JP7357292B2 - 癌治療用ペプチド - Google Patents
癌治療用ペプチド Download PDFInfo
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- JP7357292B2 JP7357292B2 JP2020508976A JP2020508976A JP7357292B2 JP 7357292 B2 JP7357292 B2 JP 7357292B2 JP 2020508976 A JP2020508976 A JP 2020508976A JP 2020508976 A JP2020508976 A JP 2020508976A JP 7357292 B2 JP7357292 B2 JP 7357292B2
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Description
本発明は、癌の治療または予防に関する。特に、本発明は、SLIT2タンパク質由来のペプチド断片、および癌の増殖、浸潤、および転移の抑制における、それらの用途を提供する。
抗癌ペプチドは近年、注目を集めてきた。しかしながら、ほとんどの従来の抗癌剤は、生物活性が低く、毒性が高い。したがって、高い生物活性と低い毒性を有する抗癌生物活性ペプチドを開発する必要性がある。
本開示は、本明細書に記載のアミノ酸配列を含むペプチドを提供する。特定の実施形態は、FHIVELLAまたはFHAVELLAのアミノ酸配列を含むペプチドを含む。他の特定の実施形態は、本明細書に記載の環状ペプチド、ペグ化ペプチド、およびフルオレニルメチルオキシカルボニルペプチドを含む。
本明細書において説明される様々な態様および実施形態は、単に例示を提供することを意図しており、特許請求の範囲を限定する役割を果たすものではないことが理解されるであろう。
LT-1:ASAIYSVETINDGNFHIVELLA(配列番号2)
LT-2:FHIVELLALDQSLSLSVDGGNPKIIT(配列番号3)
LT-3:KIITNLSKQSTLNFDSPLYVGG(配列番号4)
LT-4:GGMPGKSNVASLRQAPGQNGTSF(配列番号5)
LT-5:LRQAPGQNGTSFHGCIRNLYINSE(配列番号6)
X1-X2-X3-X4-X5-X6-X7-X8(I)
(式中、X1は疎水性側鎖を有するアミノ酸から選択され;X2は塩基性側鎖を有するアミノ酸、酸性側鎖を有するアミノ酸、または疎水性側鎖を有するアミノ酸から選択され;X3は疎水性側鎖を有するアミノ酸から選択され;X4は疎水性側鎖を有するアミノ酸から選択され;X5は塩基性側鎖を有するアミノ酸、酸性側鎖を有するアミノ酸、または疎水性側鎖を有するアミノ酸から選択され;X6は疎水性側鎖を有するアミノ酸から選択され;X7は疎水性側鎖を有するアミノ酸または親水性側鎖を有するアミノ酸から選択され;そして、X8は疎水性側鎖を有するアミノ酸または親水性側鎖を有するアミノ酸から選択される)を含むペプチド、または、その修飾ペプチドまたはその塩を提供する。
Xa1-Xa2-Xa3-X1-X2-X3-X4-X5-X6-X7-X8(II)
(式中、Xa1はヘッドトゥーテールの環化としてX8に結合しており、Xa1はDであり;Xa2はGであり;Xa3はNであり;そしてX1、X2、X3、X4、X5、X6、X7およびX8は、それぞれ本明細書において定義されるアミノ酸である)を提供する。
実施例1 LTペプチドの調製。
LT-ペプチドを溶解するための溶媒として、ジメチルスルホキシド(DMSO;>99.9%)およびγ-シクロデキストリン(γ-CD;RPMI-1640中で2.5mM(無血清))を使用した。LTペプチドをDMSOまたはγ-CDに溶解して最終濃度を2.5mMとし、30分間ボルテックスした。ペプチド溶液をさらに、RPMI培地を使用して1mM、0.5mM、および50μMに希釈した。LT1-3-PEGペプチドはRPMI-1640に直接溶解可能である。ペプチド溶液を顕微鏡下で観察して、溶解性を調べた。
