JP5639585B2 - ペプチド−ポリマー共役体 - Google Patents
ペプチド−ポリマー共役体 Download PDFInfo
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- JP5639585B2 JP5639585B2 JP2011521347A JP2011521347A JP5639585B2 JP 5639585 B2 JP5639585 B2 JP 5639585B2 JP 2011521347 A JP2011521347 A JP 2011521347A JP 2011521347 A JP2011521347 A JP 2011521347A JP 5639585 B2 JP5639585 B2 JP 5639585B2
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- peptide
- conjugate
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- 229920000642 polymer Polymers 0.000 title claims description 50
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 28
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Description
本出願は、2008年7月31日に出願された米国仮出願第61/085,072号の優先権を主張するものであり、参照によりその内容全体が本明細書に組み込まれる。
細胞生物学および組み換えタンパク質の技術はタンパク質治療の発展をもたらしている。
本発明の一形態は化学式Iのポリマー−ポリペプチド共役体に関する:
本発明のペプチド−ポリマー共役体は化学分野でよく知られた合成方法で調製されうる。例えば、リンカー分子の官能基と反応しやすい官能基を有する二つのポリマー分子と一以上の活性な官能基を有するリンカー分子と結合することができる。実質的に官能基を有するペプチド分子は前記リンカー分子の官能基と反応し本発明のペプチド−ポリマー共役体を形成する。二つの例の合成式を本明細書に記載する。
・ジPEGアルデヒドの調製
市販のホモリシン(中国のAstatech Pharmaceutical Co.,Ltd.)の二つのアミノ基をベンジルオキシカルボニルによって保護した。当該N−保護したホモリシンをエステル化し、還元してアルデヒド化合物を形成した。当該アルデヒド基を続いてエチレングリコールで保護した。それから、ベンジルオキシカルボニル保護基をパラジウム触媒の存在下での水素添加により除去した。当該N−脱保護した化合物を、穏和な塩基条件下で活性化したmPEGOH(大韓民国のSunbio Chemicals Co.,Ltd.)と反応した。最終生成物は、25℃で72時間pH2.0のクエン酸緩衝液中攪拌して、アルデヒド保護基を除去した。109gのジPEGポリマーアルデヒドを得た(収率:95%)。純度は97.7%以上(HPLCで決定)であり、95%以上(1H NMR解析で決定)であった。
ヒトINF−β Ser17をエンコードしたDNAフラグメントを発現ベクターpET24aにコピーし、発現プラスミドrhIFN−b Ser17−pET24aを生成した。この発現プラスミドを大腸菌(E.coli)に転移し、陽性形質転換細胞、すなわち前記発現プラスミドを運搬するクローンを選択し、培養しおよび結果物である大腸菌培養物を−80℃で保存した。
18.9gのrhIFN−b Ser17と1.51gのジPEGアルデヒドを26mLの0.1M リン酸ナトリウム緩衝液(pH5.0)に懸濁した。この溶液に、400eq.のNaCNBH3(ベルギー、Acros Organics)を加えた。当該反応混合物を室温で16時間攪拌し、その後25mMのトリス−HCl(pH7.8)を用いて透析した。当該粗生成物をイオン交換カラムで精製し、2mgのIFN−b−di−PEGポリマーを得た。
大腸菌プロモーターに動作可能なように結合されたIFN−βのエンコード配列を有する組み換え大腸菌BLR (DE3)−RIL細胞を、50μl/mLのカナマイシンと50μl/mLのクロラムフェニコールを添加した250mLのSYN培地(10g/Lのセレクトソイトン(select soytone)、5g/Lの酵母エキス、および10g/LのNaCl)中培養した。その後、当該細胞を、振盪培養器中220rpmで一晩(すなわち、16時間)37℃で培養した。
