JP6290193B2 - ペグ化oxm変異体 - Google Patents
ペグ化oxm変異体 Download PDFInfo
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- JP6290193B2 JP6290193B2 JP2015515646A JP2015515646A JP6290193B2 JP 6290193 B2 JP6290193 B2 JP 6290193B2 JP 2015515646 A JP2015515646 A JP 2015515646A JP 2015515646 A JP2015515646 A JP 2015515646A JP 6290193 B2 JP6290193 B2 JP 6290193B2
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 235000018770 reduced food intake Nutrition 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000013878 renal filtration Effects 0.000 description 1
- 230000003979 response to food Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
Description
別の実施形態において、PEG−Fmoc−OXMおよびPEG−FMS−OXMならびにそれらを含む医薬組成物は、高血糖の予防のため、血糖のコントロールを改善するため、非インスリン依存性糖尿病(一実施形態において、2型糖尿病)、インスリン依存性糖尿病(一実施形態において、1型糖尿病)、および妊娠糖尿病、またはそれらの任意の組み合わせからなる群から選択される糖尿病の治療のために利用される。別の実施形態において、PEG−Fmoc−OXMおよびPEG−FMS−OXMならびにそれらを含む医薬組成物は、2型糖尿病を治療するために利用される。別の実施形態において、本明細書に提供されるPEG−Fmoc−OXMおよびPEG−FMS−OXM変異体ならびにそれらを含む医薬組成物は、インスリン感受性を増大させるために利用される。別の実施形態において、本明細書に提供されるPEG−Fmoc−OXMおよびPEG−FMS−OXM変異体ならびにそれらを含む医薬組成物は、インスリン抵抗性を低下させるために利用される。
投与される
一般的に、本明細書で使用する用語および本発明で利用する実験方法として、分子、生化学、微生物学および組換えDNAの技術を挙げることができる。このような技術は、各種文献に詳細に説明されている。例えば"分子クローニング:実験室マニュアル(Molecular Cloning:A laboratory Manual)"Sambrookら(1989);"Current Protocols in Molecular Biology"I−III巻 Ausubel,R.M.(編)(1994);Ausubelら"分子生物学の最新プロトコル(Current Protocols in Molecular Biology)"、John Wiley and Sons、メリーランド州ボルチモア(1989);Perbalの"分子クローニングの実用ガイド(A Practical Guide to Molecular Cloning)"、John Wiley & Sons、ニューヨーク州(1988);Watsonらの"組換えDNA(Recombinant DNA)"、Scientific American Books、ニューヨーク州;Birrenら(編)"ゲノム解析:実験室マニュアルシリーズ(Genome Analysis:A Laboratory Manual Series)"、1〜4巻、Cold Spring Harbor Laboratory Press、ニューヨーク州(1998);米国特許第4,666,828号、同第4,683,202号、同第4,801,531号、同第5,192,659号、同第5,272,057号に記載の方法;"細胞生物学:実験ハンドブック(Cell Biology:A Laboratory Handbook)"、I−III巻 Cellis、J.E.(編)(1994);Freshneyによる"動物細胞の培養−基本技術マニュアル(Culture of Animal Cells−A Manual of Basic Technique" Wiley−Liss,ニューヨーク州(1994)、第3版;"免疫学における最新プロトコル(Current Protocols in Immunology)"I−III巻、Coligan J.E.