JP2010523487A - 哺乳動物細胞へのinvivo送達のための、プラスミド非含有機能性核酸を含有するインタクトな細菌由来ミニセル - Google Patents
哺乳動物細胞へのinvivo送達のための、プラスミド非含有機能性核酸を含有するインタクトな細菌由来ミニセル Download PDFInfo
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Abstract
【選択図】図1
Description
本出願は、2007年3月30日に出願された米国特許仮出願第60/909,074号の優先権を主張する。尚、上記文献は、参照としてその全体を本明細書に組み込むものとする。
特に明記しない限り、本明細書中で使用する全ての技術用語及び科学用語は、当業者によって一般に理解される意味と同じ意味を持つ。
本発明のミニセルは、DNA分離を伴う細胞***の二***中に、配位障害によって生じる大腸菌又は他の細菌細胞の無核形である。原核生物の染色体の複製は、細胞中央(mid-cell)隔壁形成を含む正常な二***に関連付けられる。大腸菌では、例えば、minCDなどのmin遺伝子が突然変異することによって、細胞***中の細胞極での隔壁形成の阻害が取り除かれ、正常な娘細胞及び無核ミニセルを産生させることができる。de Boerら、1992;Raskin及びde Boer、1999;Hu及びLutkenhaus、1999;Harry、2001を参照のこと。ミニセルは、ある状態で自然に発生し放出され、ミニセルとは対照的に、特定の遺伝的再構成又はエピソーム遺伝子の発現によらない他の小型小胞とは区別される。好ましい実施形態において、ミニセルはインタクトな細胞壁を有する(「インタクトなミニセル」)。
機能性核酸は、インタクトなミニセルに直接封入することができる。この方法は、以前に必要とされていたステップ、例えば、機能性核酸をコードする核酸の発現プラスミドへのクローニングステップ、該プラスミドによるミニセル産生親細菌の形質転換ステップ、及び組換えミニセルの作製ステップ、を回避する。代わりに、プラスミド非含有機能性核酸は、複数のインタクトなミニセルを該機能性核酸と共にバッファー中で共インキュベーションすることにより、インタクトなミニセルに直接封入することができる。いくつかの実施形態において、共インキュベーションは、穏やかな振盪を含んでもよく、別の実施形態では、共インキュベーションは静的である。約1時間の共インキュベーション時間が十分であることが証明されているが、より短い時間、例えば約0.5時間なども有効でありうる。一実施形態では、上記バッファーは、緩衝生理食塩水、例えば、1Xリン酸緩衝溶液を含む。緩衝生理食塩水はゼラチン形態であってもよい。別の実施形態では、共インキュベーションは、約4℃〜約37℃、約20℃〜約30℃、約25℃、又は約37℃の温度で実施する。他の態様において、共インキュベーションには、約107、108、109、1010、1011、1012、又は1013個のミニセルを含有させることができる。温度、時間、バッファー、ミニセル濃度などの具体的なパラメータは、特定の条件の組み合わせについて最適化することができる。
上述したように、機能性核酸は、RNA干渉、遺伝子発現の抑制又は他の作用機構により発現に影響を及ぼす核酸分子の包括的なカテゴリーを意味する。このような分子は、例えば一本鎖、二本鎖又は多重鎖のDNA又はRNAである。機能性核酸の例としては、限定されるものではないが、調節性RNA、例えばshRNA、siRNA、miRNA及びアンチセンスssRNA、そしてまたリボザイム及びデコイRNA、並びにアンチセンス核酸などが挙げられる。
本発明の機能性核酸は、薬物耐性を促進する、アポトーシスを阻害する、新生物の表現型を促進する、病原体の増殖を阻害する、又はウイルスの複製若しくは増殖を阻害するタンパク質の遺伝子又は転写産物を標的とする。こうした状況における機能性核酸戦略の適用の成功は、当技術分野で既になされているが、ミニセルベクターの利点によるものではない。例えば、Sioud(2004)、Caplen(2003)、Wuら(2003)、Yagueら(2004)を参照のこと。
