JP4271075B2 - 消化器官吸収性ポリペプチド - Google Patents
消化器官吸収性ポリペプチド Download PDFInfo
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- JP4271075B2 JP4271075B2 JP2004136152A JP2004136152A JP4271075B2 JP 4271075 B2 JP4271075 B2 JP 4271075B2 JP 2004136152 A JP2004136152 A JP 2004136152A JP 2004136152 A JP2004136152 A JP 2004136152A JP 4271075 B2 JP4271075 B2 JP 4271075B2
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- polypeptide
- blood
- fusion
- gastrointestinal
- fusion polypeptide
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Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Enzymes And Modification Thereof (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
納豆菌(Bacillus subtilis natto)からDneasy Tissue Kit(QUIAGEN社)を用いてゲノムDNAを調製し、これを鋳型として全長NK遺伝子cDNAをPCR増幅した。具体的には、公知のNK mRNA配列(GenBank/ AY219901:配列番号1)に基づきPCRプライマーを設計し、ゲノムDNAを鋳型とて、KOD plus(TOYOBO社)によりPCRを行った。PCR産物の分子量を電気泳動により確認後、pPCR-Scriptベクター(INVITROGEN社)にクローニングし、配列を確認した。
〔実施例2〕
インビトロ転写・翻訳系(無細胞)にて融合ポリペプチドを作製した。TOYOBO社製PROTEIOS Wheat germ cell-free protein synthesis core kitに添付されているpEU3-NIIベクターのEcoRV/XhoI部位に、終止コドンを除去してHisタグ配列を付加した3種類のNK cDNAをそれぞれ挿入した。すなわち、全長NK(381アミノ酸)をコードするcDNA、全長NKのC端から19アミノ酸を削除した活性型NK(362アミノ酸)をコードするcDNA、活性型NKのC端からさらに69アミノ酸を削除した不活性型NK(293アミノ酸)をコードするcDNAをそれぞれインサートとする発現ベクターを構築した。
(1) マウス顆粒球コロニー刺激因子(G-CSF)の一部(N端30アミノ酸を除去)をコードするcDNA(配列番号3)。
(2) マウス全長インスリンII(Ins2)をコードするcDNA(配列番号4)。
(3) マウス全長エリスロポエチン(EPO)をコードするcDNA(配列番号5)。
・活性型NK+G-CSF
・不活性型NK+G-CSF
・全長NK+Ins2
・活性型NK+Ins2
・不活性型NK+Ins2
・全長NK+EPOF
・活性型NK+EPO
・不活性型NK+EPO
NK+G-CSF融合ポリペプチドを経口投与し、G-CSFの生理活性のインビボ変化を調べた。なお、内因性G-CSFは骨髄細胞で産生されるが、10週零以下の健常幼弱マウスでは骨髄細胞の活動が活発であり、内因性G-CSFと経口投与G-CSFとの差異を明確に区別するため、事前のX-線照射によって骨髄細胞の活動を抑制した。具体的な実験手続きは以下のとおりである。
実施例3と同様に、X-線照射によって骨髄細胞の活動を抑制した状態で、NK+EPO融合ポリペプチドの経口投与によるインビボ活性を検討した。
5週齢のC57BL/5雄性マウスにSTZ(streptozodocin)2mgを腹腔投与し、1型糖尿病(インスリン欠乏型)モデルマウスを作成した。12週齢で3時間の絶食後の血糖値が約400に達したものを用いた。18あるいは24時間絶食させた後、2g/kgの糖負荷(胃ゾンデによる砂糖水の経口投与)の後、30分後に実験に供した。
(1) NK+G-CSF融合ポリペプチドの調製
実施例1クローニングしたNK cDNA(配列番号1)の第58−978番塩基までの配列(NKの第20位Metから第326位Thrまでのポリペプチドをコードするポリヌクレオチド:以下「キャリアNK cDNA」と記載することがある)を調製した。
