JP6829077B2 - グルテン不耐症及びそれから生じる障害を治療するための組成物及び方法 - Google Patents
グルテン不耐症及びそれから生じる障害を治療するための組成物及び方法 Download PDFInfo
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- JP6829077B2 JP6829077B2 JP2016573565A JP2016573565A JP6829077B2 JP 6829077 B2 JP6829077 B2 JP 6829077B2 JP 2016573565 A JP2016573565 A JP 2016573565A JP 2016573565 A JP2016573565 A JP 2016573565A JP 6829077 B2 JP6829077 B2 JP 6829077B2
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Description
本出願は、2014年6月16日に出願された米国特許仮出願第62/012865号、及び2015年2月19日に出願された第62/118396号に対して優先権を主張するものである。各先行出願の内容は、参照によりその全体が本明細書に組み込まれる。
別段規定されない限りは、本明細書で使用するすべての技術用語及び科学用語は、本発明が属する分野の当業者が一般に理解するものと同じ意味を有する。本明細書に記載のものと同様または均等ないかなる方法及び材料も本発明の実施または試験において使用することができるが、好ましい方法、装置及び材料を次に記載する。本明細書で引用されるすべての技術刊行物及び特許公報は、参照によりその全体が本明細書に組み込まれる。本明細書のいずれの記述も、先行発明によって、本発明がそのような開示に先行する権利が与えられないことを認めると解釈されるものではない。
・疾患若しくは障害を予防する若しくは疾患若しくは障害から保護すること、すなわち、異常な生物学的反応若しくは症状を発生させないようにすること;
・疾患若しくは障害を阻害すること、すなわち、異常な生物学的反応及び/若しくは臨床症状の発生を抑止または抑制すること;ならびに/または
・疾患または障害を軽減すること、すなわち、異常な生物学的反応及び/若しくは症状を後退させること
を含む。
一態様では、本発明は、患者においてグルテン不耐症によってもたらされる状態を調節する方法であって、有効量のNepenthes酵素含有医薬組成物を患者に投与することを含む方法に関する。好ましい実施形態では、状態はセリアック病またはコムギアレルギーである。
医薬組成物は、様々な組成物で、単独で、または適切な医薬的に許容可能な担体、賦形剤若しくは希釈剤とともに、投与することができる。
ネペンテシン及び/またはネプロシンを、当技術分野で既知の方法、例えば(限定されないが)、濾過または固定化されたペプスタチンに基づく親和性精製によって、Nepenthesなどの植物の嚢状葉分泌物を含めた天然源から、濃縮(若しくは抽出)または精製できることが予期される。伝統的なタンパク質クロマトグラフィー、例えば、サイズ排除クロマトグラフィー(ゲル浸透クロマトグラフィーとしても知られる)及び/またはクロマトフォーカシングクロマトグラフィーを使用して、ネペンテシン及び/またはネプロシンを濃縮(若しくは抽出)または精製することもできる。クロマトフォーカシングは、サイズ排除より前に使用してもよいし、後に使用してもよい。ネペンテシンI、ネペンテシンII及びネプロシンは、天然の植物分泌物中に比較的小量で見出される。ネペンテシンI、ネペンテシンII及び/またはネプロシンの生成は、例えば、増大した量の所望の酵素(複数可)またはその変異体を発現及び/または分泌するトランスジェニック植物を作出するための生物工学技術を使用して、増大させることができる。
g=グラム
kDa=キロダルトン
kg=キログラム
L=リットル
LC=液体クロマトグラフィー
mg=ミリグラム
min=分
mL=ミリリットル
mM=ミリモル
MS=質量分析
nM=ナノモル
pM=ピコモル
s.d.=標準偏差
μCi=マイクロキュリー
μg=マイクログラム
μL=マイクロリットル
μM=マイクロモル