ーシスのP53上方調節メディエーター(PUMA)、PDGFチロシンキナーゼ(TK)シグナル伝達経路、ホスファターゼ及びテンシンホモログ(PTEN)、ホスファチジルイノシトール3キナーゼ(PI3K)、プラスミノーゲン活性化因子、ウロキナーゼ(PLAU)受容体(PLAUr)、ポロ様キナーゼ1(Plk1)、Poly(ADPリボース)、ポリメラーゼ(PARP)、増殖性細胞核抗原(PCNA)、前立腺幹細胞抗原(PSCA)、前立腺特異抗原(PSA)773、タンパク質チロシンホスファターゼ(PTP)、Rad51タンパク質、RAF1、レチノイン酸受容体(RAr)α、レチノイン酸受容体(RAr)γ、レチノイドX受容体(RXr)β、セリン(若しくはシステイン)プロテイナーゼ阻害因子、テロメラーゼ逆転写酵素(TERT、hTERT)、テロメア、トムゼン・フリーデンライヒ(TF)抗原、トロンボスポンジン1(TSP1)、トランスフェリン、腫瘍壊死因子α(TNFa、TNFA)、腫瘍壊死因子受容体(TNFr、TNFr)、腫瘍関連炭酸脱水素酵素(CA)IX(CA9)、I型インターフェロン、ユビキチンリガーゼ、血管細胞接着分子1(VCAM1、CD106)、血管内皮増殖因子(VEGF、VEGFA)、血管内皮増殖因子D(VEGFD)、ビトロネクチン(VTN)、ウィルムス腫瘍1(WT1)などが挙げられる。
第2の態様において、本発明は、機能性核酸の送達方法であって、(a)製薬上許容される担体中の複数のインタクトなミニセルを用意するステップであって、上記複数の各々のミニセルがプラスミド非含有機能性核酸を含有する、上記ステップ、及び(b)上記複数のミニセルを哺乳動物細胞と接触させて、該哺乳動物細胞が該複数のミニセルを取り込み、これにより、該機能性核酸が標的細胞の細胞質に放出されるようにするステップを含む方法を提供する。ミニセルは、PCT出願公開WO 05/056749号に記載のように、二重特異性リガンドを介して標的哺乳動物細胞と接触させる。ミニセルと標的哺乳動物細胞との接触は、in vitro又はin vivoで行うことができる。
別の態様では、本発明は、被験体において、薬物耐性を克服し、癌やAIDSなどの疾患を治療する方法を提供する。本方法は、(a)薬物耐性を促進するタンパク質の遺伝子又は転写産物を標的化する1又はそれ以上の機能性核酸を、精製されたインタクトなミニセルに封入するステップ、(b)上記で引用した’749PCT出願(参照により本明細書に組み入れられる)に記載されているように前記機能性核酸を含有するミニセルを標的哺乳動物細胞と接触させて、該哺乳動物細胞が該ミニセルを取り込むようにするステップと、(c)PCT出願公開WO05/079854号に記載されているように該標的哺乳動物細胞に薬物を送達するステップとを含む。好ましくは、ステップ(a)及び(b)の後にステップ(c)を実施して、薬物を投与する前に機能性核酸が薬物に対する耐性を減少できるようにする。薬物の送達及び機能性核酸の導入は、任意の順序で連続的に、又は同時に行うことができる。
薬物送達は、慣用の手段により行うことができるが、PCT出願公開WO05/079854号(参照により本明細書に組み入れられる)に記載されているように、ミニセルを介した送達が好ましい。この点で、本発明者らは、異なる内容物を封入し、標的化したインタクトなミニセルにより、同一の哺乳動物細胞を首尾よく再トランスフェクトできることを発見した。例えば、機能性核酸が封入されたミニセルを哺乳動物細胞にトランスフェクトし、その後、薬物を封入したミニセルが、薬物をその同じ哺乳動物細胞に送達することができ、補完的又は相乗的な抗腫瘍効果が得られる。