水(1.46mL)中、ジPEGアルデヒド(296mg、7.4μmol)の溶液に2Mのリン酸ナトリウム緩衝液(pH4.0、0.37mL)、両性洗浄剤3−14(1.48mL、10%水溶液)およびINF−β(20mMの酢酸ナトリウム、0.7%の硫酸アンモニウムおよび0.05%の合成洗剤を含むpH4.5の緩衝液3.7mL中に14.8mg)を加えた。当該反応混合物を室温で10分間攪拌し、シアノ水素化ホウ素水溶液(400mM、92.5μL、37μmol)を加えた。当該反応混合物を暗所で40時間攪拌し、SP HPセファロースクロマトグラフィーで精製した。所望のPEG−IFNβ共役体を含む画分を保持時間および吸収度280nmに基づいて集めた。共役体の濃度をBCAタンパク質測定器(ピアス、BCATM Protein測定器)で決定した。
薬物動態学的研究をラットモデルで行い、IFN−βおよびPEG−IFN−βの血中半減期を調べた。オスのラット(250〜350gm)に600μg/kgのIFNβ(n=3)およびPEG−IFN b(n=3)を静注投与した。投与前および投与後0.1、1、2、4、6、10、24、48、72、および96時間でそれぞれのラットから血液(250μL)を採取した。当該血液から血清試料を調製し、試料中に含まれるIFN−βの量を酵素結合免疫測定法(ELISA)によって解析した。IFN−βおよびPEG−IFN−βの血中半減期を、最後3点の血清濃度から計算すると、それぞれ2時間および20時間であった。
PEG−EPOの調製
水(2.67mL)中、ジPEGアルデヒド(267mg、6.1μmol)の溶液に、2.0Mのリン酸ナトリウム緩衝液(pH4.0、1mL)およびEPO(20mMのリン酸ナトリウムおよび150mMのNaClを含むpH7.3の緩衝液3.03mL中に10mg)を加えた。当該反応混合物を室温で10分間攪拌し、続いてシアノ水素化ホウ素水溶液(400mM、100μL、40μmol)を加えた。当該反応混合物を暗所で17時間攪拌し、SP Toyopearlカラム(Tosoh製)を用いて精製した。当該カラムをpH4.5の酢酸ナトリウム緩衝液20mMで均一にした。前記反応混合物を0.3−0.4mg/mlの濃度に希釈し、前記SP Toyopearlカラムに充填した。所望のPEG−EPO共役体を含む画分を保持時間および吸収度280nmに基づいて集めた。共役体の濃度を280nmのUV吸収度で決定した。
薬物動態学的研究をラットモデルで行い、EPOおよびPEG−EPOの血中半減期を比較した。オスのラット(250〜350gm)に25μg/kgのEPO(n=5)およびPEG−EPO(n=5)を静注投与した。投与前および投与後0.088、0.75、1.5、3、6、10、24、および48時間でそれぞれのラットから血液(250μL)を採取した。PEG−EPO治療されているラットにおいては、血液サンプルをさらに投与後72および96時間でも採取した。当該血液から血清サンプルを調製し、酵素結合免疫測定法(ELISA)によって解析し、そこに含まれているEPOの量を決定した。その結果、EPOの血中半減期は9時間であり、一方、PEG−EPOの血中半減期は著しく増加し、すなわち38時間であることを示している。
0.1Mのリン酸塩緩衝液(pH5.0)に0.2mgのEPO(台湾のCashmere Scientific Company)と4mgのジPEGアルデヒド(20当量)を懸濁した。この溶液に400当量のNaCNBH3を加えた。当該反応混合物を室温で16時間攪拌した。EPO−ジPEGポリマーの形態をHPLCで確かめた。
Met−hGHの調製
発現Met−hGH機能のある形質転換大腸菌BLR (DE3)−RIL細胞をMet−hGHを発現させるため、上記の発酵方法で培養した。
リン酸ナトリウム緩衝液(pH4.0、374μL)とヒトGH(20mMの酢酸ナトリウムと150mMのNaClを含むpH4.5緩衝液6.5mL中に22.4mg)を、水(387μL)中のジPEGアルデヒド(74mg、1.7μmol)の溶液に加えた。当該反応混合物を室温で10分間攪拌し、シアノ水素化ホウ素ナトリウム水溶液(400mM、140mL、56mmol)を加えた。当該反応混合物を暗所で17時間攪拌し、SP XLセファロースクロマトグラフィーによって精製した。所望のポリマー−タンパク質共役体を含む画分を、保持時間と280nmにおける吸光度に基づき集めた。共役体の濃度をBradford法(イリノイ州ロックフォード、ピアス)を使用するタンパク質測定キットで決定した。
薬物動態学的研究をラットモデルで行い、Met−hGHおよびPEG−Met−hGHの血中半減期を比較した。オスのラット(250〜350gm)に100μg/kgの投与量でMet−hGH(n=5)またはPEG−Met−EPO(n=5)を静注投与した。投与前および投与後0.083、1、2、4、8、12、および24時間でMet−hGHで治療されたラットから、および投与前および投与後0.33、1、4、8、12、24、48、72、および96時間後にPEG−Met−EPOで治療されたラットから血液サンプルを採取した。当該血液から血清サンプルを調製し、酵素結合免疫測定法(ELISA)によって解析し、hGH濃度を決定した。Met−hGHおよびPEG−Met−hGHの血中半減期はそれぞれ3時間と35時間であった。