μm=マイクロメートル
℃=セルシウス度
A=アラニン
R=アルギニン
N=アスパラギン
D=アスパラギン酸
C=システイン
E=グルタミン酸
Q=グルタミン
G=グリシン
H=ヒスチジン
I=イソロイシン
L=ロイシン
K=リジン
M=メチオニン
F=フェニルアラニン
P=プロリン
S=セリン
T=トレオニン
W=トリプトファン
Y=チロシン
V=バリン
化学物質
Burdick and JacksonのHPLCグレードの水及びアセトニトリルをVWRから購入した。ギ酸、トリス及びグリシンをSigma Aldrichから購入した。
Nepenthes rafflesiana、Nepenthes ampularia、Nepenthes mirabilis及びNepenthes globosaの移植体をKeehns Carnivores(www.keehnscamivores.ca)から購入した。これらを、木材の樹皮、パーライト、ピートモス及び腐植土(それぞれ、40、35、10、5%)を用いて鉢植した。生育条件は、1日あたり14時間の光、湿度80%及び23℃〜28℃の範囲の温度を要し、週に2〜3回灌水した。嚢状葉が成熟すると、嚢状葉あたり1または2匹のDrosophilaを植物に与え、1週間後に嚢状葉液を採取した。嚢状葉及びその分泌物をそのままにして1週間回復させてから、2回目の給餌及び抽出を行った。
4種の植物すべてから嚢状葉液を収集し、混ぜ合わせた。この粗嚢状葉液を、最初に、0.22μmフィルターを通して清澄化し、次いで、Amicon Ultra遠心10kDa分子量カットオフフィルターを使用して、80〜100倍に濃縮した(両方ともMillipore製)。消化に使用する前に、この濃縮物を、100mMグリシンHCl(pH2.5)で3時間酸活性化し、次いで、洗浄ごとに10倍の流体量を使用して、濾過装置中で、100mMグリシン−HCl(pH2.5)で3回洗浄した。次いで、嚢状葉液の元のサンプリングに基づいて、最終的な単離物を11倍の濃度に再び希釈した。
嚢状葉植物の分泌液を濃縮し、pHを低下(pH2.5)させることにより、消化酵素を活性化した。プロテオミクス法を使用して、流体プロテオームに対する濃縮プロセス及び活性化の影響を決定した。最初に、ネペンテシン酵素の存在を確認するために、SDS−PAGEによって不活性濃縮物を分離した。非常に弱くクーマシー染色された7つの連続的なゲル領域をトリプシンで消化し、標準的な方法を使用して、ナノLC−MS/MSによって分析した。これは、活性化された流体プロテオームの完全なカタログであることは期待されないが、この分析によって、アスパラキン酸プロテアーゼのネペンテシンI/IIの存在、ならびに植物起源のグルカナーゼ、キチナーゼ、カルボキシペプチダーゼ及びペルオキシダーゼ、これらに加えてショウジョウバエ及び細菌の中程度のレベルの混入物が確認された。流体プロテオーム複雑性の低さは、最近の分析、Hatano N,Hamada T(2012)Proteomic analysis of secreted protein induced by a component of prey in pitcher fluid of the carnivorous plant Nepenthes alata.Journal of Proteomics 3;75(15):4844−52(Epub Jun.15,2012)と矛盾がないが、本分析において、ネペンテシン−Iがより広い質量範囲(40〜70kDa)にわたって分布していることが分かった。
抽出物の精製
50×2cmのIDカラム中のセファロース固定化ペプスタチンを、20mMグリシン−HCl、pH2.5〜3中で平衡化した。濾過した嚢状葉液(実施例1に記載されているように調製)を、カラムを通して2回循環させ、このカラムを100mLの平衡化緩衝液(20mMグリシンHCl、pH2.5)で洗浄した。このカラムを100mM炭酸水素アンモニウムpH8.7で溶出し、画分を収集した。最大酵素活性を保つために、画分を収集した直後に、2MグリシンHCl、pH2.5でpHを4に低下させた。消化アッセイを使用して活性を確認し、最も活性な画分を混ぜ合わせ、元の流体量に基づいて、およそ80倍に濃縮した。