(編)(1994);Stitesら(編)"基本的な臨床免疫(Basic and Clinical Immunology)"(第8版)、Appleton & Lange、コネチカット州ノーウォーク(1994);Mishell and Shiigi(編)"細胞免疫学の選択法(Selected Methods in Cellular Immunology)"、W.H.Freeman and Co.、ニューヨーク州(1980);利用可能なイムノアッセイは広範囲に特許および科学文献に記載されている。例えば、米国特許第3,791,932号、同第3,839,153号、同第3,850,752号、同第3,850,578号、同第3,853,987号、同第3,867,517号、同第3,879,262号、同第3,901,654号、同第3,935,074号、同第3,984,533号、同第3,996,345号、同第4,034,074号、同第4,098,876号、同第4,879,219号、同第5,011,771号、同第5,281,521号;"オリゴヌクレオチド合成(Oligonucleotide Synthesis)"Gait,M.J.(編)(1984);"核酸ハイブリダイゼーション(Nucleic Acid Hybridization)"Hames,B.D.およびHiggins S.J.(編)(1985);"転写と翻訳(Transcription and Translation)"Hames,B.D.およびHiggins S.J.(編)(1984);"動物細胞培養(Animal Cell Culture)"Freshney,R.I.(編)(1986);"固定化細胞および酵素(Immobilized Cells and Enzymes)"IRL Press,(1986);"分子クローニングの実用ガイド(A Practical Guide to Molecular Cloning)"Perbal,B.(1984)および"酵素学における方法(Methods in Enzymology)"1−317巻、Academic Press;"PCRプロトコル:方法と応用へのガイド(PCR Protocols:A Guide To Methods And Applications)"、Academic Press、カリフォルニア州サンディエゴ(1990);Marshakらの"タンパク質の精製および特徴づけのための戦略−研究室コースマニュアル(Strategies for Protein Purification and Characterization − A Laboratory Course Manual)"CSHL Press(1996)を参照されたく、これらの全ては、参照により援用される。他の一般的な文献は本明細書の中に提供される。
PEG30−FMS−OXM合成−異種
1.1段階1:OXM合成
以下のペプチド配列からなるオキシントモジュリンを合成した。
HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA(配列番号1)
1.キャッピング
樹脂をDMF(Rathburn社)中の0.5M無水酢酸(Fluka社)溶液を用いてキャップした。
Fmoc−保護基を、DMF(Rathburn社)中20%v/vのピペリジン(Rathburn社)溶液を用いて、成長するペプチド鎖から除去した。
DMF(Rathburn社)中0.5Mのアミノ酸(Novabiochem社)溶液を、DMF(Rathburn社)中1MのHOBt(Carbosynth社)溶液およびDMF(Rathburn社)中1MのDIC(Carbosynth社)溶液を用いて活性化した。カップリングごとに各アミノ酸の4当量を使用した。
粗ペプチドを、アセトニトリル(Rathburn社)/水(ミリQ)(5:95)に溶解し、分取HPLCカラム上に添加した。クロマトグラフィーのパラメータを以下に示す。
カラム:Phenomenex Luna C18 250mm×30、15μm、300A
移動相A:水+0.1%v/vのTFA(Applied Biosystems社)
移動相B:アセトニトリル(Rathburn社)+0.1%v/vのTFA(Applied Biosystems社)
UV検出:214または220nm
勾配:カラム体積の4倍を超える25%B〜31%B
