JP5876417B2 - 癌転移の抑制 - Google Patents
癌転移の抑制 Download PDFInfo
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- JP5876417B2 JP5876417B2 JP2012540104A JP2012540104A JP5876417B2 JP 5876417 B2 JP5876417 B2 JP 5876417B2 JP 2012540104 A JP2012540104 A JP 2012540104A JP 2012540104 A JP2012540104 A JP 2012540104A JP 5876417 B2 JP5876417 B2 JP 5876417B2
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Description
癌転移は、逐次段階の系を含み、宿主−腫瘍細胞相互作用のカスケードを必要とする過程である(Steeg PSら(2007) Nature 449:671−3)。これらの段階は、原発腫瘍からの離脱(detachment)、循環系への浸潤および循環系における停止、臓器の実質への溢出;および血管新生に伴う増殖を含む(Sawyer TKら(2004) Expert Opin Investig Drugs 13:1−19)。転移過程の重要な段階であると明らかになった遊走および浸潤の機構を調査することについて、関心が高まっている。転移カスケードを阻止するための、これらの段階のいずれか一つでの干渉は、転移性腫瘍成長の形成を阻害する魅力的なアプローチを提供する。
以下の記載において、細胞培養の分野において通常使用される多数の用語が広く利用される。明細書および請求項、ならびにかかる用語に与えられる範囲の明白で一貫性のある理解を与えるために、以下の定義が提供される。
本開示は、繊維状タンパク質を製造する方法および繊維状タンパク質を使用する治療方法に関する。前記治療方法は癌転移の抑制に関する。
癌転移を阻害するために、ある方法が本明細書において開示される。前記方法は、繊維状構造タンパク質の治療有効量を、必要とされる患者に投与することを含む。前記方法はさらに、タンパク質を供給する段階、および繊維状タンパク質の投与に先立ってタンパク質を繊維状構造へと変化させる段階を含みうる。繊維状タンパク質の投与は、腫瘍細胞の(例えば周囲の組織への)浸潤および/または遊走を阻害する。
本明細書において企図される癌に関する方法は、例えば、抗癌転移治療としての繊維状タンパク質治療の使用を含む。前記方法は、転移することができる癌(例えば上皮性悪性腫瘍(carcinoma)および肉腫(sarcoma))などの、多種多様の癌を治療するまたは予防する局面において有益である。
繊維状タンパク質の治療的投与には、免疫療法、化学療法剤および外科手術(例えばさらに以下に記載されるようなもの)を含むが、これらに限定されるものではない、さらなる標準的な抗癌治療と併用しても併用しなくてもよい、治療計画の一部分としての投与が含まれる。
繊維状タンパク質の投与は、腫瘍内、静脈内、皮内、皮下、経口(例えば吸入)、経皮(例えば局所)、経粘膜、腹腔内、動脈内、および直腸投与を含む、体の異なる部分への様々な方法を介して達成することができる。他の適した経路は、経口的に、口腔に、経鼻的に、鼻咽頭に(nasopharyngeally)、非経口的に、経腸的に、胃に(gastrically)、局所的に、経皮的に、皮下に、筋肉内に、錠剤、固体、粉末状、液体、エアゾールの形状で、腫瘍中への病巣内注射、腫瘍に隣接する病巣内注射、静脈内注入および動脈内注入での、組成物の投与を含む。投与は、局所的または全身的にされてもよく、賦形剤を添加してもしなくてもよい。投与はまた、対象の腫瘍部位で、または腫瘍部位の周りで、徐放性様式(slow release mode)で行うことができる。