ネペンテシンI(配列番号4;植物のシグナル配列を有さない、N.gracilis由来のアミノ酸残基20〜413をコードする))の遺伝子をネペンテシンIのcDNAから調製し、NdeIとHindIIIの制限部位の間に配置した。この配列を、T4DNAリガーゼ(1U)(New England Bio、NEB)、T4DNAリガーゼ緩衝液(NEB)、ATP(0.5mM)(NEB)、0.5μgのpET21aベクター及び2μgのネペンテシンIのcDNAを使用して、pET21aにクローニングした。これを18℃で4時間インキュベートした。このライゲーション混合物(5μL)を200μLのNovaBlueコンピテントセルに加え、氷上で15分間インキュベートした。細胞をヒートショック(42℃で45秒、次いで、1mlのLB培地とともに直ちに氷上)によって形質転換し、37℃で1時間インキュベートし、抗生物質(テトラサイクリン及びアンピシリン)とともにプレーティングした。いくつかの白コロニーにおいて遺伝子の存在を確認した後に、代表的なコロニーを選択して、マキシプレップを行った。得られた組換えプラスミドpET21a/R.NepIを上記のようにヒートショックによってE.coli C41に形質転換し、IPTGによる誘導下で発現させた。ここでは、0.6のOD660まで細胞を増殖させ、0.1mMのIPTGで、37℃で4時間誘導した。発現したタンパク質は封入体となった。
植物のシグナル配列を有さない、N.gracilis由来のネペンテシンIIのcDNA(配列番号14を参照されたい)を使用して、ネペンテシンIIのcDNAを調製した。この配列を、T4DNAリガーゼ(1U)(New England Bio、NEB)、T4DNAリガーゼ緩衝液(NEB)、ATP(0.5mM)(NEB)、0.5μgのpET21aベクター及び2μgのネペンテシンIIのcDNAを使用して、NdeIとHindIIIの制限部位の間でpET21aにクローニングした。これを18℃で4時間インキュベートした。このライゲーション混合物(5μL)を200μLのNovaBlueコンピテントセルに加え、氷上で15分間インキュベートした。細胞をヒートショック(42℃で45秒、次いで、1mlのLB培地とともに直ちに氷上)によって形質転換し、37℃で1時間インキュベートし、抗生物質(テトラサイクリン及びアンピシリン)とともにプレーティングした。いくつかの白コロニーにおいて遺伝子の存在を確認した後に、代表的なコロニーを選択して、マキシプレップを行った。得られた組換えプラスミドpET21a/R.NepIを上記のようにヒートショックによってE.coli C41に形質転換し、IPTGによる誘導下で発現させた。ここでは、0.6のOD660まで細胞を増殖させ、0.1mMのIPTGで、37℃で4時間誘導した。発現したタンパク質は封入体となった。
精製されたE.coli封入体のリフォールディングからのネペンテシンI(A)及びII(C)の組換え体の生成を図2に示す。リフォールディング手順の各ステップをモニターし、精製されたE.coli封入体由来の全可溶化タンパク質(レーン1)、最終的な透析後にリフォールディングされたネペンテシン(レーン2)、リフォールディング生成物の24時間酸活性化(100mMグリシン−HCl、pH2.5)(レーン3)として示す。24時間酸活性化したネペンテシンI(B)及びII(D)酵素に対してMALDI−TOF MS分析を行った。酸活性化したバンド(A及びC、レーン3)のゲル内消化物のLC−MS/MS分析によって、それぞれ、純粋なネペンテシンI及びIIの存在が確認された。
指示された酵素によって消化したグリアジンについてSDS−PAGEを行った。SDS−PAGEは、分子量に従ってタンパク質を大まかにプロファイリングする。ペプシン、精製されたNepenthes抽出物または組換えネペンテシンIIでのグリアジンの消化は、およそ100:1の基質と酵素の比で行った。グリアジン(5mg)を、指示された調製物とともに37℃で2時間インキュベートした。図4は、組換えネペンテシンII、Nepenthes抽出物またはペプシンによるグリアジンの消化のSDS−PAGEゲルを示す。このゲルは、組換えネペンテシンIIによるグリアジンの消化が、ペプシンが行うのと異なる消化パターン及びペプシンが行うより小さなペプチドへの消化をもたらすことを示す。これは、ゲルの囲まれた部分で特に顕著である。Nepenthes抽出物はグリアジンの分解において非常に効率的なので、この領域に残留グリアジンタンパク質は観察されない。