流速:43mL/分
2−アミノフルオレン(18g、99ミリモル)を、磁気撹拌しながら氷浴中でジオキサン:水(2:1)(200ml)および2NのNaOH(60ml)の混合物に懸濁した。次いで、Boc2O(109ミリモル、1.1当量)を加え、室温で攪拌し続けた。反応をTLC(Rf=0.5、ヘキサン/酢酸エチル2:1)によって監視し、2NのNaOHの添加によりpHを9〜10に維持した。反応完了時に、懸濁液をpH=3まで1MのKHSO4で酸性化した。固体を濾過し、冷水(50ml)、ジオキサン−水(2:1)で洗浄し、次いで、次のステップで使用する前に2回トルエンで共沸した。
3口RBFに、NaH(油中60%;330ミリモル、3.3当量)を、乾燥THF(50ml)に懸濁し、ステップ2に記載の乾燥THF(230ml)中2−(Boc−アミノ)フルオレン溶液(28g;100ミリモル)を20分かけて滴加した。濃厚な黄色のスラリーが観察され、混合物を窒素下、室温で10分間攪拌した。ギ酸エチル(20.1ml、250ミリモル、2.5当量)を滴加した(注意:ガス発生)。このスラリーは淡褐色溶液に変化した。この溶液を20分間攪拌した。反応をTLC(Rf=0.5、ヘキサン/酢酸エチル1:1)によって監視し、出発材料の痕跡のみが観察された時に、氷水(300ml)でクエンチした。混合物を、THFの大部分が除去されるまで減圧下で蒸発させた。得られた混合物をpH=5まで酢酸で処理した。得られた白色沈殿物を酢酸エチルに溶解し、有機層を分離した。水層を酢酸エチルで抽出し、全ての有機層を合わせ、飽和重炭酸ナトリウム、ブラインで洗浄し、MgSO4で乾燥させた。濾過および溶媒除去後、黄色固体が得られた。この物質を次のステップで使用した。
上記の化合物3をMeOH(200ml)に懸濁し、水素化ホウ素ナトリウムを15分かけて少しずつ添加した。混合物を30分間撹拌した(注意:発熱反応およびガス発生)。反応をTLC(Rf=0.5、ヘキサン/EtOAc 1:1)により監視し、完成させた。水(500ml)を添加し、酢酸でpHを5に調整した。仕上げ作業には、酢酸エチルでの2回抽出、合わせた有機層の重炭酸ナトリウムおよびブラインでの洗浄、MgSO4での乾燥、濾過および濃縮乾燥が伴う。得られた粗生成物を、ヘプタン/EtOAc(3:1)を用いるフラッシュクロマトグラフィーにより精製し、黄色泡状物を得た(36g、純度97.5%、酢酸エチルおよびジエチルエーテルの痕跡が1H−NMRで観察された)。
オーバーヘッド撹拌によりクリーンな乾燥RBF500mlに乾燥THF(55ml)中のトリホスゲン(1.58g、0.35当量)を添加し、周囲環境で溶液を形成させた。これを氷/水浴で0℃まで冷却し、乾燥THF(19ml)中NHS(0.67g、0.38当量)の溶液を窒素下、0℃で10分間かけて滴加した。得られた溶液を30分間攪拌した。乾燥THF(36ml)中のNHS(1.34g、0.77当量)を、さらに0℃で10分かけて滴加し、15分間撹拌した。
トリフルオロ酢酸(10ml)中のMAL−Fmoc−NHS(100mg、0.2ミリモル)の溶液に、クロロスルホン酸(0.5ml)を加えた。15分後、氷冷したジエチルエーテル(90ml)を添加し、生成物が沈殿した。この物質を遠心分離により収集し、ジエチルエーテルで洗浄し、真空乾燥した。ベージュ色の固体41.3mg(35%)を得た。
OXMペプチド中の3つのアミン部位(Lys12、Lys30およびアミノ末端)の異種結合を「ワンポット反応」として行い、OXM、mPEG−SHおよびFMSリンカーの各成分の1当量を、30分間、pH7.2で混合した。pHを4まで下げるために酢酸を添加することによって、反応を停止した。
段階1:スペーサー MAL−FMS−NHS(FMS)合成:異種結合体について説明した通りである。
N末端部位特異的OXM−異種結合体について上記で説明した通りである。
FMSのOXMへのカップリング:
MAL−FMS−NHSリンカー溶液(0.746ml、DMF中10mg/ml、2当量)をOXM樹脂(1当量、樹脂200mg、31.998μモル/gの遊離アミン)に添加した。樹脂が自由に可動可能になるまでDMFを添加し、次いで、19時間超音波処理した。樹脂をDMFおよびメタノールで洗浄し、真空デシケーター中で一晩乾燥した。切断カクテルは、TFA/TIS/H2Oを含んでいた。切断を、室温で3.5時間かけて行った。樹脂を濾過した後、FMS−OXMを冷ジエチルエーテルで沈殿させた。切断段階の最後に、粗FMS−OXM(36%純度)42.1mgを得た。
