JP6466971B2 - 臓器、組織又は細胞移植用組成物、キット及び移植方法 - Google Patents
臓器、組織又は細胞移植用組成物、キット及び移植方法 Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N9/1241—Nucleotidyltransferases (2.7.7)
- C12N9/1276—RNA-directed DNA polymerase (2.7.7.49), i.e. reverse transcriptase or telomerase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/07—Nucleotidyltransferases (2.7.7)
- C12Y207/07049—RNA-directed DNA polymerase (2.7.7.49), i.e. telomerase or reverse-transcriptase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Environmental Sciences (AREA)
- Dentistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Enzymes And Modification Thereof (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Materials For Medical Uses (AREA)
Description
(1) 疎水性:ノルロイシン、met、 ala、val、leu、ile、
(2) 中性親水性:cys、ser、thr、
(3) 酸性: asp、glu、
(4) 塩基性:asn、gln、his、lys、arg、
(5) 鎖の配向に影響を及ぼす残基:gly、 pro、及び
(6) 芳香族:trp、tyr、phe。
配列番号1のペプチド(以下、「PEP1」という)を、従来知られている固相ペプチド合成法(solid phase peptide synthesis, SPPS)に従って製造した。具体的に、ペプチドは、ASP48S(Peptron, Inc., 大韓民国・大田)を用いて、Fmoc固相合成法でC−末端からアミノ酸を一つずつカップリングすることにより合成した。以下のように、ペプチドのC−末端の一番目のアミノ酸が、レジンに付着されたものを用いた。例えば、次の通りである。
NH2−Ala−2−クロロ−トリチルレジン
NH2−Arg(Pbf)−2−クロロ−トリチルレジン
1)カップリング
NH2−Lys(Boc)−2−クロロ−トリチルレジンに、保護されたアミノ酸(8当量)と、カップリング試薬HBTU(8当量)/HOBt(8当量)/NMM(16当量)とをDMFに溶解して加えた後、常温で2時間反応させ、DMF、MeOH 、DMFの順に洗浄した。
2)Fmoc脱保護
20%のDMF中のピペリジン(piperidine in DMF)を加えて、常温で5分間2回反応させ、DMF、MeOH 、DMFの順に洗浄した。
3)前記1)と2)の反応を繰り返して行い、ペプチドの基本骨格NH2−E(OtBu)−A−R(Pbf)−P−A−L−L−T(tBu)−S(tBu)−R(Pbf)L−R(Pbf)−F−I−P−K(Boc)−2−クロロ−トリチルレジンを作製した。
4)切断(Cleavage):合成が完了されたペプチドレジンに、切断カクテル(Cleavage Cocktail)を加えて、レジンからペプチドを分離した。
5)得られた混合物に、冷却ジエチルエーテルを加えた後、遠心分離して得られたペプチドを沈殿した。
6)Prep−HPLCで精製した後、LC/MSで分子量を確認し、凍結してパウダーとして製造した。
腎臓移植で起こりうる腎臓虚血再灌流の誘導を、以下のように進行した後、PEP1の効果を観察した。
虚血再灌流の24時間後に、血液を採取し、腎臓毒性指標である血中尿素窒素(BUN:blood urea nitrogen)、クレアチン(creatine)を測定し、腎臓組織は、摘出し、パラフィンブロック(paraffin block)を作製し、免疫組織化学検査及び組織学的検査(immunohistochemical and histological study)を進め、タンパク質を抽出してサイトカイン(cytokine)レベルを測定した。クレアチン濃度とBUNは、自動分析機(Technicon RA−1000;Bayer,Tarrytown,NY)を用いて測定した。