水素/重水素交換(HDX)用途のために設計されたLEAP HTX−PALオートサンプラー及び分注システムを使用して、ネペンテシンによるグリアジンの消化を溶液中で行った。AB SciexのTriple−TOF 5600 QqTOF質量分析計を使用してデータを収集した。Mascot(v2.3)を使用して、MS/MSデータからペプチドを同定した。手短に言えば、12pmolの粗グリアジン(Sigma Aldrichから購入)を、実施例1に記載されているように生成した2μLの100倍濃縮抽出物と混合した。消化後、質量分析計に連結した逆相LCシステムに全量を注入した。ペプチドを7cmの150μm i.d.Magic C18カラムでトラップし、10分または30分内に、10%〜40%のアセトニトリル勾配で溶出した。これらの分析で検出されたペプチドを選択して、MS/MSスペクトルの複数情報依存的獲得におけるCIDフラグメンテーションを行った。スペクトルを、すべての同定されたコムギグリアジン(α、β、γ、ω)タンパク質に加えて低分子量及び高分子量のグルテニンに関する配列を含む小型のデータベースに対して検索した。
ネプロシンをNepenthes sp消化流体から抽出した。凍結したショウジョウバエを与えてから5日後の植物の嚢状葉から流体を収集した。収集した液体を濾過して、死んだ昆虫を除去し、10kDの分子量カットオフ膜を通す複数の濃縮/濾過サイクルによって、20mM酢酸アンモニウムpH5.0で繰り返して洗浄した。
目的;グリアジン感作化NOD−DQ8マウスを使用して、インビボでのグリアジン誘導性損傷の予防における、Nepenthes抽出物または組換えネペンテシンIIを使用するグリアジンのインビトロ消化の有効性を試験すること
陽性対照(n=8):感作及びグリアジン負荷。マウスをコレラ毒素(CT)及びペプシングリアジン(P−G)で感作した(1週間につき1回で3週間)。実験期間中、マウスをP−グリアジンで強制栄養した(1週間につき3回で3週間)。
4群すべてのマウスを、ペプシン−グリアジンの消化物に加えてコレラ毒素で感作した。陰性対照は、感作後にグリアジン負荷がないままにした。陽性対照及び処理群は、感作後にグリアジンで経口的に負荷した。処理群の違いは、グリアジン負荷物がNepenthes抽出物で前もって消化されるか、またはネペンテシンIIで前もって消化されるかである。この方法では、「陰性対照」は、(感作フェーズ間に曝露されたため)全くグリアジンの処理を受けておらず、それにより、グルテンフリーの食事に忠実である間、寛解の状態になるセリアック病患者の臨床状況を模倣した。
マウスにおいて、Nepenthes抽出物またはネペンテシンIIで前もって消化したグリアジンでの3週間の負荷は安全であり、体重の短期低下を、またはいかなる臨床的有害事象も誘導しなかった。
粗ネプロシン抽出物をグリアジンとともにpH2.5でインキュベートし、得られたペプチドフラグメントをMSによって分析した。図15A及び15Bに結果を示す(ドット[.]は切断部位を示す)。抽出物によるタンパク質配列カバー率は61%であった。グリアジンの潜在的なプロリン(P)切断部位(C末端)のおよそ57%は粗ネプロシン抽出物によって処理された。理論に拘束されないが、グルタミン切断部位の少なくとも一部は、ネペンテシンタンパク質を含む抽出物の少量の混入のためであると考えられる。
Claims (15)
- 患者の腸におけるグルテンの存在が原因の腸の炎症を減弱または予防するための、ネプロシンまたはその変異体、若しくは、ネプロシンまたはその変異体とネペンテシンI及び/またはネペンテシンIIとの混合物、を含む医薬組成物の製造における使用であって、
前記ネプロシンまたはその変異体は、
配列番号1のアミノ酸配列に対して90%以上の配列同一性を有するアミノ酸配列、または配列番号1の25番目〜380番目のアミノ酸配列に対して90%以上の配列同一性を有するアミノ酸配列、
を含むタンパク質であって、プロリルエンドプロテアーゼ活性を有するタンパク質である、