本明細書に開示されている全ての特徴はいかなる組み合わせで組み合わされてもよい。本明細書に開示されているそれぞれの特徴は同一の、等価の、または同様の目的を与える代替可能な特徴で置き換えられてもよい。このように、明示的に述べられていない限り、開示されているそれぞれの特徴は等価なまたは同様の特徴の包括的なシリーズの単なる例である。
Claims (4)
- 以下の化学式のいずれかで表されるペプチド−ポリマー共役体:
ル部分であり、EPOはエリスロポエチン部分であり、GHは成長ホルモン部分である。 - 前記共役体が
ル部分である、
である、請求項1の共役体。 - 前記共役体が
ル部分であり、EPOはエリスロポエチン部分である、
である、請求項1の共役体。 - 前記共役体が
ル部分であり、GHは成長ホルモン部分である、
である、請求項1の共役体。
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US5919455A (en) | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
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US20040142870A1 (en) * | 2002-11-20 | 2004-07-22 | Finn Rory F. | N-terminally monopegylated human growth hormone conjugates, process for their preparation, and methods of use thereof |
RS20050501A (en) * | 2002-12-26 | 2007-08-03 | Mountain View Pharmaceuticals Inc., | Polymer conjugates of cytokines,chemokines,growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity |
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US20070254834A1 (en) | 2003-11-24 | 2007-11-01 | Defrees Shawn | Glycopegylated Erythropoietin |
US20060024953A1 (en) * | 2004-07-29 | 2006-02-02 | Papa Rao Satyavolu S | Dual damascene diffusion barrier/liner process with selective via-to-trench-bottom recess |
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WO2010014874A3 (en) | 2010-05-06 |
EP2313457A4 (en) | 2014-10-01 |
AR072850A1 (es) | 2010-09-22 |
UA104146C2 (ru) | 2014-01-10 |
TWI421093B (zh) | 2014-01-01 |
EA201170278A1 (ru) | 2011-08-30 |
US20110098451A1 (en) | 2011-04-28 |
AU2009276458B2 (en) | 2014-06-19 |
HK1158236A1 (zh) | 2012-07-13 |
EP2313457A2 (en) | 2011-04-27 |
AU2009276458A1 (en) | 2010-02-04 |
CN102131844B (zh) | 2016-03-02 |
MX2011001167A (es) | 2011-04-12 |
EA020347B1 (ru) | 2014-10-30 |
EP2313457B1 (en) | 2020-01-15 |
WO2010014874A2 (en) | 2010-02-04 |
MY156568A (en) | 2016-03-15 |
KR20110059600A (ko) | 2011-06-02 |
KR101533757B1 (ko) | 2015-07-03 |
JP2011529910A (ja) | 2011-12-15 |
NZ591167A (en) | 2012-06-29 |
US8273343B2 (en) | 2012-09-25 |
BRPI0911722B1 (pt) | 2022-09-13 |
CN102131844A (zh) | 2011-07-20 |
US20100029907A1 (en) | 2010-02-04 |
BRPI0911722A2 (pt) | 2016-09-13 |
TW201008583A (en) | 2010-03-01 |
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