MAL−FMS−NHSリンカー溶液(DMF中10mg/ml、2.5当量)を、(Lys12)OXM樹脂(1当量)に添加し、DIEA(5当量)を添加した。樹脂が自由に可動可能になるまでDMFを添加し、次いで、一晩超音波処理した。樹脂をDMFおよびメタノールで洗浄し、真空デシケーター中で一晩乾燥した。切断および沈殿を、N末端部位特異的OXMについて記載したように行った。
MAL−FMS−NHSリンカー(2.5当量)をDCMに溶解させ、DIEA(5当量)を加えた。このリンカー/DIEA溶液を(Lys30)OXM樹脂に添加し、次いで、一晩超音波処理した。樹脂をDCMおよびメタノールで洗浄し、真空デシケーター中で一晩乾燥した。切断および沈殿を、N末端部位特異的OXMについて記載したように行った。
得られた粗FMS−OXMを一度に精製した。
試料希釈剤:水中の10%アセトニトリル
カラム:Luna C18(2),100Å,250×21.2mm
注入流量:9ml/分
実行中の流速:9ml/分
緩衝液A:水(0.1%TFA)
緩衝液B:アセトニトリル(0.1%TFA)
勾配:32分かけて10〜45%B
監視:230nm
FMS−OXM溶液(1当量、1.5mlのDMF中15.1mg)を調製した。PEG30(1当量、10mg/mlのリン酸緩衝液(pH6.5)中9.2ml)をFMS−OXM溶液に添加した。次いで、反応混合物を、室温で30分撹拌し、氷酢酸(200μl)を加え、pHを低下させることによって反応をクエンチした。
カラム:Luna C18(2)、100Å、250×21.2mm
注入流量:5ml/分
実行中の流量:20ml/分
緩衝液A:水&0.1%TFA
緩衝液B:アセトニトリル/水(75:25)&0.1%TFA
勾配:41分かけて10〜65%B
監視:220nm、240nm、280nm
C57BL/6雄マウスを一晩絶食させ、秤量し、血糖値を、ハンドヘルドグルコメーターを用いて尾静脈サンプリングにより測定した。マウスに、PEG−SH(ビヒクル)、PEG30−FMS−OXM(異種)およびPEG30−FMS−OXMの3種類の同種変異体(アミノ、Lys12およびLys30)をIP注射した。グルコース(1.5gr/kg)を試験品投与後15分の時点でIP投与した。血糖値を、グルコース投与前ならびにグルコース投与後10、20、30、60、90、120および180分の時点でハンドヘルドグルコメーターを用いて尾静脈サンプリングにより測定した。
GLP−1受容体活性化を、共にGLP−1受容体を過剰発現している2種類の異なる細胞株のHTS163C2(Millipore社)およびcAMPハンター(登録商標)CHO−K1 GLP1R(Discoverx社)を用いて評価した。HTS163C2(Millipore社)を100,000細胞/ウェルの密度で96ウェルハーフエリアホワイトプレート(Greiner社)に播種し、37℃で24時間インキュベートした。これらの細胞を、異種のPEG30−FMS−OXMおよび3種類の同種PEG30−FMS−OXM変異体(アミノ、Lys12およびLys30)の濃度を増加させてインキュベートした。細胞のcAMP濃度をHTRFアッセイ(Cisbio社62AM4PEB)によって定量し、EC50パラメータをPRISMソフトウェアにより分析した。cAMPハンター(登録商標)CHO−K1 GLP1Rは、リガンドの受容体への結合の際にcAMPを分泌する。50万細胞/mlの密度で細胞を96ウェルプレートに播種し、5%CO2、37℃で24時間インキュベートした。リガンドを、IBMXを含む希釈剤で希釈し、5%CO2、37℃で30分間、培養ウェルに2連で添加した。PEG30−FMS−OXMの濃度範囲は、1.5×10−10〜1.2×10−6Mであった。溶解緩衝液および検出試薬をウェルに添加し、cAMP濃度を、化学発光シグナルを用いて検出した。用量依存曲線を作成して、様々なリガンドの結合親和性(EC50)を、最適用量反応モデル(4パラメータ)を適用することによってPRISMソフトウェアを用いて算出した。
グルカゴン受容体活性化を、グルカゴン受容体を過剰発現するcAMPハンター(登録商標)CHO−K1 GCGR細胞株を用いて評価した。この細胞株は、リガンドのグルカゴン受容体への結合の際にcAMPを分泌する。細胞を96ウェルプレートに500000細胞/mlの密度で播種し、5%CO2、37℃で24時間インキュベートした。リガンドを、IBMXを含む希釈剤で希釈し、5%CO2、37℃で30分間、培養ウェルに2連で添加した。MOD−6031の濃度範囲は、5.8×10−11〜2.7×10−7Mであった。溶解緩衝液および検出試薬をウェルに添加し、化学発光シグナルを用いてcAMP濃度を検出した。用量依存曲線を作成し、様々なリガンドの結合親和性(EC50)を、最適用量反応モデル(4パラメータ)を適用することによってPRISMソフトウェアを用いて算出した。