本発明で有用な薬物は、動物、特に哺乳動物及びヒトで所望の局所的又は全身的効果をもたらす、任意の生理学的に又は薬理学的に活性な物質でありうる。薬物は、限定されるものではないが、ペプチド、タンパク質、核酸、及び小分子をはじめとする無機又は有機化合物であってよく、そのいずれも特性決定されていても又は特性決定されていなくてもよい。薬物は、様々な形態、例えば、未変化分子、分子複合体、薬理学的に許容される塩、例えば、塩酸塩、臭化水素酸塩、硫酸塩、ラウリン酸塩、パルミチン酸塩、リン酸塩、亜硝酸塩、硝酸塩、ホウ酸塩、酢酸塩、マレイン酸塩、酒石酸塩、オレイン酸塩、サリチル酸塩などであってよい。酸性薬物には、金属塩、アミン、又は有機カチオン、例えば、四級アンモニウムを使用することができる。塩基、エステル、及びアミドなどの薬物の誘導体を使用することもできる。非水溶性薬物は、その水溶性誘導体の形で、又はその塩基誘導体として使用することができ、その誘導体は、どちらの場合でも、又はその送達により、酵素により転換される、身体のpHにより、又は他の代謝過程により、元の治療活性形態へ加水分解される。
本発明の一態様では、PCT出願公開WO05/056749号及びWO05/079854号に記載されているように、ミニセルは、二重特異性リガンドを介して標的哺乳動物細胞に指向する。ミニセルと哺乳動物細胞成分の両方に対する特異性を有する二重特異性リガンドは、ミニセルが哺乳動物細胞によって取り込まれ、それにより機能性核酸が哺乳動物細胞の細胞質に放出されるように、ミニセルと哺乳動物細胞とを結合させる。この標的化した送達法は、in vivo若しくはin vitroで、又はin vivoとin vitroの両方で実施することができる。
さらに、本発明は、細菌由来ミニセルを貪食能又はエンドサイトーシス能を有する哺乳動物細胞と接触させることによる送達を提供する。細胞内細菌性病原体の方式で、親細菌細胞を取り込むことができる哺乳動物細胞は、同様にミニセルを取り込み、その内容物を哺乳動物細胞の細胞質中に放出する。この送達手法は、標的化リガンドの使用なしに達成することができる。
一態様において、(a)複数の各々のミニセルがプラスミド非含有機能性核酸を含有する、複数のインタクトなミニセルと、(b)その製薬上許容される担体とを含む組成物を提供する。
本明細書に記載の製剤は、様々な経路により、哺乳動物の身体の様々な部位に、所望の治療効果を実現するために局所に又は全身に投与することができる。送達は、例えば、経口投与、体腔への製剤の塗布、吸入又は吹入、あるいは非経口、筋肉内、静脈内、門脈内、肝内、腹膜、皮下、腫瘍内、又は皮内投与により行いうる。投与方法及び投与部位は、標的細胞の位置に依存する。例えば、嚢胞性−線維性細胞は、標的化ミニセルの吸入送達によって有効に標的化しうる。同様に、腫瘍転移は、標的化ミニセルを静脈内送達することにより、より有効に治療しうる。原発性卵巣癌は、標的化ミニセルを腹腔内送達することにより治療しうる。
一態様において、ミニセルは、混入親細菌細胞を実質的に含まない。すなわち、ミニセル含有製剤は、107個ミニセル当たり約1個未満の混入親細菌細胞を含有するのが好ましく、108個ミニセル当たり約1個未満の混入親細菌細胞を含有するのがより好ましく、109個ミニセル当たり約1個未満の混入親細菌細胞を含有するのがさらにいっそう好ましく、1010個ミニセル当たり約1個未満の混入親細菌細胞を含有するのがよりさらに好ましく、1011個ミニセル当たり約1個未満の混入親細菌細胞を含有するのが最も好ましい。
ステップA:ミニセル産生細菌細胞培養物の分画遠心法。2000gで約20分間実施しうるこのステップによって、ほとんどの親細菌細胞は除去されるが、ミニセルは上清中に残存する。
ステップB:等張無毒の密度勾配媒体を使用する密度勾配遠心分離。このステップでは、ミニセルの損失を最小にして、親細菌細胞を含む多くの混入物質からミニセルを分離する。このステップは精製法内で繰り返すのが好ましい。
ステップC:0.45μmフィルターにより、クロスフローろ過を行って親細菌細胞の混入をさらに低減する。
ステップD:ストレス誘発による残存する親細菌細胞の線維化。これは、ミニセル懸濁液を数種のストレスのいずれかを誘発する環境条件に供することによって実現しうる。
ステップE:親細菌細胞を死滅させるための抗生物質による処理。
ステップF:膜ブレブ、膜断片、細菌破片、核酸、媒体成分など、微小な混入物質を除去し、ミニセルを濃縮するためのクロスフローろ過。0.2μmフィルターを使用して微小な混入物質からミニセルを分離し、0.1μmフィルターを使用してミニセルを濃縮しうる。