本方法において、繊維状タンパク質の有効量が、必要とされる患者に投与される。とりわけ、特に重要な繊維状タンパク質は、繊維状タンパク質が治療有効量で投与される時、宿主において癌の転移を阻害するものである。投与される量は、投与の目標、治療される個体の健康状態および身体状態、年齢、治療される個体の分類群(例えば、ヒト、ヒト以外霊長類、霊長類、等)、所望の解消度(degree of resolution)、繊維状タンパク質組成物の製剤、治療する臨床医の医学的状況の評価、および他の関連する要因に依存して変動する。量は、ルーチンの試験を通して決定することができる比較的広い範囲に収まる(fall)ことが予想される。例えば、癌転移を阻害するために採用される繊維状タンパク質の量は、対象にとって不可逆的に毒性となりかねない量(すなわち、最大耐量)より多くない。他の場合、量は、毒性閾値の近くまたはそれを十分に下回るが、まだ免疫効果的濃度範囲にあるか、または閾値用量程度に低い。
上述の治療方法において採用される繊維状タンパク質を含有する医薬組成物もまた提供される。「繊維状タンパク質組成物」という用語は、便宜上、本開示の繊維状タンパク質を含む組成物、コンジュゲート化繊維状タンパク質を含む組成物、またはその両方を総称的に指すために、本明細書において使用される。癌細胞の成長および/または転移の抑制に有益な組成物は以下に記載される。
本開示によると、繊維状タンパク質を投与することにより癌転移を治療するため、方法が開示される。繊維状タンパク質は自然発生的であり、それ自体、上述の治療方法における使用のため、技術分野において知られた方法を使用して単離されうる。繊維状タンパク質は、技術分野において知られた任意の方法、例えば、球状タンパク質構造を繊維状タンパク質構造へと変化することによって、人工的に作製することもできる。一例を挙げれば、タンパク質の繊維化は、その開示が出典明示により本明細書に組み込まれる、米国特許出願公開第2008/0800186号において開示されるように、フィブリル種(fibrl seed)の補助無しでの工程によって誘導することができる。この工程は、制御の容易性、生産物の均一性、及びスケールアップの実現可能性を含む利点を有する。さらに、タンパク質の繊維化は、フィブリル種で補助することなくこの工程によって誘導することができる。微量のタンパク質でさえ、この工程へ適用できるだろう。本明細書において用いる場合、「タンパク質」は、一以上のタンパク質、タンパク質フラグメント、ポリペプチドまたはペプチドを含む。タンパク質は、合成タンパク質および自然発生的なタンパク質の両方を含む。
細胞株および培養。SK−OV−3細胞(ヒト卵巣癌細胞株;ATCC HTB−77)およびSK−OV−3ip.1細胞、ならびにCaSki細胞(ヒト子宮頸癌細胞株;ATCC CRL−1550)は、それぞれ、McCoy’s 5A培地ならびにRPMI−1640培地において37℃で維持された。MDA−MB−231細胞(ヒト乳腺腺癌細胞株;ATCC HTB−26)およびTS/A細胞(マウス乳腺腺癌細胞株)は、それぞれ、ダルベッコ改変イーグル培地(DMEM)/F12培地およびDMEMにおいて37℃で維持された。PC−3細胞(ヒト前立腺腺癌細胞株;ATCC CRL−1435)および22Rv1細胞(ヒト前立腺癌細胞株;ATCC CRL−2505)は、RPMI−1640培地において37℃で維持された。全ての培地は、10%ウシ胎仔血清(FBS)、2mM L−グルタミン、100ユニット/ml ペニシリン、および100μg/ml ストレプトマイシンが添加された。
rVP1が腫瘍細胞の浸潤および/または遊走を抑制するかどうかを調査するため、ボイデンチャンバーアッセイを使用して細胞の浸潤および/または遊走が測定された。様々な濃度のrVP1処理(ヒト乳腺腺癌細胞株MDA−MB−231細胞、ヒト前立腺腺癌細胞株PC−3細胞、ヒト前立腺癌細胞株22Rv1細胞において0.1μMから0.2μM rVP1;ヒト卵巣癌細胞株SK−OV−3細胞およびSK−OV−3ip.1細胞において0.2μMから0.4μM rVP1;ヒト子宮頸癌細胞株CaSki細胞において0.2μMから0.6μM rVP1)の後、細胞の浸潤および/または遊走は著しく抑制された。注目すべきは、rVP1のこれらの濃度は、MTTアッセイおよびWSTアッセイを使用して決定された細胞生存能力へ影響しなかったことである(図1−3)。それゆえrVP1は、インビトロで、ヒト乳癌、前立腺癌、子宮頸癌、および卵巣癌の細胞株の転移を著しく抑制する。