試験1:25匹の雄のob/obマウス(雄、B6.V−Lep^ob/OlaHsd、5〜6週齢、Harlan社)を、動物を扱う取扱プロトコルに従って、投与するかのように施設に順応させた(10日間)が、実際には秤量または投与は行わなかった(10日間)。その後、動物に、20ml/kgの容量で皮下経路により適切なビヒクルを週に2回投与する7日間のベースライン期間を受けさせた。体重、食物および水の摂取量を毎日記録し、非空腹時および空腹時のグルコース測定および非空腹時および空腹時インスリン測定のために試料を採取した。その後、動物を、体重および血糖プロファイルに基づいて5つの治療群(N=5)に割り当てた。表1に記載したように4日ごと(1、5、9、13および16日目)に、動物に投与した。治療期間中、投与前に、摂食量、水分摂取量および体重を測定し、毎日記録した。2、6、14および17日目に非空腹時および空腹時のグルコース(17日目のみ非空腹時のグルコースを測定した)、空腹時および非空腹時のインスリン(2、6および14日目)のようないくつかの手順およびサンプリングを行った。19日目の最後の試料はコレステロールについて分析した。
100匹の雄のob/obマウス(5〜6週齢、Charles River社)を、動物を扱う取扱プロトコルに従って、投与するかのように施設に順応させた(3日間)が、実際には秤量または投与は行わなかった(7日間)。その後、動物に、20ml/kgの容量で皮下経路によりPEG30−SHビヒクル(146mg/ml)を週に2回投与する7日間のベースライン期間を受けさせた。体重、食物および水の摂取量を毎日記録した。その後、動物を、8つの治療群(群A〜H、N=8)、対照群、同時飼育群に割り当てた(表2)。同時飼育群を、高用量(6000ナノモル/kg)のMOD−6031の群と同時飼育し、群Dのペアの相手が前日に摂取したのと同量の食事配給を毎日与えた。3種類の追加群(群I〜K、N=12)に、1000、3000および6000ナノモル/kgでMOD−6031を投与し、PK分析のサンプリングのために使用した。これらの同時飼育群に、PEG−SHビヒクル(292mg/ml)、1000、3000および6000ナノモル/kgのMOD−6031を32日間、週に2回投与し、OXM、リラグルチド(登録商標)、PBSを1日に2回投与した。体重、食物および水の摂取量を毎日測定した。非空腹時および空腹時のグルコースを週に1回測定し、OGTTを2日目および30日目に行った。末梢血液試料(33日目)を、グルコース、インスリン、コレステロール、およびMOD−6031、PEG−FMSおよびOXMの濃度について分析した。PK群のマウスにMOD−6031を単回投与し、LC−MS/MS法によってMOD−6031およびその化合物の濃度の定量化を可能にするPK分析のために、血液試料を4、8、24、36、48、72、96および120時間の時点(各時点につきn=3)で採取した。
実施例1
製造および開発合成
PEG−FMS−OXM結合体の組成はその合成手順に依存する。PEG−FMS−OXM結合体の異なる変異体を作製した(図1)。
MOD−6030(PEG30−FMS−OXM)の合成を以下のように行った:FMSスペーサーを、(ワンポット反応として)OXMおよびPEG(30)−SHと混合した。このFMSスペーサーを、一方の側でそのNHS活性化エステルによってOXMに結合させ、同時に反対側でマレイミド基に連結されたPEG−SHによってOXMに結合させた。このように、PEG−FMS−OXM結合体の異種混合物は、OXMペプチドの3つのアミン(N末端、Lys12およびLys30)のうちの1つによって連結された3種類の変異体で構成されている。
結合手順を、制御された部位特異的な方法でFMSスペーサーへの付着を実行する2段階プロセスでさらに進めた。最初のステップでは、FMSスペーサーをOXM(樹脂上の部分的に保護されたOXM)に結合させ、次いで、切断し、その後、(RP−HPLCによる)FMS−OXMの脱保護および精製を行った。第2のステップは、精製された同種のFMS−OXMにPEG30−SHを取り付けた。最終的な結合生成物をさらにRP−HPLCにより精製する。追加の精製ステップには、イオン交換もしくはSEC−HPLCまたは任意の他の精製ステップなどを適用することができる。
