JP5898071B2 - 腫瘍成長の阻害剤としてのデルマセプチンb2 - Google Patents
腫瘍成長の阻害剤としてのデルマセプチンb2 Download PDFInfo
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- JP5898071B2 JP5898071B2 JP2012518115A JP2012518115A JP5898071B2 JP 5898071 B2 JP5898071 B2 JP 5898071B2 JP 2012518115 A JP2012518115 A JP 2012518115A JP 2012518115 A JP2012518115 A JP 2012518115A JP 5898071 B2 JP5898071 B2 JP 5898071B2
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- dermaseptin
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Description
したがって、本発明は、以下の:
デルマセプチンB2の配列、デルマセプチンB2の前駆体の配列、
デルマセプチンB2の配列又はデルマセプチンB2の前駆体の配列と少なくとも80%の同一性を有するアミノ酸配列、及び
これらの配列の断片、
からなる群から選ばれるアミノ酸配列を含むか又はそれから成り、増殖性疾患、眼病変又は自己免疫疾患の治療又は予防において使用するため、好ましくは細胞成長及び/又は増殖を阻害するための、単離されたペプチドに関し、ただし、上記単離されたペプチドは細胞成長及び/又は増殖を阻害する。
a)増殖性疾患の治療のために有用な治療用化合物、
b)増殖性疾患の治療のために有用な治療用化合物に分子を変換することができる酵素、又は
c)キャリア分子、
と連結されている。
a)化学経路を介する、上で定義されたペプチドの合成、及び
b)以下の:
i)増殖性疾患の治療のために有用な治療用化合物、
ii)増殖性疾患の治療のために有用な治療用化合物に分子を変換することのできる酵素、及び
iii)キャリアタンパク質、
から選ばれる化合物と上記ペプチドのコンジュゲーション、
を含む、上記方法にも関する。
本明細書においては、「デルマセプチンB2」又は「アデノレグリン」は、フタイロネコメガエル(Phyllomedusa bicolor)属の南アメリカのカエルの皮膚分泌物から最初に単離された33アミノ酸のペプチドを意味する(Daly et al. (1992) Proc. Natl. Acad. Sci. USA 89: 10960-10963)。このペプチドのアミノ酸配列は、以下の配列に相当する:
本発明のペプチドは生理活性を有する。本明細書においては、「生理活性」は特に、血管新生及び/又は細胞増殖及び/又は腫瘍成長を阻害する活性を意味する。本発明のペプチドは、上記の活性の少なくとも1つを有し次第、生理活性を有する。好ましくは、該ペプチドは細胞増殖及び/又は細胞成長、特に腫瘍又は血管細胞の増殖及び/又は成長、を阻害する活性を有する。
−インビトロで、(i)上記ペプチドを、成長因子により刺激された(NIH3T3などの)線維芽細胞タイプの細胞と血清の非存在下で接触させ、(ii)放射能標識されたチミジンを添加し、そして(iii)液体シンチレーションなどを用いて、細胞により取り込まれた放射能を測定することにより;
−インビトロで、軟寒天中で上記ペプチドを(PC-3などの)腫瘍細胞と接触させ、そしてその直径の測定による細胞成長の観察により;
−インビボで、PC-3の注射により腫瘍が誘発されたヌードマウスにペプチドを注射し、そして上記腫瘍の体積及び/又は重量の測定による腫瘍成長の観察により;
容易に評価されることができる。
−配列番号1又は配列番号2と、少なくとも80%、85%、90%、95%又は100%の配列同一性を有する配列の断片;及び
−配列番号1又は配列番号2の配列と、少なくとも80%、85%、90%、95%又は100%の配列同一性を有する配列、
から選ばれる配列を含むか又はそれから成ることができる。
−N-末端脱アミノ化又はアシル化(好ましくは、アセチル化)、或いは、C-末端アミド化又はエステル化などの、ペプチドのC-末端又はN-末端の修飾;
−窒素又はα炭素におけるアシル化(好ましくは、アセチル化)又はアルキル化などの、2つのアミノ酸間のアミド結合の修飾;
−天然アミノ酸(L-エナンチオマー)の対応するD-エナンチオマーによる置換などのキラリティーの変化、この修飾は、場合により、側鎖の(C-末端からN-末端への)反転を伴ってよい;