(2) 実験群
正常BALB/cマウス(25週齢、雄性、SLCより購入)を各群5匹とし、以下のサンプルを投与した。なお、投与サンプルにはBSA(bovine serum albumin)を100mg/mlとなるように加えた。各サンプルのタンパク質量は、BSAを対照として吸光度計で測定した。
第2群:NK+G-CSF(経口) 1.6μg/0.2ml/匹 1/10
第3群:NK+G-CSF(皮下注射) 6μg/0.2ml/匹 1/1
第4群:キャリアNK(経口) 16μg/0.2ml/匹
第5群:PBS(皮下注射) 0.2ml/匹
(3) 実験方法
予備実験により、0.3mlの採血により2日以上に渡って大きな影響が出ることが確認されていた。まず、BALB/cマウスの眼窪から0.3ml採血し、その日のうちに白血球数を計測した。次いで、18時間の絶食後に、それぞれのマウスに胃ゾンデでの経口あるいは皮下注射で、上記のサンプルを投与した。サンプルの投与から24時間後、および48時間後に、マウスの眼窪静脈洞から0.3ml採血し、直ちに白血球数を計測した。なお、白血球数の計測は三菱化学BCL社にて行った。
(4) 結果
結果は図10に示したとおりである。すなわち、NK+G-CSFの経口投与(第1群、第2群)では、投与48時間後に投与量16μg/匹(600μg/kg)では統計学的に有意な白血球数増多作用が確認できたが、1.6μg/匹(60μg/kg)では有意な効果が認められなかった。
(5) 考察
コントロールのPBS投与群(第5群)では、24、48時間後にも白血球増多が認められた。実際に単回のNK+G-CSF経口投与(第1、第2群)では、48時間後にむしろ減少傾向があり、骨髄にG-CSFが強く作用した後、G-CSFの濃度維持が続かなかった場合、白血球がむしろ減少し、連日の全血液量の約30%に相当する採血の影響では、むしろ白血球数は増え続ける可能性が示唆された。
(1) NK+Insulin融合ポリペプチドの調製
実施例6と同様のキャリアNK cDNAを調製した。pQE-TriSystem His・Strep 1 vector(Qiagen社)のSmaI/BamHIサイトにキャリアNK cDNAを組み込み、大腸菌用のキャリアーNK発現ベクターを構築した。またキャリアNK cDNAの下流(pQEベクターのBamHI/EcoRIサイト)にマウスInsulin2 cDNAを組み込み、大腸菌用のNK+Insulin発現ベクターを作成した。NK+Insulinをコードする融合ポリヌクレオチドの配列は配列番号8のとおりである。なお、配列番号8において、5'端のSer-Arg-Gluをコードする塩基配列はpQEベクターのSmaIサイトの配列であり、3'端のPro-Asn-Serをコードする配列はpQEベクターのEcoRIサイトの配列である。さらに、第311〜313位のVal-Asp-Proをコードする配列はpQEベクター由来の配列である。
(2) 実験群
正常C57BL/6マウス(6-7週齢、雄性、SLCより購入)を各群6-9匹とし、10日間の予備飼育後、180mg/kgのSTZを腹腔内注射した。約3週間後(11週齢時)に血糖値および血中インスリン値を検討した後、以下のサンプルを投与した。なお、投与サンプルにはBSA(bovine serum albumin)を100mg/mlとなるように加えた。各サンプルのタンパク質量は、BSAを対照として吸光度計で測定した。
第2群:NK+Insulin(経口) 4.0μg/0.2ml/匹 1/10
第3群:NK+Insulin(皮下注射) 40μg/0.2ml/匹 1/1
第4群:キャリアNK(経口) 40μg/0.2ml/匹
第5群:PBS(皮下注射) 0.2ml/匹
第6群:NK+Insulin(経口) 160μg/0.2ml/匹 1/1
第7群:NK+Insulin(経口) 16μg/0.2ml/匹 1/1
第8群:キャリアNK(経口) 160μg/0.2ml/匹
(3) 実験方法
3時間絶食時の血糖値が400mg/dl前後のSTZ投与C57BL/6マウスを18時間絶食し、空腹時血糖を測定した後に、グルコース(2g/kg BW)の経口投与を胃ゾンデで行った。各サンプルの投与は、18時間の絶食後に、それぞれのマウスに経口あるいは皮下で行った。
(4) 結果
結果は図11、12に示したとおりである。すなわち、図11に示したように、NK+Insulinの経口投与(第1群、第2群)では、投与量40μg/匹(2.4mg/kg)で統計学的に有意な血糖降下作用が確認できたが、4.0μg/匹(240μg/kg)では有意な効果が認められなかった。キャリアNK単独(第4群)でも、40μg/匹(2.4mg/kg)では、採血の影響およびBSAによる作用か、若干の血糖降下傾向が認められた。なお、コントロール(第5群)でも、投与後に若干の血糖降下傾向があった。
(5) 考察
10、2.4、1.0mg/kgのNK+Insulin融合ポリペプチドの1回の経口投与では統計学的に有意な血糖降下活性が確認できたが、0.24mg/kgの経口投与では統計学的に有意な生理活性が確認できなかった。しかしキャリアーNK単独10、2.4および0.24mg/kgの1回の経口投与では、若干の傾向は認めたものの、有意の血糖降下作用を観察できなかった。使用した融合ポリペプチドとしてのInsulinの内、Insulin分は約1/4であり、それぞれ2.5、0.6、0.25mg/kgに相当する。これは十分臨床応用可能な投与量であり、かつ投与4時間後にも有意な血糖降下作用が持続した。この作用の持続時間は、Insulinの静脈注射の血糖降下作用よりも優れている。
(1) NK+Insulin融合ポリペプチドの調製
実施例6と同様のキャリアNK cDNAを調製した。pGEX-5X-3 vector (Amersham Biosciences)のBamHI/EcoRIサイトにキャリアNK cDNAを組み込み、大腸菌発現用Carrier発現ベクターを作成した。またキャリアNK cDNAの下流(pGEXベクターのEcoRI/SmaIサイト)にマウスInsulin2 cDNAを組み込み、大腸菌用のNK+Insulin発現ベクターを作成した。NK+Insulin融合ポリペプチドをコードする融合ポリヌクレオチドの配列は配列番号7のとおりである。なお、配列番号7において、5'端のGly-Ile-Proをコードする塩基配列はpGEXベクターのBamHIサイトの配列であり、3'端のSer-Arg-Valをコードする配列はpQEベクターのSmaIサイトの配列である。さらに、第311〜313位のArg-Asn-Serをコードする配列はpGEXベクター由来の配列である。
(2) 実験群
正常C57BL/6マウス(6-7週齢、雄性、SLCより購入)を各群5-8匹とし、10日間の予備飼育後、180mg/kgのSTZを腹腔内注射した。約3週間後(11週齢時)に血糖値および血中インスリン値を検討した後、以下のサンプルを投与した。なお、NK+Insulinサンプル中には、タンパク質生成キット培地からの精製成分を含んでいる。
第2群:NK+Insulin(皮下注射) 20μg/0.1ml/匹 1/1
第3群:PBS(皮下注射) 0.1ml/匹、0.5ml/匹
(3) 実験方法
3時間絶食時の血糖値が400mg/dl前後のSTZ投与C57BL/6マウスを18時間絶食し、空腹時血糖を測定した後に、グルコース(2g/kg BW)の経口投与を胃ゾンデで行った。各サンプルの投与は、18時間の絶食後に、それぞれのマウスに経口あるいは皮下で行った。
(4) 結果
結果は図13に示したとおりである。すなわち、NK +Insulinの経口投与(第1群)では、投与量20μg/匹(1.2mg/kg)で、コントロールとなるPBS単独(第3群)に比較して統計学的に有意なインスリン誘導が投与後に観察された。同じく皮下投与(第2群)でも、NK+Insulinの投与量20μg/匹(1.2mg/kg)で統計学的に有意なインスリン誘導が投与後に観察された。なお、図13に示していないPBS皮下注射(第3群)の血中インスリン量はいずれの個体も24pg/ml以下であった。
(5) 考察
1.2mg/kgのNK+Insulin融合ポリペプチドの1回の経口あるいは皮下注射投与で統計学的に有意なインスリンの血中での濃度維持が確認された。使用した融合ポリペプチドの内、Insulin分は約1/4であり、0.3mg/kgに相当する。これは十分臨床応用可能な投与量であり、かつ投与4時間後にも有意な血中インスリン濃度が持続した。この作用の持続時間は、Insulinの皮下注射の血糖降下作用よりも優れている。また血中濃度の変化も、投与量が経口投与と同じ皮下注射と比較して、決して劣るものではなかった。
(1) 融合ポリペプチドの調製
実施例6と同様のキャリアNK cDNAを調製した。pQE-TriSystem His・Strep 1 vector(Qiagen社)のSmaI/BamHIサイトにキャリアNK cDNAを組み込み、大腸菌用のキャリアーNK発現ベクターを構築した。またキャリアNK cDNAの下流(pQEベクターのBamHI/EcoRIサイト)にマウスAdiponectin cDNAを組み込み、大腸菌用のNK+Adiponectin発現ベクターを作成した。NK+Adiponectinをコードする融合ポリヌクレオチドの配列は配列番号9のとおりである。なお、配列番号9において、5'端のSer-Arg-Gluをコードする塩基配列はpQEベクターのSmaIサイトの配列であり、3'端のAsp-Pro-Asn-Serをコードする配列はpQEベクターのEcoRIサイトの配列である。さらに、第311〜313位のVal-Asp-Proをコードする配列はpQEベクター由来の配列である。