A. BALB/cマウスへの静脈内注射が後続するインビトロrVP1−処理MDA−MB−231細胞。我々はそれから、インビトロで転移能力を阻害するために、24時間rVP1で前処理され、その後マウスへ静脈内注射された、MDA−MB−231ヒト乳腺腺癌細胞が、マウス肺におけるそれらの転移を、rVP1前処理無しのMDA−MB−231と比較して減少できるかどうかを試験した。データから、0.1および0.2μMのrVP1処理MDA−MB−231細胞が、マウス肺組織における癌細胞転移を著しく減少したことが示された(図4A)。関連する肺重量および肺における腫瘍巣の数もまた、rVP1処理無しの腫瘍群と比較して著しく減少した(図4B−C)。
F−HSAなどの他の繊維状タンパク質もまた腫瘍細胞の浸潤および/または遊走を抑制するのかどうかを試験するため、ボイデンチャンバーアッセイを使用して腫瘍細胞の浸潤および/または遊走におけるF−HSAの効果が測定された。様々な濃度のF−HSA処理(MDA−MB−231細胞において0.1μMから0.2μM F−HSA;PC−3細胞において0.025μMから0.1μM F−HSA;22Rv1細胞において0.025μMから0.05μM F−HSA;CaSki細胞において0.2μMから0.4μM F−HSA)の後、様々な腫瘍細胞の浸潤能および/または遊走能は著しく抑制された。これらの濃度で、F−HSAがMTTアッセイの使用による細胞生存能力へ影響しなかったことは、注目すべきことである(図7)。
F−HSAがインビボで腫瘍細胞の転移を抑制するかどうかをさらに試験するため、それぞれ、マウス乳腺腺癌TS/A細胞がBALB/cマウスの側面尾静脈内へ静脈内注射され、または、ヒト乳腺腺癌MDA−MB−231細胞がヌードマウスへ注射された。次いで翌日、および、2日に一回、10回、F−HSA(1mg/kg)が静脈内注射された。F−HSA処理の終わりに、マウスを犠死させ、肺の転移を検出した。我々のデータから、F−HSAが、対照培地のみで処理されたTS/AまたはMDA−MB−231を有するマウスに比較して、TS/A細胞およびMDA−MB−231細胞の肺への転移を著しく抑制したことが示された(図8Aおよび9A)。F−HSA処理されたTS/AまたはMDA−MB−231を有するマウスの関連する肺重量および肺における腫瘍巣の数は、任意の薬剤処理無しのTS/AまたはMDA−MB−231を有するマウスのものより著しく少なかった(図8B−Cおよび図9B−C)。
我々はまた、F−BSAなどの他の繊維状タンパク質もCaSkiヒト子宮頸癌細胞の浸潤を抑制するのかどうかを試験した。細胞浸潤はボイデンチャンバーアッセイを使用して測定された。我々は、0.1μM−0.2μMで、F−BSAはF−BSAはMTTアッセイにより示されるような細胞生存能力へ影響しなかったが、CaSki細胞の遊走および/または浸潤を著しく抑制することを発見した。
図12は、アミロイド繊維Aβ(1−42)に似た、F−HSAが、スーパーデックス200(Superdex 200)カラムによって処理されなかったBSAと比較して、用量依存的に、アミロイド特異的色素ThTの増大した蛍光レベルを示すことを示す実験データの実施である。この結果は、F−HSAがAβ(1−42)のような繊維状構造を有する一方で、HSAが球状構造を有することを示す。(ThTへの結合は、アミロイド様タンパク質の特徴の一つである。)
図13はTS/A細胞におけるF−HSAの細胞毒性効果を示し、図14はMDA−MB−231細胞におけるF−HSAの細胞毒性効果を示す。各細胞型(type)は様々な濃度のF−HSAで無血清培地において16時間処理された。細胞生存能力をMTTアッセイによって決定した。球状HSAは正常細胞または腫瘍細胞において細胞毒性を有しない。