下記のペプチドをFmocで修飾し、DMSOおよびγ-CDに溶解した後、細胞増殖アッセイに使用した。10%FBSを含むRPMI培地中でCL1-5細胞を80%コンフルエンスまで培養した。剥離後、3×104個の細胞を12ウェルプレートに播種した。16時間のインキュベーション後、細胞を処置前に回収するか(0時間と指定)、または24時間LTペプチドで処置し(24時間と指定)、生細胞を計数した。細胞数の相対的な倍率変化または細胞増殖の増加率(%)は、次の式により計算した:(細胞数24時間-細胞数0時間)/(対照の細胞数24時間-対照の細胞数0時間)。
Fmoc-LT1-3ペプチドを細胞浸潤アッセイにおいて使用した。ポリカーボネート膜(8-μm孔径)を備えた24ウェル修飾ボイデンチャンバーをin vitro浸潤アッセイに使用した。膜は18μgのマトリゲル(Becton Dickinson、RPMI-1640で希釈)でコーティングした。様々な濃度のペプチドを含むRPMI培地中のCL1-5細胞(3×104細胞/ウェル)を上部チャンバーに播種した。下部チャンバーでは、RPMI-1640培地のみを使用した。24時間のインキュベーション後、細胞を氷冷した100%メタノールで固定し、10%ギムザで染色した。染色後、膜の上側の細胞を綿棒で取り除いた。ポリカーボネート膜の下面に付着した浸潤細胞の数を光学顕微鏡下で計数した。全ての実験を3回実施した。図5Aおよび5Bに示されるように、Fmoc-LT1-3とFmoc-LT-A3の両方が細胞浸潤を抑制したが、Fmoc-LT1-3はFmoc-LT-A3よりも優れた浸潤抑制能力を有していた。興味深いことに、Fmoc-LT-A3のC末端のペグ化は、浸潤抑制活性を大幅に増加させた(図5C)。
6週齢の免疫不全BALB/CAnN.Cg-Foxn1nu/CrlBltwマウスを個別換気ケージ(IVC)に収容した。100μLのPBS中の合計2×106個のCL1-5肺癌細胞を100μLの10×マトリゲルと混合した。肺癌細胞/マトリゲル混合物をマウスの背中下部に皮下注射した。3日後、マウスに1日あたり0、10、20、または30nmolのFmoc-LT-1-3を皮下投与した。Fmoc-LT-1-3ペプチドを100%DMSOに溶解し、3日目から17日目までPBSで所望の濃度に希釈した。18日目に、我々は、対照群の動物の80%、10nmol群の動物の40%、20nmol群の動物の20%、および30nmol群の動物の40%で腫瘍が生じたことを観察した。腫瘍のない動物の割合は、Fmoc-LT1-3のレベルが10nmolと20nmolの間で増加するにつれて増加した。しかし、30nmol群は、腫瘍のない動物の割合のさらなる増加を示さなかった(図6)。この現象は、高濃度のFmoc-LT1-3の溶解度が低いためである可能性がある。したがって、我々は、溶媒をDMSOからγ-CDに置き換え、18日目以降の注入に望ましい濃度にペプチドを希釈した。腫瘍の体積は定期的に測定した。結果は、20nmolのFomc-LT1-3が腫瘍増殖抑制に最大の効果を有することを示した(図7)。10nmolおよび30nmolのFmoc-LT1-3/DMSOは、図6に示されているように、18日目までに同じ初期腫瘍発生率を示したが、30nmolのFmoc-LT1-3/γ-CD治療群は、溶媒をγ-CDに置き換えた後、腫瘍の増殖を有意に抑制した(図7)。39日目に動物を屠殺した。腫瘍と臓器の重さを計り、固定し、パラフィンに包埋した。組織学的分析のために、包埋組織を切片化し、ヘマトキシリン・エオシンで染色した。図8に示されるように、20nmolおよび30nmolのFmoc-LT-1-3は、ベシクル対照群と比較して、腫瘍重量を有意に抑制した。図9は、治療群と対照群の間で臓器の相対重量に有意差がないことを示している。組織学的分析は、Fmoc-LT1-3で処置した場合、動物における明らかな毒性を示さなかった。