(2) 実験群
C57BL db/dbマウス(6週齢、雄性、クレアより購入)を各群4匹とし、4週間の予備飼育後、10週齢で絶食後血糖値を検討した後、以下の各サンプルを投与した。なお、投与サンプルにはBSA(bovine serum albumin)を100mg/mlとなるように加えた。各サンプルのタンパク質量は、BSAを対照として吸光度計で測定した。
第2群:NK+Adiponectin(経口) 2.5μg/0.2ml/匹 1/10
第3群:Adiponectin(経口) 25μg/0.2ml/匹 1/1
第4群:キャリアNK(経口) 25μg/0.2ml/匹、1/1
(3) 実験方法
(3-1) 予備実験
血糖値400mg/ml前後の8週齢の上記C57BL db/dbマウスに対し、絶食3時間後に血糖測定と採血を行い、そのまま18時間まで絶食を続けた後に1回めのサンプル投与を行った。翌日、翌々日にも同時刻にサンプルの投与を行い、計3回の投与の効果を、再び3時間絶食後の血糖値を測定することによって検討した。
(3-2) 投与後経時変化実験
上記の血糖変化を検討し終ったC57BL db/dbマウスを18時間絶食し、空腹時血糖を測定した後に、グルコース(2g/kg BW)の経口投与を胃ゾンデで行った。各サンプルの投与は、18時間の絶食後に、それぞれのマウスに経口あるいは皮下で行った。
(4) 結果
結果は図14に示したとおりである。経口投与後の時間経過観察実験では、NK+Adiponectinの投与量25μg/匹(625μg/kg)(第1群)では統計学的に有意な血糖降下作用が確認できたが、2.5μg/匹(62.5μg/kg)(第2群)では有意の効果が認められなかった。また、キャリアNK単独(第4群)でも、20μg/匹(500μg/kg)では、採血の影響およびBSAによる作用か、統計学的有意差がなかったが、若干の血糖降下傾向があった。さらに、コントロール(第4群)でも、投与後に若干の血糖降下傾向があった。
(5) 考察
0.625mg/kgのNK+Adiponectin融合ポリペプチドの経口投与では4回目の投与1時間後に統計学的に有意な血糖降下活性が確認できたが、1/10量の62.5μg/kgの経口投与では統計学的に有意な生理活性が確認できなかった。また、キャリアーNK単独500μg/kgの1回の経口投与では、若干の傾向は認めたものの、有意の血糖降下作用を観察できなかった。使用した融合ポリペプチドの内、Adiponectin分は約1/2であり、約300μg/kgに相当する。これは十二分に臨床応用可能な投与量である。食直後の血糖の上昇を抑制する意味は小さくないと考えられる。
Claims (10)
- 枯草菌ナットーキナーゼの部分ペプチドであって、配列番号2のアミノ酸配列における1ないし20番目から293番目ないし326番目までのいずれかのアミノ酸配列からなり、生理活性ポリペプチドと連結して経口摂取された場合に、生理活性ポリペプチドを消化管から吸収させることを特徴とする消化器官吸収性ポリペプチド。
- 請求項1の消化器官吸収性ポリペプチドと、生理活性ポリペプチドとを含む融合ポリペプチド。
- 請求項1の消化器官吸収性ポリペプチドと、薬剤成分候補物質と、標識物質とを含む標識化融合ポリペプチド。
- 請求項1の消化器官吸収性ポリペプチドをコードするポリヌクレオチド。
- 請求項4のポリヌクレオチドを保有し、消化器官吸収性ポリペプチドを発現する発現ベクター。
- 請求項4ポリヌクレオチドと、生理活性ポリペプチドをコードするポリヌクレオチドとを含む融合ポリヌクレオチド。
- 請求項6の融合ポリヌクレオチドを保有する発現ベクター。
- 請求項2の融合ポリペプチドを含有する経口組成物。
- 消化管非吸収性物質の生体内毒性を試験する方法であって、請求項1の消化器官吸収性ポリペプチドと消化管非吸収性物質との結合体を非ヒト動物に経口投与する工程を含むことを特徴とする毒性試験方法。
- 消化管非吸収性物質の生体内毒性を試験するためのキットであって、請求項1の消化器官吸収性ポリペプチドと消化管非吸収性物質との結合体を含むことを特徴とする試験キット。
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