医薬組成物の製造における使用。 - 前記患者がグルテン過敏症、セリアック病、注意欠陥多動性障害、自閉症、関節リウマチ、線維筋痛症及びヘルペス状皮膚炎からなる群から選択される疾患を罹患している、請求項1に記載の使用。
- 前記ネプロシンまたはその変異体が組換えタンパク質である、請求項1に記載の使用。
- 前記医薬組成物の単位用量が、約1mg〜約25gのネプロシンまたはその変異体を含む、請求項1〜3のいずれか1項に記載の使用。
- 前記医薬組成物が約pH5〜約pH8の間である、請求項1〜3のいずれか1項に記載の使用。
- 前記ネプロシンが、配列番号1のアミノ酸配列または配列番号1の25番目〜380番目のアミノ酸配列を有するタンパク質である、請求項1〜3のいずれか1項に記載の使用。
- 単離されたネプロシン及び医薬的に許容可能な適切な賦形剤からなる医薬組成物であって、前記ネプロシンが、配列番号1のアミノ酸配列または配列番号1の25番目〜380番目のアミノ酸配列を含むタンパク質である、医薬組成物。
- ネペンテシンI及び/またはネペンテシンIIをさらに含む、請求項7に記載の医薬組成物。
- ネプロシンと、ネペンテシンI及び/またはネペンテシンIIと、医薬的に許容可能な適切な賦形剤と、からなる医薬組成物であって、前記ネプロシンが、配列番号1のアミノ酸配列または配列番号1の25番目〜380番目のアミノ酸配列を含むタンパク質である、医薬組成物。
- 前記ネプロシンの前記アミノ酸配列が、配列番号1のアミノ酸配列を含む、請求項8または9に記載の医薬組成物。
- 前記ネプロシンが組換えネプロシンを含む、請求項7〜10のいずれか1項に記載の医薬組成物。
- 持続性放出製剤である、請求項7〜10のいずれか1項に記載の医薬組成物。
- 前記組成物が投与前に中性pHで維持される、請求項7〜10のいずれか1項に記載の医薬組成物。
- 前記ネプロシンが多層中に存在し、その結果、前記製剤が胃の中に存在する間、前記ネプロシンが継続的に放出される、請求項7〜13のいずれか1項に記載の組成物を含む経口医薬製剤。
- さらに医薬的に許容可能な緩衝液を含み、その結果、製剤のpHが投与前においてpH5〜8である、請求項7〜12のいずれか1項に記載の組成物を含む経口医薬製剤。
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US10857214B2 (en) | 2015-12-16 | 2020-12-08 | Codexis, Inc. | Compositions and methods for treating gluten intolerance and disorders arising therefrom |
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CN106794228B (zh) | 2021-09-03 |
EP3220946A4 (en) | 2018-08-15 |
CN106794228A (zh) | 2017-05-31 |
US11723960B2 (en) | 2023-08-15 |
ES2883347T3 (es) | 2021-12-07 |
DK3220946T3 (da) | 2021-08-02 |
US20210220451A1 (en) | 2021-07-22 |
JP2017519763A (ja) | 2017-07-20 |
EP3220946A1 (en) | 2017-09-27 |
EP3943104A1 (en) | 2022-01-26 |
JP2021073236A (ja) | 2021-05-13 |
EP3220946B1 (en) | 2021-06-09 |
US10960059B2 (en) | 2021-03-30 |
SI3220946T1 (sl) | 2021-11-30 |
CN113827708A (zh) | 2021-12-24 |
US20160022785A1 (en) | 2016-01-28 |
WO2015192211A9 (en) | 2016-02-25 |
US20190022194A1 (en) | 2019-01-24 |
JP7369893B2 (ja) | 2023-10-27 |
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