5週齢の免疫不全BALB/CAnN.Cg-Foxn1nu/CrlBltwマウスをIVCに収容した。CL1-5細胞を24時間、200μMのFmoc-LT1-3で前処理した後、細胞を回収する6時間前にFmoc-LT1-3ペプチドを含む新鮮な培地で培養した。CL1-5細胞を剥離し、遠心分離し、注射のために200μMのFmoc-LT1-3ペプチドを含むPBS中に再懸濁した。尾静脈注射の30分前に、マウスを20nmolのFmoc-LT1-3でも皮下的に処置した。合計1×106個のCL1-5細胞をマウスに静脈内注射した。尾静脈注射後2日目、1日あたり20nmolのFmoc-LT1-3/0.5%DMSOまたはFmoc-LT1-3/γ-CDをマウスに皮下注射した。56日目までに、動物を屠殺し、全ての臓器の転移形成を調べた。肺の表面の転移性結節を解剖顕微鏡下で計数した。臓器を固定し、パラフィンに包埋した。組織学的分析のために、包埋組織を切片化し、ヘマトキシリン・エオシンで染色した。図10に示されるように、Fmoc-LT1-3は両溶媒において、尾静脈注射によりCL1-5細胞の転移を有意に抑制した。
CL1-5細胞を洗浄し、剥離し、PBSに再懸濁した。その後、80μLのPBS中に2×106個の細胞を含む単一の細胞懸濁液を20μLの10×マトリゲル(コーニング、5117012)と混合した。細胞懸濁液を免疫不全BALB/CAnN.Cg-Foxn1nu/CrlBltwマウスの背中上部に皮下注射した。腫瘍を10日間増殖させ、その間にマウスの90%が腫瘍を生じた。担癌マウスを5群に分けた(n=8/群)。5つの群:対照、Fmoc-LT1-3、シスプラチン、維持療法、および併用療法における平均腫瘍体積は120~140mm3であった。13日目に、Fmoc-LT1-3群のマウスに1日あたり20nmolのFmoc-LT1-3/γ-CDを背中下部に皮下注射した。シスプラチン群のマウスには、4mg/kgのシスプラチンの腹腔内注射(IP)を毎週、合計4回施した。維持療法群のマウスには、シスプラチンのIPを4回与え、シスプラチンの3回目のIP注射の際に1日あたり20nmolのFmoc-LT1-3/γ-CDを投与した。併用療法群のマウスには、シスプラチンのIPを週に4回、1日あたり20nmolのFmoc-LT1-3/γ-CDを投与した。各治療の過程で、腫瘍体積を3日ごとに測定した。マウスの死亡率を記録したところ、腫瘍体積が1500mm3を超えるマウスが含まれていた。生存率の割合が図11に記録されており、各群の生存期間の中央値が表1において計算されている。結果は、ベシクル対照群の生存期間中央値が27.5日であり、シスプラチンのみとFmoc-LT1-3のみの群は生存期間中央値が37.5日まで延長し、シスプラチンとFmoc-LT1-3の併用療法は生存期間中央値をさらに47.5日まで延長し、そして、維持療法群も生存期間中央値を44日間に延長することを示した。興味深いことに、我々の観察では、シスプラチンのみの群におけるシスプラチン注射後と維持群の最初の2サイクルにおいてマウスが死亡したが、併用療法群では死亡しなかったため、Fmoc-LT1-3は、シスプラチンが誘発する毒性を軽減するように思われた(図11)。さらに、併用療法のマウスは、シスプラチンのみの群よりも活動的で健康的であった。したがって、Fmoc-LT1-3は、腫瘍の増殖と転移を阻害するだけでなく、シスプラチンの毒性も低下させ、シスプラチンとの併用療法における動物の生存率を有意に高める。
0μM、12.5μM、25μMおよび50μMの濃度のペプチド断片LT-1、LT-2、LT-3、LT-4およびLT-5の細胞増殖アッセイおよび浸潤アッセイを、実施例2および3に記載の方法に従ってアッセイした。LT-1は、増殖および浸潤活性に対する抑制効果を有する一方、LT-3、LT-4およびLT-5は細胞浸潤のみに対して抑制効果を有する。ペプチド合成中の環化効果のために、最終分析用の完全長LT-2ペプチドは得られなかった。しかしながら、LT-2のN末端配列はLT1-3の配列を含んでおり、したがって、LT-2は増殖および浸潤活性に対して抑制効果を有する可能性が高い(図12および以下の表を参照)。