インビトロでのGLP−1受容体活性化のキャラクタライゼーション
PEG−FMS−OXM(MOD−6030;異種)のGLP−1受容体結合活性化ならびにPEG−FMS−OXMの3種類の異なる同種変異体であるアミノ(MOD−6031)、Lys12およびLys30を、GLP−1受容体を過剰発現する2種類の異なる細胞株:Millipore社のHTS163C2細胞株およびcAMPハンター(登録商標)CHO−K1 GLP1Rを用いて評価した。各変異体のEC50を算出し、その後、異種(MOD−6030)変異体に対する各変異体の相対的効力を算出する(各同種変異体のEC50を異種変異体のEC50で割り、それに100を掛ける)ことにより効力を決定した。EC50値および算出した相対的効力を表3に示す。比較のために、cAMPハンターCHO−K1 GLP1R細胞株のGLP−1受容体に対するOXMおよびGLP−1の結合親和性を測定した。
インビトロでのグルカゴン受容体活性化のキャラクタライゼーション
PEG−FMS−OXM変異体のグルカゴン受容体への結合親和性を、グルカゴン受容体を過剰発現するcAMPハンター(登録商標)CHO−K1 GCGR細胞株を用いて決定した。この細胞株を用いて、異種PEG−FMS−OXM(MOD−6030)およびPEG−FMS−OXMの3種類の異なる同種変異体であるアミノ(MOD−6031)、Lys12およびLys30をキャラクタライゼーションした。各変異体のEC50を算出し、その後、異種変異体に対する各変異体の相対的効力を算出する(各同種変異体のEC50を異種変異体のEC50で割り、それに100を掛ける)ことにより効力を決定した。EC50値および算出した相対的効力を表3に示す。アミノ変異体は、異種変異体と同程度の結合活性を示した。Lys30変異体は、最も高い生物活性を示し、Lys12は1.8倍の低下を示した。OXMおよびグルカゴンペプチドのグルカゴン受容体結合活性化を測定した。OXMおよびグルカゴンが、異種PEG30−FMS−OXMと比較して、11.1倍および283倍高い受容体結合活性化を示すことが判明した。
PEG30−FMS−OXM変異体による耐糖能の誘導
異種PEG30−FMS−OXMおよび3種類のPEG30−FMS−OXM変異体(アミノ、Lys12およびLys30)のインビボ活性を評価するために、IPGTTモデルを適用した。一晩絶食させたC57BL/6マウスに異なる化合物およびビヒクル(PEG−SH)をIP注射し、その後、グルコースのIP注射を行い、グルコメーターを用いて尾静脈から血糖値を測定した。PEG−SH(238.10ナノモル/kg)、異種および同種のPEG30−FMS−OXM(100ナノモル/kgのペプチド含量)を、グルコースのIP注射(1.5gr/kg)の15分前にIP投与した。全ての化合物は、ビヒクル群と比較して耐糖能を誘導した。意外にも、同種のアミノ変異体は、インビトロ活性の結果と対照的に、他の2つの変異体および異種PEG30−FMS−OXMと比較して効力はわずかに低く(表4、図3)、他の変異体と比較してわずかに高いグルコースAUCを反映した。しかし、ビヒクルPEG−SH対照と比較して、全ての変異体において耐糖能が著しく改善した。
ob/obマウスモデルにおけるPEG30−FMS−OXM変異体による体重、血糖および脂質プロファイルの改善
ob/obマウスモデルは、レプチンを産生することができず、高インスリン血症、肥満、過食症、インスリン抵抗性およびその後の高血糖症を特徴とする表現型を発現するようなob遺伝子の変異を示す。これらのマウスを、PEG30−FMS−OXM(異種)およびPEG30−FMS−OXMの3種類の同種変異体(アミノ酸、Lys12およびLys30)の有効性を評価するために、2つの異なる試験で糖尿病の遺伝モデルとして用いた。
ob/obマウスモデルにおけるMOD−6031変異体による薬物動態パラメータの改善
ob/obマウスの3群(n=12)に、1000、3000および6000ナノモル/kgのMOD−6031を単回投与し、PK分析のために投与後4、8、24、36、48、72、96および120時間の時点で採血し(時点当たりn=3)、MOD−6031の量およびその化合物濃度をLC−MS/MS法により決定した。Cmax、Tmax、AUC、T1/2ClおよびVzなどの薬物動態パラメータをMOD−6031(PEG−FMS−OXM)およびその加水分解物であるPEG−FMSおよびOXMについて算出し、これらのパラメータをそれぞれ、表6a、図6bおよび図6cに示す。AUC 0−∞は、全投与量において全成分のAUC 0−tの15%以内であり、サンプリング計画が各成分の薬物動態プロファイルをキャラクタライゼーションするのに十分であったことを示す。全3種類の成分について、暴露は用量に比例しているように思われた。一般的に、CmaxおよびAUC0−tは投与量と共に増加し、投与量が増加するのとほぼ同じ割合で増加した。
