JP2022023041A - クロストリジウム・ヒストリチクム(clostridium histolyticum)酵素およびその使用のための方法 - Google Patents
クロストリジウム・ヒストリチクム(clostridium histolyticum)酵素およびその使用のための方法 Download PDFInfo
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Abstract
Description
本願は、2012年1月12日提出の米国特許仮出願第61/585,909号の優先権を主張する。上記で示される願書の全内容は本明細書中で参照により組み込まれる。
「a」または「an」という語は、別段の断りがない限り、1以上を包含するものとする。例えば「ヘモロイティック毒素(hemoloytic toxin)」は、1以上の溶血性毒素を指す。
コラゲナーゼの主要な供給源は、C.ヒストリチクム(C.histolyticum)の発酵由来である。C.ヒストリチクム(C.histolyticum)コラゲナーゼIおよびコラゲナーゼIIを含む注射用製剤は、商品名XIAFLEX(登録商標)のもと販売されており、デュプイトラン拘縮の処置に対してU.S.Food and Drug Administrationにより承認されている。それぞれcolGおよびcolH遺伝子によりコードされるコラゲナーゼIおよびコラゲナーゼIIに対するアミノ酸配列は、文献に記載されている。例えば、colGは、GenBank受託番号D87215およびMatsushitaら(1999)、Journal of Bacteriology 181(3):923-933に記載されており、colHは、GenBank受託番号D29981およびYoshiharaら(1994)、Journal of Bacteriology 176(21):6489-6496(これらのそれぞれの内容が、本明細書中で参照により明確に組み込まれる。)に記載されている。本発明は、機能性コラゲナーゼIおよびコラゲナーゼIIを産生し、分泌するC.ヒストリチクム(C.histolyticum)株(実施例中、下記のクローン004)においてコラゲナーゼIおよびコラゲナーゼIIをコードする遺伝子の配列決定分析に一部基づく。コラゲナーゼIおよびコラゲナーゼIIをコードする遺伝子のヌクレオチド配列は、C.ヒストリチクム(C.histolyticum)(例えば、GenBank受託番号D87125およびD29981)に対する文献記載配列とは異なることが分かっている(配列番号19および20)(図9および10)。
いくつかの実施形態において、本発明は、コラゲナーゼを産生する細菌発酵において溶血性毒素の存在を検出する方法を包含する。ある一定の態様において、本発明は、医薬品産生株中で溶血性毒素の存在を検出することを含む、患者へのコラゲナーゼ製剤原料の治療投与前に、コラゲナーゼ医薬品に出荷許可を与えるための方法を提供する。「医薬品産生株」、「産生株」、「コラゲナーゼ産生株」および「細菌性産生株」という用語は、交換可能に使用され、コラゲナーゼが得られる細菌株を指す。他の態様において、本発明は、医薬品中で溶血性毒素の存在を検出することを含む、患者へのコラゲナーゼ製剤原料の治療投与前に、コラゲナーゼ医薬品に出荷許可を与えるための方法を提供する。
C.ヒストリチクム(C.histolyticum)クローン004のα、δおよびε毒素のアミノ酸配列は、図面で示され、それぞれ配列番号8、配列番号12および配列番号16である。C.ヒストリチクム(C.histolyticum)クローン004のα、δおよびε毒素のヌクレオチド配列も図面で示され、それぞれ配列番号21、配列番号22および配列番号23である。配列番号8、配列番号12、配列番号16の各アミノ酸の配列は、これらのタンパク質を非機能性にし、および/または分泌されないようにする配列特性を有する。
本明細書中に記載の発明は、タンパク質配列および組み換えタンパク質を含む医薬組成物およびまた、本明細書中に記載の方法に従いアッセイされるコラゲナーゼ医薬品を含む医薬組成物も包含する。本明細書中で使用される場合、「医薬的に許容可能な担体または賦形剤」という用語は、無毒性の、不活性固形物、半固形物または液体充填剤、希釈剤、封入材料または何らかのタイプの製剤補助剤を意味する。「処置する」または「処置」とは、発症、合併症もしくは疾患の生化学的兆候を阻止するかもしくは遅延させ、症状を緩和もしくは改善するかまたは疾患、状態もしくは障害のさらなる発現を停止させるかもしくは抑制するための本発明の態様の、組成物、化合物または物質の投与を含む。「治療的有効量」または「有効量」は、単独で、または1以上の他の活性剤と組み合わせて、処置しようとする疾患または状態の1以上の症状を、調節、軽減、抑制、改善、阻止するかまたはそれに影響を与え得る量である。免疫反応を生成させる内容において、またはワクチンの調製において、「有効量」は、抗原に対する抗体の産生を含め、免疫反応を生成させるために効果的である量を包含する。
実施例1:C.ヒストリチクム(C.histolyticum)ゲノム配列決定および毒素配列分析