虚血再灌流の24時間後、腎臓組織をPAS(peridodic acid-Schiff)染色(製造社:Polysciences株式会社(ウォリントン、PA、米国)のプロトコルに従って、PASキットでPAS染色)を行った。染色を行った後、腎臓組織損傷スコアリング(renal tissue injury scoring)で腎蔵組織の損傷を評価した。PEP1の投与群は、PBS対照群に比べ、腎臓組織の損傷が著しく緩和された様相を示した(図2及び図3を参照)。
虚血再灌流の24時間後、腎臓組織に対して、TUNEL染色で腎臓組織細胞の死滅(apoptosis)を評価した。ロシュ応用科学(インディアナポリス、IN、米国)で作ったTUNEL染色キットを介して、パラフィン腎臓セクションにTUNEL染色を行った。
虚血再灌流の24時間後、腎臓組織に対して、F4/80(macrophage marker)、Gr−1(neutrophil marker)の免疫組織染色で、先天性免疫細胞の浸潤を評価した。具体的には、大食細胞に特異的な抗体(F4/80、abcam.、Cambridge、MA)を用いて、パラフィン含有セクション上の免疫化学的な方法で、大食細胞及び好中球細胞の浸透染色を行った。
虚血再灌流の24時間後、腎臓組織からタンパク質を抽出し、サイトメトリックビードアレイ(cytometric bead array)方法で、IL−6、MCP−1、TNF−αのレベルを測定した。マウスIL6、MCP−1、TNF−αELISAキットは、R&D Systemsから購入し、製造社のプロトコルに従って実験を行った。
測定の結果、PEP1投与群は、PBS対照群に比べ、IL−6、MCP−1レベルを有意的に低下したが、TNF−αでは、有意な変化が観察されなかった(図8〜図10を参照)。
腹直筋皮膚弁の移植を、以下のように行った。
白ラット(Sprague-Dawley Rat、180gから230g)の腹の皮膚から、5cmx5cmサイズで皮弁を採取した後、PEP1又は食塩水(saline)を投与し、クランプ(clamping)を行い、局所貧血(ischemia)を起こさせ、7時間後にクランプを除去し、血流を復元する方法で虚血再灌流損傷を誘導して得た(図11を参照)。
PEP1の虚血再灌流損傷の予防効果を測定するための肺移植モデルは、以下のようにセットした。
(1)供与体である白いラットに、Rompun:Zoletil(1:2、1ml/kg)を腹腔内に注入(i. p injection)して麻酔する。
(2)器官切開術の後に、16ゲージ静脈内カテーテル(16-gauge intravenous catheter)を用いたチューブを挿管し、人工呼吸器(Harvard Rodent Ventilator Model; Harvard Apparatus CO, Holliston, MA)に連結する(Vt=10ml/kg、PEEP=2cmH2O、respiratory rate=80/min)。100%酸素で機械換気を行う。
(3)開腹及び正中胸骨切開を施行し、下大静脈を通してへパリン(Heparin)300IUを注入する。
右心室の流出路を通して、主肺動脈に18ゲージ血管カテーテル(18-gauge angio-catheter)を挿入した後、腹腔内で下大静脈を切断し、左心房を切断しながら、主肺動脈カテーテルを通して20cmH2O圧力で、10℃の50mLの生理食塩水を注入する。灌流中、機械呼吸を持続して、肺灌流が均一に行われるようにする。
(4)灌流が終わると、器官挿管下部で、肺が膨張した状態で器官を結紮し、心肺ブロックを摘出した後、冷ペトリディッシュ(petri-dish)で食道などの周辺構造物を除去する。心肺ブロックの重さを量った後、肺灌流液と同一の灌流液中に心肺ブロックを浸して、冷蔵保存する。虚血時間(ischemic time)は、3時間と決めた。
(1)摘出した肺を、冷フラッシュ(cold flush)溶液が入っているペトリディッシュに置いた後、ウェットスポンジ(wet sponge)で覆い、カフス(cuff)を設ける間は、低体温(hypothermia)を保持する。
(2)カフスを連結するほど十分な距離を確保し、肺動脈は18G、肺静脈は16G、気管支は16Gのカテーテルでカフスを入れ、4−0絹糸(silk)を用いて固定する。
(1)受容体ラットを、腹腔注射で落ち着かせた後、器官切開術の後に16ゲージ静脈内カテーテル(16-gauge intravenous catheter)を用いたチューブを挿管し、4−0絹糸で固定する。供与体と同様に機械換気を行う。
(2)右側の側臥位の姿勢を取り、大胸筋と広背筋とを切開し、4番目の肋間に左後側方開胸術を実施する。