LT1-3およびLT-A3は疎水性である。LT-A3はLT1-3よりも増殖抑制活性が優れている一方(図1)、LT1-3はLT-A3よりも細胞浸潤抑制が優れている(図13および図14)。ペプチドの溶解性を高めるために、LT1-3およびLT-A3のNまたはC末端のいずれかにPEG修飾を適用した。結果は、LT-1-3およびLT-A3ペプチドのN末端のPEG3修飾(PEG-1-3およびPEG-A3)が、CL1-5細胞の浸潤抑制活性を無効にするのに対し、LT-A3(A3-PEG)は、良好な浸潤抑制活性を有することを示した(図15)。肺癌細胞の浸潤抑制に対するLT-A3-PEGの用量効果は、LT-A3と比較して(図14)、LT-A3-PEGがペプチドの浸潤抑制活性を大幅に増強することを明らかにした(図16)。C末端PEG3修飾LT-1-3(LT1-3-PEG)は、LT1-3と比較した場合(図13)、浸潤抑制活性も増強した(図17)。
LTペプチドがCL1-5以外の肺癌細胞の発達を抑制するか否かを調べることは重要である。結果は、LT1-3-PEGがA549およびH1299細胞の浸潤も効率的に抑制することを示した(図18および19)。LT1-3-PEGは、H460およびH1355肺癌細胞の浸潤も抑制したが、これら2つの細胞株に対するLT1-3-PEGの用量効果は現在調査中である。
LT-A3は、CL1-5細胞において優れた増殖抑制活性を有するが、LT-A3のN末端またはC末端のPEG3修飾(PEG-A3&A3-PEG)およびLT1-3のN末端PEG3修飾(PEG-1-3)は、増殖抑制活性を無効にした(図20A)。幸いなことに、C末端PEG3修飾LT1-3(LT1-3-PEG)は、増殖抑制活性を保持していた(図20B)。
様々な細胞株の細胞増殖に対するLT1-3-PEGの用量効果を調べた。結果は、LT1-3-PEGがCL1-5、A549、H460およびH1355の増殖を効果的に抑制するが、H1299ではそうでないことを示した(図21)。
LTペプチドが正常な細胞株にどのように影響するかを調査することは重要である。我々は、SV40形質転換ヒト気管支上皮細胞Beas2B、ヒト胚性肺線維芽細胞MRC5、およびHUVECをLTペプチドで処置し、細胞増殖アッセイを実施している。我々の予備的な結果は、LTペプチドがこれらの正常細胞の増殖を抑制しないことを示した(図22)。
LT1-3-PEGは、MCF-7、T-47D、MDA-MB-231およびMDA-MB-453乳癌細胞株の増殖も抑制した(図23)。
PKA阻害剤(H89)およびJNK阻害剤(SP600125)は、CL1-5肺癌細胞におけるLT1-3およびLT1-3-PEGを介した増殖抑制を強化した(図24および25)。これらの観察結果を確認するために、CL1-5細胞においてPKAおよびJNK1の触媒サブユニットをsiRNAによって妨げた後、細胞にLTペプチド処置を行った。結果は、PKAおよびJNKの活性の低下が、LT-1-3-ペプチドが媒介する増殖に対する抑制効果を高めることを証明した(図26および27)。
Claims (13)
- ASAIYSVETINDGNFHIVELLALDQSLSLSVDGGNPKIITNLSKQSTLNFDSPLYVGGMPGKSNVASLRQAPGQNGTSFHGCIRNLYINSE(配列番号1)、ASAIYSVETINDGNFHIVELLA(LT-1)(配列番号2)、KIITNLSKQSTLNFDSPLYVGG(LT-3)(配列番号4)、GGMPGKSNVASLRQAPGQNGTSF(LT-4)(配列番号5)、LRQAPGQNGTSFHGCIRNLYINSE(LT-5)(配列番号6)、FHIVELLA(LT1-3)(配列番号9)、FHAVELLA(LT-A3)(配列番号10)、FKAVELLA(LT-K2)(配列番号11)、FRAVELLA(LT-R2)(配列番号12)、FHAVDLLA(LT-D5)(配列番号13)、FHAVHLLA(LT-H5)(配列番号14)、FHAVOLLA(LT-Orn5)(配列番号15)、AHAVELLA(LT-A13)(配列番号16)、FHAAELLA(LT-A34)(配列番号17)、FHAVEALA(LT-A36)(配列番号18)、FHAAEALA(LT-A346)(配列番号19)、FAIVALLA(LT-A25)(配列番号20)、FEAVHLLA(LT-E2H5)(配列番号21)、YHAVELLA(LT-Y1)(配列番号22)、WHAVELLA(LT-W1)(配列番号23)、FHAVELSA(LT-S7)(配列番号24)、FHAVELLS(LT-S8)(配列番号25)、DGNFHIVELLA(LT-11AA)(配列番号26)、AHIVELLA(LT-A1)(配列番号27)、FAIVELLA(LT-A2)(配列番号28)、FHIAELLA(LT-A4)(配列番号29)、FHIVALLA(LT-A5)(配列番号:30)、FHIVEALA(LT-A6)(配列番号31)、FHIVELAA(LT-A7)(配列番号32)からなる群より選択されるペプチド、または改善された安定性もしくは溶解性を有する修飾を有する環状ペプチド、ペグ化ペプチドまたはフルオレニルメチルオキシカルボニル(Fmoc)ペプチドであるその修飾ペプチド、またはその塩。
- FHIVELLA(配列番号9)またはFHAVELLA(配列番号10)である、請求項1のペプチド;またはその修飾ペプチドまたはその塩。
- 修飾ペプチドがFmocペプチドであり、ここで、Fmocは配列番号9~32からなる群より選択されるペプチドのN末端またはC末端に結合している、請求項1または2のペプチド。
- 修飾ペプチドがPEGペプチドであり、ここで、PEGは配列番号9~32からなる群より選択されるペプチドのN末端またはC末端に結合している、請求項1または2のペプチド。
- 環状ペプチドが、請求項1または2のペプチドのN末端に結合している2つの親水性アミノ酸および1つの疎水性アミノ酸を含む、請求項1または2のペプチド。
- 環状ペプチドがDGNFHIVELLA(配列番号26)であり、Dはヘッドトゥーテールの環化としてAに結合している、請求項5の環状ペプチド。
- 請求項1~6のいずれか一項のペプチドまたはその修飾ペプチドもしくはその塩と、薬学的に許容される担体とを含む、医薬組成物、ナノ粒子またはリポソーム。
- 第2の抗癌剤をさらに含む、請求項7の医薬組成物、ナノ粒子またはリポソーム。
- 第2の抗癌剤が、エルロチニブ、アファチニブ、ゲフィチニブ、ベバシズマブ、ラムシルマブ、ゲフィチニブ、ラパチニブ、エルロチニブ、シスプラチン、パクリタキセル、メトトレキサート、シクロホスファミド、イホスファミド、クロラムブシル、カルムスチン、カルボプラチン、ビンクリスチン、ビンブラスチン、チオテパ、ロムスチン、セムスチン、5-フルオロウラシル、コルチコステロイド、カルシニューリン阻害剤、NSAID、5-リポキシゲナーゼの阻害剤、またはシタラビンである、請求項8の医薬組成物、ナノ粒子またはリポソーム。
- 請求項1~6のいずれか一項のペプチドまたはその修飾ペプチドもしくはその塩の有効量を含む、癌を予防、治療および/または改善するか、癌の増殖、浸潤および/または転移を抑制するために用いるための医薬組成物。
- 第2の抗癌剤をさらに含むか、または第2の抗癌剤と組み合わせて投与される、請求項10の医薬組成物。
- 第2の抗癌剤が、エルロチニブ、アファチニブ、ゲフィチニブ、ベバシズマブ、ラムシルマブ、ゲフィチニブ、ラパチニブ、エルロチニブ、シスプラチン、パクリタキセル、メトトレキサート、シクロホスファミド、イホスファミド、クロラムブシル、カルムスチン、カルボプラチン、ビンクリスチン、ビンブラスチン、チオテパ、ロムスチン、セムスチン、5-フルオロウラシル、コルチコステロイド、カルシニューリン阻害剤、NSAID、5-リポキシゲナーゼの阻害剤、またはシタラビンである、請求項11の医薬組成物。
- 併用療法または維持療法に使用するための、請求項11の医薬組成物。
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