, for use in the preparation of a medicament for the treatment of ABL overexpressing B-cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT) lymphoma.
  • bcr-abl inhibitors such as imatinib, dasatinib or nilotinib
  • the invention further relates to a method of treatment of ABL overexpressing B-cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT) lymphoma comprising administering to a patient in need thereof a therapeutically effective amount of a bcr-abl inhibitor, such as imatinib, dasatinib or nilotinib.
  • a bcr-abl inhibitor such as imatinib, dasatinib or nilotinib.
  • miR-203 is down-regulated in gastric MALT lymphoma due to promoter hypermethylation.
  • the ectopic re-expression of miR-203 in a lymphoma cell line or in primary MALT lymphoma cells down-regulates the expression of the miR-203 target ABL1 and blocks tumor cell proliferation in vitro.
  • ABL1 tyrosine kinase activity by imatinib blocks MALT lymphoma cell proliferation ex vivo and prevents tumor formation in mice, suggesting for the first time an important oncogenic role for ABL1 in the
  • mice Female BALB/c mice were infected orally at six weeks of age with three consecutive doses of -5x10 7 H. felis (CS1 , ATCC 49179) and maintained in a University of Zurich SPF facility.
  • imatinib treatment at the 15 month infection time point mice received 1.2 mM imatinib (-75 mg/kg per day) through their drinking water for 3 months.
  • imatinib treatment at the 15 month infection time point mice received 1.2 mM imatinib (-75 mg/kg per day) through their drinking water for 3 months.
  • macroscopically visible tumors were collected and single cell suspensions were generated and cultured in RPMI supplemented with 10% FCS and antibiotics.
  • Tumor cells were stimulated with 10 ⁇ g/ml Helicobacter lysate and cultured either in the presence or absence of imatinib (Novartis, Basel, Switzerland) or dasatinib (Bristol-Myers Squibb) for 3 days. Tumor cell proliferation was quantified by [ 3 H]-thymidine incorporation assay.
  • the Burkitt's lymphoma BL2 cell line was described in Cohen J.H. et al., J Natl Cancer Inst 1987, 78:235.-242.
  • BL2 cells were seeded at 5x10 5 cells/ml 24 hours prior to treatment with 5 ⁇ 5'-azacytidine and/or 3 mM 4-phenylbutyric acid (both from Sigma-Aldrich).
  • 1x10 6 BL2 cells were nucleoporated using an Amaxa Nucleoporator (Gaithersburg, MD) with either 50 nM or 100 nM of precursor oligonucleotides (either miR-203 specific miRNA precursor or negative control precursor 1 , Ambion, Austin, TX) in a total volume of 2 ml.
  • ABL1 expression was analyzed by real time RT-PCR (LightCycler 480 SYBR Green I master kit; Roche, Basel, Switzerland) or Western Blot, using antibodies against ABL1 (BD Biosciences, CA, USA) and a-tubulin (Sigma-Aldrich, St. Louis, MO).
  • Primary MALT lymphoma cells were transduced with lentiviral particles harboring a miR-203 expression construct (Systems Biosciences, Mountain View, CA) in the presence of 8 ⁇ g/ml polybrene by spinoculation. Tumor cell proliferation was quantified by a [ 3 H]-thymidine incorporation assay. Expression of mature mir-203 was validated by real-time PCR.
  • Microarray-based miRNA expression profiling and bisulfite genomic sequencing miRNA microarray experiments were performed using the Agilent Human miRNA Microarray Kit version 10.0. Normalization and statistical analysis was performed using the quantile normalization implemented in the package PreprocessCore and the package genefilter, respectively. Specific oligonucleotides for methylation-specific PCR (MS-PCR) and bisulfite sequencing of the miR-203 CpG island were performed as described by Bueno M.J. et al., Cancer Cell 2008, 13:496-506.

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des inhibiteurs bcr-abl, tels que l'imatinib, le dasatinib ou le nilotinib, destinés au traitement du lymphome B surexprimant ABL, en particulier le lymphome du tissu lymphoïde associé aux muqueuses (lymphome MALT), ainsi que les compositions comportant en outre un antibiotique et/ou un inhibiteur de la pompe à protons à ces fins. L'invention concerne aussi les inhibiteurs bcr-abl destinés à être utilisés dans la préparation de médicaments permettant de traiter le lymphome B surexprimant ABL, ainsi qu'un procédé de traitement du lymphome B surexprimant ABL consistant à administrer un inhibiteur bcr-abl, l'invention étant basée sur l'observation qu'ABL1 joue un rôle oncogène important dans la pathogenèse du lymphome MALT.
PCT/EP2011/066070 2010-09-16 2011-09-16 Traitement du lymphome b surexprimant abl WO2012035131A1 (fr)

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JP2016523850A (ja) * 2013-06-14 2016-08-12 インスティトゥト キミク デ サリア、セツ フンダシオ プリバダＩｎｓｔｉｔｕｔ Ｑｕｉｍｉｃ Ｄｅ Ｓａｒｒｉａ，Ｃｅｔｓ Ｆｕｎｄａｃｉｏ Ｐｒｉｖａｄａ ４−アミノ−６−（２，６−ジクロロフェニル）−２−（フェニルアミノ）−ピリド［２，３−ｄ］ピリミジン−７（８Ｈ）−オン誘導体、その合成および使用
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US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016523850A (ja) * 2013-06-14 2016-08-12 インスティトゥト キミク デ サリア、セツ フンダシオ プリバダＩｎｓｔｉｔｕｔ Ｑｕｉｍｉｃ Ｄｅ Ｓａｒｒｉａ，Ｃｅｔｓ Ｆｕｎｄａｃｉｏ Ｐｒｉｖａｄａ ４−アミノ−６−（２，６−ジクロロフェニル）−２−（フェニルアミノ）−ピリド［２，３−ｄ］ピリミジン−７（８Ｈ）−オン誘導体、その合成および使用
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
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