(3)左肺靭帯を切断し、左側肺を胸郭の外に取り出して固定し、肺門部を剥離して肺動脈、肺静脈、左主気管支を露出する。
(4)上記の3つの構造物を全て微細血管クリップ(microvascular clips)(Micro-Serrefine, Fine Science Tools, Foster city, CA)を用いて鉗子する。
(5)左側肺を摘出し、移植肺の肺動脈、肺静脈、気管支をカフス技法(cuff technique)を利用して連結する。
(1)生理食塩水(Normal Saline)50mL投与群
(2)PerfadexTM50mL投与群
(3)PerfadexTM50mL+PEP1 5mg投与群
(4)PerfadexTM50mL+PEP1 50mg投与群
虚血再灌流損傷による肺損傷が起こると、出血(hemorrhage)が発生し、肺胞壁が厚くなるが、上記の四つの溶液を、肺保存溶液として用いた時に発生する虚血再灌流損傷の程度を、出血の発生と肺胞壁の厚さとを介して測定するために、以下のように、ヘマトキシリン&エオジン染色を行った。
移植した肺の下葉を切除し、直ちに重さを量った後、24時間60℃の乾燥機で乾燥した後に、さらに重さを量った。
5mLの生理食塩水(normal saline)を、気管内に点滴注入(instillation)し、それを取り出し、好中性白血球内容(neutrophil content)を分析した。
Claims (12)
- 臓器、組織又は細胞の移植における使用のための組成物であって、
(1)配列番号1のアミノ酸配列から成るペプチド、又は
(2)前記(1)のペプチドと90%以上の配列相同性を有し、かつ、前記(1)のペプチドと同等の活性を有するペプチド
を含む、臓器、組織又は細胞の移植における使用のための組成物。 - 前記組成物は、虚血再灌流損傷の治療又は予防のために使用される、請求項1に記載の臓器、組織又は細胞の移植における使用のための組成物。
- 前記組成物は、供与者及び/又は受容者に投与されるものである、請求項1に記載の臓器、組織又は細胞の移植における使用のための組成物。
- 前記組成物は、移植前、移植中及び移植後のうちいずれか一つ以上の段階で投与されるものである、請求項3に記載の臓器、組織又は細胞の移植における使用のための組成物。
- 前記組成物は、供与者から分離した臓器、組織又は細胞を保存するために使用される、請求項1に記載の臓器、組織又は細胞の移植における使用のための組成物。
- 前記組成物は、受容者に移植した後の臓器、組織又は細胞の生存力又は機能を強化するために使用される、請求項1に記載の臓器、組織又は細胞の移植における使用のための組成物。
- 投与されるペプチドの一日投与用量は、1μg/kg/日〜10g/kg/日である、請求項3に記載の臓器、組織又は細胞の移植における使用のための組成物。
- リン酸塩緩衝化生理食塩水(PBS)、セルシオ(Celsior)(商標)溶液、パーファデックス(Perfadex)(商標)、コリンズ(Collins)溶液、クエン酸塩溶液、及びユニバーシティ・オブ・ウィスコンシン(UW)溶液から成る群から選択される、臓器、組織又は細胞を保持するのに適合した液体をさらに含む、請求項1に記載の臓器、組織又は細胞の移植における使用のための組成物。
- 請求項1〜請求項8のうちいずれか1項に記載の臓器、組織又は細胞の移植における使用のための組成物、及び
前記組成物の使用方法を含む説明書を含む、臓器、組織又は細胞の移植における使用のためのキット。 - 前記組成物は、
移植前に供与者に投与される組成物、
移植前に受容者に投与される組成物、
移植中に供与者に投与される組成物、
移植中に受容者に投与される組成物、
供与者から分離した臓器、組織又は細胞を保存するための組成物、
移植後に供与者に投与される組成物、及び
移植後に受容者に投与される組成物のうちいずれか一つ以上である、請求項9に記載の臓器、組織又は細胞の移植における使用のためのキット。 - 前記説明書は、前記各組成物の投与量、投与方法及び投与間隔を含む、請求項10に記載の臓器、組織又は細胞の移植における使用のためのキット。
- 前記説明書は、前記組成物を、臓器、組織又は細胞が供与者又は受容者の体内に存在する状態で、体内で臓器、組織又は細胞を灌流させる方式で投与する内容を含む、請求項11に記載の臓器、組織又は細胞の移植における使用のためのキット。
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US20170058001A1 (en) | 2017-03-02 |
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