−1つ以上のα炭素が窒素原子で置換される、アザペプチドへの変化;及び/又は
−1つ以上の炭素が主鎖のN-α側又はC-α側へ付加される、ベータペプチドへの変化
が言及されてよいが、これらには限定されない。
−アミド化:この修飾は、(アセチル又はフェニルアセチルなどの)疎水性基により置換されているリジンを陽性荷電するために単純であり;
−アミノ化:例えば、N-メチル、N-アリル又はN-ベンジル基の形成による、一級アミンR=(CH2)4-NH3 +からの二級アミドの形成による;及び
−N-オキシド、N-ニトロソ、N-ジアルキルホスホリル、N-スルフェニル、又はN-グリコシド基の形成、
により、ペプチドの1つ以上のリジンアミノ酸(K)を修飾することが可能である。
−エステル化により、置換された又はされていないメチルエステル、エチルエステル、ベンジルエステル、チオール(活性化エステル)を形成して;及び
−アミド化により、特に、N,Nジメチル基、ニトロアニリド、ピロリジニルを形成して、1つ以上のグルタミン酸(E)及び/又はアスパラギン酸(D)アミノ酸を修飾することが可能である。
本発明は、少なくとも上で定義された本発明のペプチドを含む、キメラ分子にも関し、ここで、該ペプチドは、以下の:
a)増殖性疾患の治療のために有用な治療用化合物;
b)増殖性疾患の治療のために有用な治療用化合物に分子を変換することのできる酵素;又は
c)キャリア分子、
に連結されている。
本発明のペプチドは、細胞増殖及び/又は細胞成長を阻害する性質を有する。これに関して、これらのペプチド及びそれらを含むキメラ分子は、細胞増殖及び成長に関連するさまざまな病状の治療のために特に有用である。
1つの好ましい実施態様においては、本発明は、本発明のペプチド又はキメラ分子の使用又は投与に関する。
本発明において有用なポリペプチドは、当業者に知られた任意の方法を用いて合成されることができる。かかる方法は、特に、(固相又は液体均一相中での)慣用の化学合成、構成的アミノ酸又はその誘導体からの酵素的合成、及び組換え宿主細胞を介する生物学的生産方法を含む。
a)好ましくは化学的経路を介する、本発明のペプチドの合成、
b)増殖性疾患を治療するために有用な治療用化合物、増殖性疾患を治療するために有用な治療用化合物に分子を変換することのできる酵素、又はキャリアタンパク質と、上記ペプチドのコンジュゲーション、
を含む、上記方法にも関する。
本出願はまた、少なくとも本発明のペプチド又はキメラ分子を活性成分として含む、医薬組成物も記載する。一般的に、上記組成物は、1つ以上の医薬として許容可能な賦形剤を含む。
以下の実施例は、細胞増殖を阻害するデルマセプチンB2の能力、そしてしたがって増殖性疾患の治療におけるその使用の利益を示す。
デルマセプチンB2の抗増殖作用を、異なるタイプの細胞:PC-3腺癌細胞及びG1947ヒト前立腺過形成細胞及びマウス胚細胞(CES)においてインビトロで評価した。異なるタイプの細胞を、0.5mlの培地(PC-3及びG1947細胞のための、5%ウシ胎仔血清を補充したRPMI、又はCES細胞のための、10%ウシ胎仔血清を補充したDMEM)中、104細胞/cm2で、24ウエルプレート中に播いた。24時間後、細胞を異なる用量のデルマセプチンB2で処置した。その後、細胞播種の3及び5日後に処置を更新した。6日目にクリスタルバイオレットによる染色により、細胞カウントの推定を行った。細胞をPBSですすぎ、無水エタノールで脱水することによりプラスチック上に固定し、そして、2%エタノール中のクリスタルバイオレットの0.2%溶液で15分間染色した。洗浄後、細胞を1%SDS溶液で可溶化した。分光光度計を用いて595nmにおいてクリスタルバイオレットの光学密度(OD)を測定した。細胞のOD数の変換のために、標準レンジを作成した。
PC-3細胞についてプラスチック上で観察した細胞成長の阻害を確認するために、発明者らは、寒天中でコロニーを形成することによる固着とは無関係に増殖するPC-3細胞の能力に対するデルマセプチンB2の効果を試験した。このアッセイのために、0.35%の寒天及び可変濃度のデルマセプチンB2を含む完全培地(5%ウシ胎仔血清を補充したRPMI)で希釈した細胞を1cm2あたり2.5×103個の密度で、1mlの0.6%固形寒天を含む12ウエルの皿に播種した。同じ可変濃度のデルマセプチンB2を、播種の日及び1週間に2回、培養上に被覆した完全培地にも加えた。水蒸気で飽和し、7%CO2を含むインキュベーター中、37℃での12日間のインキュベーション後、直径が50μmより大きいコロニーを数えた。各測定を三連で行い、各実験は3回繰り返した。