ステップG:フィラメント化死滅細菌細胞を除去するためのデッドエンドろ過。このステップには0.45μmフィルターを使用しうる。
ステップH:ミニセル調製物からのエンドトキシンの除去。このステップには抗リピドA被覆磁気ビーズを使用しうる。
一般に、本明細書に開示した製剤は、いかなる潜在的毒性も最小限に抑えながら、最適の生理学的効果を得るために、慣用試験により求めた適当な投与量で使用しうる。投与レジメンは、患者の年齢、体重、性別、健康状態、治療しようとする病状の重症度、投与経路、並びに患者の腎機能及び肝機能をはじめとする様々な要因に従って選択しうる。
米国特許公開US 2004/0265994号に記載のように、細菌由来のインタクトなミニセルを調製し、精製した。Cy3標識グリセルアルデヒド-3-リン酸デヒドロゲナーゼ(GAPDH)siRNA(最大励起(λmax)547 nm、最大発光(λmax)563 nm)(Ambion(Austin、米国テキサス)の製品)を取得し、これを終濃度50μMまでヌクレアーゼを含まない水中で再構成した。
調節性RNAを保有するミニセルが、in vitroにおいて血清中で安定であること、並びに、これらが特異的標的化哺乳動物細胞に内在化することができることを実証するために、以下の実験を実施した。
siRNAは、細菌細胞又は細菌由来のミニセルには天然に存在しないため、このような粒子からsiRNAを抽出するための確立された方法が存在しないことは、意外ではない。従って、本発明者らは、本発明に従って、インタクトなミニセルに封入されたsiRNAの定量的抽出方法を開発した。
調節性RNA封入ミニセルが、治療に有効な濃度のインタクトな調節性RNAを腫瘍細胞にin vivoで送達できることを明らかにするために、以下の試験を実施した。
ほとんどの抗癌療法は薬物耐性を伴う。同じことが調節性RNA治療にも言える。というのは、標的遺伝子が、調節性RNAにより標的化された配列内で突然変異を起こすと、腫瘍細胞内の遺伝子突然変異は、調節性RNAを無効にすることができるからである。
本発明の方法が、インタクトなミニセルに治療有効量の調節性RNAを封入することを実証するためには、二重特異性抗体で標的化した調節性RNA封入ミニセルが効率的かつ効果的に腫瘍細胞増殖停止を誘発して、アポトーシス細胞死を誘導することを実証する必要があった。
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Claims (71)
- (a)複数の各々のミニセルがプラスミド非含有機能性核酸を含有する、複数のインタクトなミニセルと、(b)その製薬上許容される担体とを含む組成物。
- 前記複数が、治療上有効な量の機能性核酸を含有する、請求項1に記載の組成物。
- 前記機能性核酸が調節性RNAである、請求項1に記載の組成物。
- 前記調節性RNAが、siRNA、miRNA及びshRNAからなる群より選択される、請求項3に記載の組成物。
- 前記機能性核酸が化学的に修飾されていない、請求項1に記載の組成物。
- 前記機能性核酸がDNAである、請求項1に記載の組成物。
- 前記機能性核酸が、薬物耐性に関与するタンパク質をコードするRNA転写産物を標的とする、請求項1に記載の組成物。
- 前記機能性核酸が、P-糖タンパク質、MDR-2又はMDR-3の転写産物を標的とする、請求項1に記載の組成物。
- 前記機能性核酸が、MRP2、BCR-ABL、STI-571耐性関連タンパク質、肺耐性関連タンパク質、シクロオキシゲナーゼ-2、核内因子κ、XRCC1、ERCC1、GSTP1、変異型β-チューブリン、又は成長因子(増殖因子)の転写産物を標的とする、請求項1に記載の組成物。
- 前記機能性核酸が、アポトーシス耐性に関与するタンパク質をコードするRNA転写産物を標的とする、請求項1に記載の組成物。
- 前記機能性核酸が、Bcl-2、Bcl-XL、A1/Bfl 1、焦点接着キナーゼ、又はp53タンパク質の転写産物を標的とする、請求項10に記載の組成物。
- 前記機能性核酸が、腫瘍性に関与するタンパク質をコードするRNA転写産物を標的とする、請求項1に記載の組成物。