Claims (22)
- 請求項1に記載の結合体であって、
PEGは、PEG30であることを特徴とする結合体。 - 請求項1に記載の結合体であって、
R2は、2位にあることを特徴とする結合体。 - 請求項1〜3のいずれか1項に記載の結合体と、
薬学的に許容される担体とを含む、医薬組成物。 - 医薬を製造するための、請求項1〜3のいずれか1項に記載の結合体または請求項4に記載の医薬組成物の使用。
- 肥満を治療するための医薬を製造するための、請求項1〜3のいずれか1項に記載の結合体または請求項4に記載の医薬組成物の使用。
- 以下の構造式によって表される結合体の製造方法であって、
前記オキシントモジュリン(OXM、配列番号1のもの)は、前記オキシントモジュリンの末端アミノ基を介してリンクされ、R2は、HまたはSO3Hであり、それぞれはPEG−Fmoc−OXM(N末端)及びPEG−FMS−OXM(N末端)を表し、
前記方法は、
下記のMAL−FMS−NHSまたはMAL−Fmoc−NHS、即ち
または
と、
樹脂結合した配列番号1のオキシントモジュリンであって、前記樹脂結合した配列番号1のオキシントモジュリンのLys12及びLys30のアミノ側鎖は、各々保護基で保護されている、該樹脂結合した配列番号1のオキシントモジュリンと反応させて、樹脂結合MAL−Fmoc−保護OXM(N末端)または樹脂結合MAL−FMS−保護OXM(N末端)を得る反応ステップを含み、
前記方法は更に、前記反応ステップの後に、
(a)前記樹脂結合MAL−Fmoc−保護OXM(N末端)または前記樹脂結合MAL−FMS−保護OXM(N末端)とスルフヒドリルPEGポリマー(PEG−SH)とを反応させ、その後に前記保護基及び前記樹脂の除去を行うか、または
(b)前記保護基及び前記樹脂の除去を行ってMAL−Fmoc−OXM(N末端)またはMAL−FMS−OXM(N末端)を得て、その後前記MAL−Fmoc−OXM(N末端)または前記MAL−FMS−OXM(N末端)とスルフヒドリルPEGポリマー(PEG−SH)とを反応させて、
PEG−Fmoc−OXM(N末端)またはPEG−FMS−OXM(N末端)を得るステップを含むことを特徴とする方法。 - 請求項7に記載の方法であって、
前記PEGは、PEG30であることを特徴とする方法。 - 請求項7に記載の方法であって、
R2またはSO3Hは、2位にあることを特徴とする方法。 - 請求項7に記載の方法であって、
前記MAL−Fmoc−保護OXM(N末端)及び前記MAL−FMS−保護OXM(N末端)の前記Lys12及びLys30のアミノ側鎖の前記保護基は除去されて、MAL−Fmoc−OXM(N末端)及びMAL−FMS−OXM(N末端)がそれぞれ得られ、前記MAL−Fmoc−OXM(N末端)及び前記MAL−FMS−OXM(N末端)は更に精製されることを特徴とする方法。 - 請求項7に記載の方法であって、
前記MAL−Fmoc−保護OXM(N末端)及び前記MAL−FMS−保護OXM(N末端)の前記Lys12及びLys30のアミノ側鎖の前記保護基は、ivDde(1−[(4,4−ジメチル−2,6−ジオキソシクロヘキサ−1−イリジン)エチル])であることを特徴とする方法。 - 請求項7に記載の方法であって、
前記保護基は、塩基性条件下で除去されることを特徴とする方法。 - 以下の構造式によって表される結合体の製造方法であって、
前記オキシントモジュリン(OXM、配列番号1のもの)は、前記オキシントモジュリンのLys12のアミノ側鎖を介してリンクされ、R2は、HまたはSO3Hであり、それぞれはPEG−Fmoc−OXM(Lys12)及びPEG−FMS−OXM(Lys12)を表し、
前記方法は、
下記のMAL−FMS−NHSまたはMAL−Fmoc−NHS、即ち
または
と、
樹脂結合した配列番号1のオキシントモジュリンであって、前記樹脂結合した配列番号1のオキシントモジュリンのLys30のアミノ側鎖及びHis1のアミノ末端は、各々保護基で保護されている、該樹脂結合した配列番号1のオキシントモジュリンと反応させて、樹脂結合MAL−Fmoc−保護OXM(Lys12)または樹脂結合MAL−FMS−保護OXM(Lys12)を得る反応ステップを含み、