デルマセプチンB2が寒天上のPC-3及びMDA-MB231細胞の成長を阻害する能力を有するということを立証して、発明者らは、PC-3のヌードマウスへの注射により誘導された腫瘍の成長に対するこのペプチドの効果を試験した。1群10匹のヌードマウス(ヌード/ヌード、Laboratoire IFFA CREDO)の群に2×106個のPC-3細胞を注射した。細胞の注射の1週間後に、触知可能な腫瘍を有する動物を無作為にケージに割り当て、1日あたり100μlのPBS溶液(対照群)又はPBSで希釈したデルマセプチンB2溶液を腫瘍中に注射することによって処置した。処置の第1週にはデルマセプチンB2を5mg/kgの濃度で注射し、その後、12日間はこの用量を0.5mg/kgに減少させた。いくつかの処置動物における腫瘍成長の再開に続いて、デルマセプチンB2を再び5mg/kgで1週間注射し、その後、処置終了まで用量を2mg/kgに減少させた。対照として、1群のマウスをタキソール(登録商標)(パクリタキセル、Bristol-Myers Squibb)で1週間に2回、10mg/kgの腹腔内注射により処置した。処置開始から29日後に動物をと殺するまで、腫瘍のサイズを1週間に2回キャリパーを用いて測定した。と殺後、腫瘍を除去して重量測定した。
デルマセプチンB2の血管新生抑制活性を、第一にプラスチック上でのウシ成体動脈内皮細胞(ABAE)の増殖、そして、第二にコラーゲンゲル中でのこれらの同じ細胞による擬似毛細血管の形成、を阻害するその能力に関して評価した。増殖試験のために、ABAE細胞を104細胞/ウエルの密度で、10%ウシ胎仔血清及び5ng/mlのFGF-2を補充したDMEM培地中、24ウエルプレートに播いた。先に記載の増殖試験については、播種の24時間後に細胞を異なる用量のデルマセプチンB2で処置した。その後、細胞播種の3及び5日後に処置を更新した。7日目に細胞カウントを、クリスタルバイオレット染色により推定した。
PC-3又はABAE細胞の増殖アッセイの間、デルマセプチンB2の存在下、急速に観察された阻害剤効果及び処置した細胞の非屈折性は、デルマセプチンB2が、感受性細胞の成長をブロックするよりも、細胞障害性の役割又は細胞死を誘導する役割を有しうるとの推測に導く。デルマセプチンB2が感受性細胞のアポトーシスを誘導しうるか否かを決定するために、発明者らは、プラスチック上の培養中の、デルマセプチンB2で処置されるか又はされないPC-3細胞に対する、アネキシンV及びヨウ化プロピジウムによる二重標識実験を実施した。これらの実験に続いて、標識細胞のフローサイトメトリー分析を行った。
Claims (6)
- 増殖性疾患の治療又は予防において細胞成長及び/又は増殖を阻害するための医薬組成物であって、
上記医薬組成物が以下の:
デルマセプチンB2の配列、デルマセプチンB2の前駆体の配列;及び
前記デルマセプチンB2又はデルマセプチンB2の前駆体の配列と、少なくとも90%の同一性を有するアミノ酸配列、
から成る群から選ばれるアミノ酸配列を含むか又はそれから成る単離されたペプチドを含んで成り、ただし、前記単離されたペプチドが細胞成長及び/又は増殖を阻害し、ここで、投与される該ペプチドの用量は、1日あたり0.5〜5mg/kgである、医薬組成物。 - 請求項1に記載の医薬組成物であって、前記ペプチドが以下の:
配列番号1及び配列番号2の配列;並びに
配列番号1又は配列番号2の配列と、少なくとも90%の同一性を有するアミノ酸配列、
から成る群から選ばれるアミノ酸配列を含むか又はそれから成り、ただし、前記単離されたペプチドが細胞成長及び/又は増殖を阻害する、医薬組成物。 - 増殖性疾患の治療又は予防において細胞成長及び/又は増殖を阻害するための医薬組成物であって、
請求項1又は2に定義されたペプチドを少なくとも1つ含むキメラ分子を含んでなり、ここで、該ペプチドが以下の:
a)増殖性疾患の治療のために有用な治療用化合物;
b)増殖性疾患の治療のために有用な治療用化合物に分子を変換することができる酵素;又は
c)キャリア分子、
に連結され、ここで、投与される該ペプチドの用量は、1日あたり0.5〜5mg/kgである、医薬組成物。 - 増殖性疾患の治療のために有用な第二の治療用化合物をさらに含む、請求項1〜3のいずれか1項に記載の医薬組成物。
- 増殖性疾患の治療又は予防において細胞成長及び/又は増殖を阻害するための医薬の製造のための、
デルマセプチンB2の配列、デルマセプチンB2の前駆体の配列;及び
前記デルマセプチンB2又はデルマセプチンB2の前駆体の配列と、少なくとも90%の同一性を有するアミノ酸配列、