C.ヒストリチクム(C.histolyticum)α、δおよびε(α、δおよびε毒素)に関する科学的研究が不足しているため、これらの毒素のタンパク質構造に関する知識は限られたものとなっている。この知識不足に対処するため、推定毒素遺伝子の同定に特に焦点を当てて産生生物をより詳細に理解するために、ゲノム配列決定の取り組みが行われた。この努力の結果として、最近になってようやく、コラゲナーゼクロストリジウム・ヒストリチクム(Clostridium Histolyticum)産生株(クローン004)(Auxilium Product Operation,Malvern,PA)の完全なゲノムが作製されたが、これは明らかに、あらゆるC.ヒストリチクム(C.histolyticum)株の中で初めて報告されたゲノム配列であった。
クローン004由来のC.ヒストリチクム(C.histolyticum)(CLH)WCBの増殖物から単離されるゲノムDNAの試料をゲノム配列決定のためにCreative Genomics(Shirley,NY,USA)に回した。Creative Genomicsは、クライアントにより提出されたゲノムDNA試料の配列決定のために使用された標準的方法を用いた。Illumina/Solexaゲノム分析装置付きのチタン化学(titanium chemistry)(断片配列決定)を用いてRoche/454 GS-FLXシステムから、ゲノム配列を作製した。プライマーウォーキングによってゲノムの仕上げを行うために、ANI 3730xlを使用した。29.44%GC含量である2,842,906塩基対のゲノム配列全体を完遂したが、これらの値は、他のクロストリジウムゲノムに対して得られた典型的なゲノムサイズおよびGC含量であった。同定された2,887個のオープン・リーディング・フレーム(ORF)のそれぞれに固有のCLH番号を割り当てた。GenBankのBLAST分析およびSwissProtデータベースを用いて、推定2,887遺伝子のそれぞれをさらに調べ、その結果、β、γ、αおよびε毒素に対して遺伝子座が仮に割り当てられた。最初の評価の結果を表1で与える。したがって、2つのデータベースの包括的な検索を介した自動分析の結果として、モデルタンパク質の割り当てが完遂された。モデルタンパク質割り当ては、操作者の解釈により影響を受けなかった。
シグナルペプチドを同定するために、候補シグナルペプチド配列を同定するSignalPと呼ばれるプログラムにおいて試料および調節配列を分析した(Nielsen(2004),J.Glasgowら、eds.,Proc.Sixth Int.Conf.on Intelligent Systems for Molecular Biology,122-130.AAAI Press,1998)。シグナルペプチドは通常、タンパク質配列の最初の70アミノ酸(またはN末端領域)内に位置し、分泌されるべき酵素に対するシグナル配列として作用する。シグナルペプチドが切断され、得られたタンパク質配列が成熟タンパク質となる。SignalPを用いて、使用者は、成熟タンパク質のN末端を同定するために、シグナルペプチド切断部位の位置を同定し得る。しかし、一部の試料配列の場合、特にα毒素およびβ毒素(AUX-I)の場合、成熟タンパク質のみが同定され、シグナルペプチド配列を含むタンパク質配列全体は同定されなかった。さらなる試験から、使用した配列断片化手順によって、成熟タンパク質からシグナルペプチド配列が分離されたことが明らかになった。成熟タンパク質およびシグナル配列を再構築し、アラインメントツールを通じてプロセシングした。
Bowen(1952)(Yale J Biol Med 25:124-138)の研究の後、C.ヒストリチクム(C.histolyticum)α毒素に関して文献には僅かな情報しか存在しない。したがって、推定毒素遺伝子に対するゲノム配列の照合は興味深かった。ゲノムの予備分析から、2つのデータベースのBLAST分析により判定されるように、C.ヒストリチクム(C.histolyticum)が、C.セプチクム(C.septicum)α毒素と顕著なアミノ酸相同性を共有する1個のORFを保持したことが示唆された。したがって、C.ヒストリチクム(C.histolyticum)内の推定α毒素遺伝子が、C.セプチクム(C.septicum)α毒素の相同体として割り当てられている。Rodney K.Twetenの研究室により幅広く研究されているように、C.セプチクム(C.septicum)α毒素は、毒素のアエロリジン様ファミリーのメンバーとして分類された。とりわけ、C.セプチクム(C.septicum)α毒素は、溶血性活性を保持せず(Ballardら(1992)、Infect Immun 60:784-790;Melton-Wittら(2006)、Biochem 45:14347-14354)、C.ヒストリチクム(C.histolyticum)ε毒素に対して記載されるように(Hatheway(1990),Clin Microbiol Rev 3:66-98)、酸素不安定性ヘモリジンとは区別される。
Hathewayら(1990)(Clin Microbiol Rev 3:66-98)は、C.ヒストリチクム(C.histolyticum)のδ毒素を、主にTakahashiら(1970)(BBRC 39:1058-1064)による最初の研究コミュニケーションに基づきエラスターゼとして定義している。その後、この毒素におけるさらなる実質的な研究は明確に公表されてない。Takahashiらによって、ディファレンシャル限外ろ過(differential ultrafiltration)を用いて、エラスターゼ活性を示す4つの分画がC.ヒストリチクム(C.histolyticum)から単離された。最初に、名目50kDaカットオフ膜の膜を通過したが、名目10kDaのカットオフの膜により保持された分画に焦点を当てた。