前記方法は更に、前記反応ステップの後に、
(a)前記樹脂結合MAL−Fmoc−保護OXM(Lys12)または前記樹脂結合MAL−FMS−保護OXM(Lys12)とスルフヒドリルPEGポリマー(PEG−SH)とを反応させ、その後に前記保護基及び前記樹脂の除去を行うか、または
(b)前記保護基及び前記樹脂の除去を行ってMAL−Fmoc−OXM(Lys12)またはMAL−FMS−OXM(Lys12)を得て、その後前記MAL−Fmoc−OXM(Lys12)または前記MAL−FMS−OXM(Lys12)とスルフヒドリルPEGポリマー(PEG−SH)とを反応させて、
PEG−Fmoc−OXM(Lys12)またはPEG−FMS−OXM(Lys12)を得るステップを含むことを特徴とする方法。 - 請求項13に記載の方法であって、
前記PEGは、PEG30であることを特徴とする方法。 - 請求項13に記載の方法であって、
R2またはSO3Hは、2位にあることを特徴とする方法。 - 請求項13に記載の方法であって、
前記MAL−Fmoc−保護OXM(Lys12)及び前記MAL−FMS−保護OXM(Lys12)の前記Lys30のアミノ側鎖及びHis1のアミノ末端の前記保護基は除去されて、MAL−Fmoc−OXM(Lys12)及びMAL−FMS−OXM(Lys12)がそれぞれ得られ、前記MAL−Fmoc−OXM(Lys12)及び前記MAL−FMS−OXM(Lys12)は更に精製されることを特徴とする方法。 - 以下の構造式によって表される結合体の製造方法であって、
前記オキシントモジュリン(OXM、配列番号1のもの)は、前記オキシントモジュリンのLys30のアミノ側鎖を介してリンクされ、R2は、HまたはSO3Hであり、それぞれはPEG−Fmoc−OXM(Lys30)及びPEG−FMS−OXM(Lys30)を表し、
前記方法は、
下記のMAL−FMS−NHSまたはMAL−Fmoc−NHS、即ち
または
と、
樹脂結合した配列番号1のオキシントモジュリンであって、前記樹脂結合した配列番号1のオキシントモジュリンのLys12のアミノ側鎖及びHis1のアミノ末端は、各々保護基で保護されている、該樹脂結合した配列番号1のオキシントモジュリンと反応させて、樹脂結合MAL−Fmoc−保護OXM(Lys30)または樹脂結合MAL−FMS−保護OXM(Lys30)を得る反応ステップを含み、
前記方法は更に、前記反応ステップの後に、
(a)前記樹脂結合MAL−Fmoc−保護OXM(Lys30)または前記樹脂結合MAL−FMS−保護OXM(Lys30)とスルフヒドリルPEGポリマー(PEG−SH)とを反応させ、その後に前記保護基及び前記樹脂の除去を行うか、または
(b)前記保護基及び前記樹脂の除去を行ってMAL−Fmoc−OXM(Lys30)またはMAL−FMS−OXM(Lys30)を得て、その後前記MAL−Fmoc−OXM(Lys30)または前記MAL−FMS−OXM(Lys30)とスルフヒドリルPEGポリマー(PEG−SH)とを反応させて、
PEG−Fmoc−OXM(Lys30)またはPEG−FMS−OXM(Lys30)を得るステップを含むことを特徴とする方法。 - 請求項17に記載の方法であって、
前記PEGは、PEG30であることを特徴とする方法。 - 請求項17に記載の方法であって、
R2またはSO3Hは、2位にあることを特徴とする方法。 - 請求項17に記載の方法であって、
前記MAL−Fmoc−保護OXM(Lys30)及び前記MAL−FMS−保護OXM(Lys30)の前記Lys12のアミノ側鎖及びHis1のアミノ末端の前記保護基は除去されて、MAL−Fmoc−OXM(Lys30)及びMAL−FMS−OXM(Lys30)がそれぞれ得られ、前記MAL−Fmoc−OXM(Lys30)及び前記MAL−FMS−OXM(Lys30)は更に精製されることを特徴とする方法。 - 生物学的半減期の長いオキシントモジュリンを含む組成物の製造方法であって、
請求項7〜20のいずれか1項に記載の方法によってオキシントモジュリン結合体を製造するステップを含むことを特徴とする方法。 - 必要な投与頻度が小さいオキシントモジュリンを含む組成物の製造方法であって、
請求項7〜20のいずれか1項に記載の方法によってオキシントモジュリン結合体を製造するステップを含むことを特徴とする方法。
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