から成る群から選ばれるアミノ酸配列を含むか又はそれから成る単離されたペプチドの使用であって、
ただし、上記単離されたペプチドが細胞成長及び/又は増殖を阻害し、ここで、投与される該ペプチドの用量は、1日あたり0.5〜5mg/kgである、使用。 - 前記ペプチドが、
配列番号1及び配列番号2の配列;並びに
配列番号1又は配列番号2の配列と、少なくとも90%の同一性を有するアミノ酸配列、
から成る群から選ばれるアミノ酸配列を含むか又はそれから成る、
請求項5に記載の、使用。
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FR0954505 | 2009-07-01 | ||
FR0954505A FR2947455B1 (fr) | 2009-07-01 | 2009-07-01 | La dermaseptine b2 comme inhibiteur de la croissance tumorale |
PCT/FR2010/051347 WO2011001097A1 (fr) | 2009-07-01 | 2010-06-29 | La dermaseptine b2 comme inhibiteur de la croissance tumorale |
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US5433955A (en) | 1989-01-23 | 1995-07-18 | Akzo N.V. | Site specific in vivo activation of therapeutic drugs |
DK0465529T3 (da) | 1989-03-21 | 1998-10-05 | Vical Inc | Ekspression af exogene polynukleotidsekvenser i et hvirveldyr |
EP0753069A1 (en) * | 1994-04-15 | 1997-01-15 | Targeted Genetics Corporation | Gene delivery fusion proteins |
FR2735983B1 (fr) * | 1995-06-29 | 1997-12-05 | Centre Nat Rech Scient | Peptide permettant de modifier l'activite du systeme immunitaire humain ou animal |
US20020150964A1 (en) * | 1995-12-19 | 2002-10-17 | Centre National De La Recherche Scientifique | Peptides for the activation of the immune system in humans and animals |
US5760072A (en) | 1995-12-29 | 1998-06-02 | Pharmachemie B.V. | Paclitaxel prodrugs, method for preparation as well as their use in selective chemotherapy |
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JP2012531218A (ja) | 2012-12-10 |
CN102596222A (zh) | 2012-07-18 |
EP2448594A1 (fr) | 2012-05-09 |
CN102596222B (zh) | 2014-11-26 |
US20120184498A1 (en) | 2012-07-19 |
US20140369987A1 (en) | 2014-12-18 |
FR2947455A1 (fr) | 2011-01-07 |
CA2767012A1 (fr) | 2011-01-06 |
FR2947455B1 (fr) | 2014-01-03 |
IL217247A0 (en) | 2012-02-29 |
EP2448594B1 (fr) | 2018-02-28 |
IL217247A (en) | 2016-02-29 |
WO2011001097A1 (fr) | 2011-01-06 |
CA2767012C (fr) | 2018-10-16 |
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