図15はSKOV−3細胞におけるF−HSAの細胞毒性効果を示し、図16はCaSki細胞におけるF−HSAの細胞毒性効果を示す。各細胞型(type)は様々な濃度のF−HSAで無血清培地において16時間処理された。細胞生存能力をMTTアッセイによって決定した。
図17はPC−3細胞におけるF−HSAの細胞毒性効果を示し、図18は22Rv1細胞におけるF−HSAの細胞毒性効果を示す。各細胞型(type)は様々な濃度のF−HSAで無血清培地において16時間処理された。細胞生存能力をMTTアッセイによって決定した。
図19に示される実施によると、F−HSAは、腺癌細胞株A549、CL1−0、CL1−5、H1299、PC13およびPC14;扁平上皮癌肺癌細胞株H520;および大細胞肺癌細胞株H661において、細胞毒性を誘導した。図19は各細胞株の各々のIC50を示す。
F−HSAはまた、図20における実験データの実施によって示されるように、インビトロでの腫瘍細胞の浸潤および遊走を抑制することにおいて効果的であることが示された。図9A、9C、9E、および9Gにおいて示されるように、F−HSAは、癌細胞もしくは正常細胞のどちらか一方の生存能力に影響を与えない濃度で、腫瘍細胞の浸潤/遊走能を著しく低下させた。
F−HSAはインビボで乳癌細胞株TS/AおよびMDA−MB−231を抑制した。図21Aおよび22Aは、F−HSAが、F−HSA処理無しのTS/AまたはMDA−MB−231を有するマウスと比較して、TS/A細胞およびMDA−MB−231細胞の肺への転移を著しく抑制したことを示す。図21B、21C、22B、および22Cは、体重および肺組織における腫瘍細胞巣の数を測定し、さらにインビボでのF−HSAの有効性を確かめた。
F−HSAの調製。20ミリグラムのHSAを1%(w/v)SDSを含む10mlのPBSへ溶解した。HSA溶液を5分間超音波破砕し、続いて、予め溶出溶液(25mM Tris−HCL(pH8.0)、1mM EDTA、0.1M NaCl、および0.05% SDS)で平衡化したスーパーデックス200(Superdex 200)へ注いだ。カラムは1ml/分の流速で溶出し、HSAを含有するC3からC7画分を貯えた。貯えられた画分は、2〜3mg/mlへ濃縮され、次いでCellu−Sep T4/Nominal(MWCO:12,000−14,000 Da)透析膜で、PBSで透析された。新しいPBSバッファーを2時間毎に室温で3回交換した。HSA−S200の収量は約75%であった。
Claims (4)
- 癌を患っているほ乳類における癌転移を抑制するための、治療有効量の繊維状ヒト血清アルブミンおよび医薬上許容される担体を含む、医薬組成物であって、前記医薬組成物がほ乳類における癌転移を抑制するのに十分な量の前記繊維状ヒト血清アルブミンを含有し、さらに前記癌がα5β1および/またはαvβ3インテグリンの過剰発現によって特徴づけられる、医薬組成物。
- 以下の段階:
繊維状ヒト血清アルブミンを製造すること;および
治療有効量の繊維状ヒト血清アルブミンを医薬上許容される担体と混合すること、
を含む、請求項1に記載の医薬組成物を製造するための方法。 - 繊維状ヒト血清アルブミンを製造する段階が、以下の段階:
界面活性剤溶液へヒト血清アルブミンを溶解すること;
溶解したヒト血清アルブミンを分子量70kDa以上のタンパク質を分離するための細孔径を備えるゲル濾過カラムへ注ぐこと;および
カラムからヒト血清アルブミンを溶出すること、
を含む、請求項2に記載の方法。 - 静脈内注射、皮下注射、腹腔内注射、動脈内注射、筋肉内注射、腫瘍への病巣内注射、腫瘍に隣接する病巣内注射、静脈内注入および動脈内注入からなる群から選択される投与経路によって対象に投与される、請求項1に記載の医薬組成物。
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