- 前記機能性核酸が、β-カテニン、PKC-α、C-RAF、K-Ras、DP97 DeadボックスRNAヘリカーゼ、cdk1、DNMT1、FLIP、C-Sfc、53BPI、ポリコーム群タンパク質EZH2、ErbB1、HPV-16 E5及びE7、フォルティリン(Fortilin)及びMCI1P、KSP、DIP13α、MBD2、p21、KLF4、tpt/TCTP、SPK1及びSPK2、P300、PLK1、Trp53、Ras、ErbB1、VEGF、又はBAG-1の転写産物を標的とする、請求項12に記載の組成物。
- 薬物をさらに含む、請求項1に記載の組成物。
- 前記機能性核酸が、前記薬物に対する耐性に関与するタンパク質をコードする転写産物を標的とする、請求項14に記載の組成物。
- 前記薬物がインタクトなミニセル中に封入されている、請求項14に記載の組成物。
- 前記機能性核酸及び前記薬物が同一のミニセル中に封入されている、請求項16に記載の組成物。
- 二重特異性リガンドをさらに含む、請求項1に記載の組成物。
- 前記二重特異性リガンドが、ミニセル表面構造に対する特異性を有する第1アームと、非貪食性哺乳動物細胞表面受容体に対する特異性を有する第2アームとを含む、請求項18に記載の組成物。
- 前記ミニセル表面構造が、該ミニセル表面上のリポ多糖のO-多糖成分である、請求項19に記載の組成物。
- 前記哺乳動物細胞表面受容体が、前記ミニセルの受容体介在エンドサイトーシスを活性化することが可能なものである、請求項19に記載の組成物。
- 前記二重特異性リガンドが抗体又は抗体フラグメントを含む、請求項18に記載の組成物。
- 107個ミニセル当たり約1個未満の混入親細菌細胞を含有する、請求項1に記載の組成物。
- 108個ミニセル当たり約1個未満の混入親細菌細胞を含有する、請求項1に記載の組成物。
- 109個ミニセル当たり約1個未満の混入親細菌細胞を含有する、請求項1に記載の組成物。
- 1010個ミニセル当たり約1個未満の混入親細菌細胞を含有する、請求項1に記載の組成物。
- 1011個ミニセル当たり約1個未満の混入親細菌細胞を含有する、請求項1に記載の組成物。
- 機能性核酸の送達方法であって、(a)製薬上許容される担体中の複数のインタクトなミニセルを用意するステップであって、その複数の各々のミニセルがプラスミド非含有機能性核酸を含有する、上記ステップ、及び(b)前記複数のミニセルを哺乳動物細胞と接触させて、該哺乳動物細胞が該複数のミニセルを取り込み、これにより該機能性核酸が標的細胞の細胞質に放出されるようにするステップを含む方法。
- 前記機能性核酸が調節性RNAである、請求項28に記載の方法。
- 前記調節性RNAが、siRNA、miRNA及びshRNAからなる群より選択される、請求項29に記載の方法。
- 前記機能性核酸がDNAである、請求項28に記載の方法。
- 前記ミニセルと前記哺乳動物細胞との接触をin vitroで行う、請求項28に記載の方法。
- 前記ミニセルと前記哺乳動物細胞との接触をin vivoで行う、請求項28に記載の方法。
- 前記複数の少なくとも一部が治療上有効な量の前記機能性核酸を含む、請求項33に記載の方法。
- 前記機能性核酸が、薬物耐性に関与するタンパク質をコードする転写産物を標的とする、請求項28に記載の方法。
- 前記機能性核酸が、P-糖タンパク質、MDR-2又はMDR-3の転写産物を標的とする、請求項28に記載の方法。
- 前記機能性核酸が、MRP2、BCR-ABL、STI-571耐性関連タンパク質、肺耐性関連タンパク質、シクロオキシゲナーゼ-2、核内因子κ、XRCC1、ERCC1、GSTP1、変異型β-チューブリン、又は成長因子(増殖因子)の転写産物を標的とする、請求項28に記載の方法。
- 前記機能性核酸が、アポトーシス耐性に関与するタンパク質の転写産物を標的とする、請求項28に記載の方法。
- 前記機能性核酸が、Bcl-2、Bcl-XL、A1/Bfl 1、焦点接着キナーゼ、又はp53タンパク質の転写産物を標的とする、請求項38に記載の方法。