MacLennanら(1962)(Bact Rev 26:176-274)およびHathewayは、酸素不安定性へモリシンとしてのC.ヒストリチクム(C.histolyticum)のε毒素が、クロストリジウム属(Clostridium)の他の株、例えばC.テタニ(C.tetani)、C.ノビー(C.novyi)およびC.セプチクム(C.septicum)などにより産生されるものと血清学的に類似することを記載した。Bowen(1952)(Yale J Biol Med 25:124-138)は、α毒素活性に対して観察されるように、対数期中にε毒素が発現され、定常期中に分解され、同様にインビトロでプロテイナーゼによって分解されたことを明らかにした。
C.ヒストリチクム(C.histolyticum)のγ毒素は、クロストリパイン、システインエンドぺプチダーゼ(EC3.4.22.8)として記載されている。Dargatzら(1993)(Mol Gen Genet 240:140-145)は、クロストリパインに対するC.ヒストリチクム(C.histolyticum)遺伝子をクローニングし、配列決定し、この情報を受託番号X63673下でGenBankに寄託した(http://www.ncbi.nlm.nih.gov/nuccore/X63673.1)。CLH_1861γ毒素の一次構造を理解するために、CLH_1861γ毒素理論的配列とともにモデルタンパク質(C.ヒストリチクム(C.histolyticum)クロストリパイン)のMATLAB(登録商標)からのタンパク質配列アラインメントを作成した。結果を図8で与える。
推定C.ヒストリチクム(C.histolyticum)β毒素遺伝子座の配列分析を図9および10で与える。図9で示されるように、クローン004の成熟コラゲナーゼIのアミノ酸配列(CLH_1768および1769;配列番号3)は、翻訳colG配列(配列番号19)とアミノ酸が3個異なる。図10は、クローン004の成熟コラゲナーゼIIのアミノ酸配列(CLH_2116;配列番号4)が、翻訳colH配列(配列番号20)と8個のアミノ酸で異なることを示す。両コラゲナーゼとも完全に機能性である。
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Claims (17)
- 配列番号2の91~3063位のヌクレオチドまたは配列番号2の91~3063位のヌクレオチドの相補体と、前記配列番号2の91~3063位のヌクレオチドまたはその相補体に操作可能に連結された異種制御配列と、を含む組み換え核酸分子。
- 前記制御配列がプロモーターである、請求項1に記載の組み換え核酸。
- 請求項1または2に記載の核酸によってコードされる、組み換えポリペプチド。
- 請求項1または2に記載の核酸を含む、発現カセット。
- 請求項1または2に記載の核酸または請求項4に記載の発現カセットを含む、ベクター。
- プラスミドである、請求項5に記載のベクター。
- 請求項5または6に記載のベクターを含む、組み換え宿主細胞。
- 前記宿主細胞が、細菌細胞、真菌細胞、昆虫細胞、植物細胞および哺乳動物細胞からなる群から選択される、請求項7に記載の組み換え宿主細胞。
- 前記宿主細胞が、E.コリ(E.coli)、ストレプトミセス属(Streptomyces)、シュードモナス属(Pseudomonas)、セラチア・マルセッセンス(Serratia marcescens)、サルモネラ・チフィムリウム(Salmonella typhimurium)、酵母細胞、植物細胞、胸腺細胞、チャイニーズハムスター卵巣(CHO)細胞、COS細胞、またはラクトコッカス・ラクティス(lactococcus lactis)である、請求項8に記載の組み換え宿主細胞。
- 前記宿主細胞が、ラクトコッカス・ラクティス(lactococcus lactis)細胞である、請求項9に記載の組み換え宿主細胞。
- 前記宿主細胞が、E.コリ(E.coli)である、請求項9に記載の組み換え宿主細胞。
- 成熟コラゲナーゼIIを産生する方法であって、請求項7~11のいずれか1項に記載の組み換え宿主細胞を、前記核酸の発現に適切な条件下で培養することと、前記成熟コラゲナーゼIIを回収することと、を含む、方法。
- 成熟コラゲナーゼIIを産生する方法であって、配列番号2の91~3063位のヌクレオチドを有する核酸を含むベクターまたはプラスミドを含む組み換え宿主細胞を培養することを含む、方法。
- 請求項12または13に記載の方法によって産生される、コラゲナーゼII。
- 医薬的に許容可能な担体と、請求項3に記載の組み換えポリペプチドと、を含む医薬組成物。
- コラーゲン介在状態に罹患している患者を処置する方法であって、請求項15に記載の医薬組成物の有効量を対象に投与することを含む、方法。
- 前記状態が、デュプイトラン拘縮、ペイロニー病、癒着性関節包炎、外側上顆炎、手根管症候群、セルライト、および脂肪腫からなる群から選択される、請求項16に記載の方法。
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