- 前記機能性核酸が、腫瘍性に関与するタンパク質の転写産物を標的とする、請求項28に記載の方法。
- 前記機能性核酸が、β-カテニン、PKC-α、C-RAF、K-Ras、DP97 DeadボックスRNAヘリカーゼ、cdk1、DNMT1、FLIP、C-Sfc、53BPI、ポリコーム群タンパク質EZH2、ErbB1、HPV-16 E5及びE7、フォルティリン(Fortilin)及びMCI1P、DIP13α、KSP、MBD2、p21、KLF4、tpt/TCTP、SPK1及びSPK2、P300、PLK1、Trp53、Ras、ErbB1、VEGF、又はBAG-1の転写産物を標的とする、請求項40に記載の方法。
- (c)前記標的哺乳動物細胞に薬物を送達するステップ、をさらに含む、請求項28に記載の方法。
- 前記機能性核酸が、前記薬物に対する耐性に関与するタンパク質の転写産物を標的とする、請求項42に記載の方法。
- 前記薬物がインタクトなミニセル中に封入されている、請求項42に記載の方法。
- 前記機能性核酸及び前記薬物が同一のミニセル中に封入されている、請求項44に記載の方法。
- 前記ステップ(c)をステップ(a)及び(b)に続けて行う、請求項42に記載の方法。
- 前記薬物をステップ(b)と同時に送達する、請求項42に記載の方法。
- ステップ(b)の結果として、二重特異性リガンドが前記インタクトなミニセルの少なくとも一部及び前記標的哺乳動物細胞と接触させられ、それにより該二重特異性リガンドが該ミニセルを該哺乳動物細胞に結合させる、請求項28に記載の方法。
- 前記標的哺乳動物細胞が非貪食性細胞である、請求項48に記載の方法。
- 前記二重特異性リガンドが、ミニセル表面構造に対する特異性を有する第1アームと、非貪食性哺乳動物細胞表面受容体に対する特異性を有する第2アームとを含む、請求項48に記載の方法。
- 前記ミニセル表面構造が、該ミニセル表面上のリポ多糖のO-多糖成分である、請求項50に記載の方法。
- 前記哺乳動物細胞表面受容体が、前記ミニセルの受容体介在エンドサイトーシスを活性化することが可能である、請求項50に記載の方法。
- 前記二重特異性リガンドが抗体又は抗体フラグメントを含む、請求項48に記載の方法。
- 前記哺乳動物細胞が、貪食能又はエンドサイトーシス能を有する、請求項28に記載の方法。
- バッファー中で複数のインタクトなミニセルを機能性核酸と共インキュベーションするステップを含む、請求項1に記載のミニセルの組成物を製剤化する方法。
- 前記機能性核酸が調節性RNAである、請求項55に記載の方法。
- 前記調節性RNAが、siRNA、miRNA及びshRNAからなる群より選択される、請求項55に記載の方法。
- 前記機能性核酸がDNAである、請求項55に記載の方法。
- 前記共インキュベーションが穏やかな振盪を含む、請求項55に記載の方法。
- 前記共インキュベーションが約0.5時間持続する、請求項55に記載の方法。
- 前記共インキュベーションが約1時間持続する、請求項55に記載の方法。
- 前記バッファーが緩衝生理食塩水を含む、請求項55に記載の方法。
- 前記緩衝生理食塩水がゼラチン形態である、請求項62に記載の方法。
- 前記バッファーが1Xリン酸緩衝溶液を含む、請求項55に記載の方法。
- 前記共インキュベーションが約4℃〜約37℃の温度で行われる、請求項55に記載の方法。
- 前記共インキュベーションが約20℃〜約30℃の温度で行われる、請求項55に記載の方法。
- 前記共インキュベーションが約25℃の温度で行われる、請求項55に記載の方法。
- 前記共インキュベーションが約37℃の温度で行われる、請求項55に記載の方法。
- 前記共インキュベーションが約1010個のミニセルを含む、請求項68に記載の方法。
- 前記共インキュベーションが約107、108、109、1010、1011、1012又は1013個のミニセルを含む、請求項55に記載の方法。
- 前記共インキュベーションが約1010個のミニセルを含む、請求項55に記載の方法。
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