JP4685443B2 - 悪性新生物および他の過剰増殖性疾患の治療におけるラクトフェリン - Google Patents
悪性新生物および他の過剰増殖性疾患の治療におけるラクトフェリン Download PDFInfo
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- JP4685443B2 JP4685443B2 JP2004506847A JP2004506847A JP4685443B2 JP 4685443 B2 JP4685443 B2 JP 4685443B2 JP 2004506847 A JP2004506847 A JP 2004506847A JP 2004506847 A JP2004506847 A JP 2004506847A JP 4685443 B2 JP4685443 B2 JP 4685443B2
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Description
本発明は、ラクトフェリンの組成物を単独でまたは標準的な抗癌療法と組合せて投与することにより過剰増殖性疾患を治療する方法に関する。ラクトフェリン組成物は、経口投与、静脈内投与、腫瘍内投与、または局所投与することができる。
っていく。
本発明に従って使用されるラクトフェリンは、天然の供給源、例えば、哺乳動物の乳(これに限定されるものではない)から単離および精製することにより得ることができる。ラクトフェリンは、哺乳動物のラクトフェリン、例えばウシまたはヒトのラクトフェリンが好ましい。好ましい態様において、ラクトフェリンは、当該技術においてよく知られかつ使用される遺伝子工学の手法(例えば、遺伝子改変した動物、植物、または真核生物における組換え発現または直接的生産)を用いて組換えにより生産されるヒトラクトフェリン、あるいは化学合成を用いて製造されるヒトラクトフェリンである(米国特許出願第5,571,896、5,571,697および5,571,691号参照。この引用により、これらの内容は本明細書に記載されたものとする)。
本発明によれば、上述した薬学的担体のいずれかにおいて提供されたラクトフェリン組成物を、過剰増殖性疾患の疑いのあるまたは過剰増殖性疾患を有する対象に投与する。当業者は、いくつかの考慮すべき事柄、例えば吸収、代謝、送達の方法、年齢、体重、疾患の重症度、および治療に対する反応に基づいて、対象に投与すべきヒトラクトフェリンの治療上有効な量を決定することができる。
本発明のヒトラクトフェリン組成物の有効性を高めるため、過剰増殖性疾患の治療に有効な他の薬剤、例えば抗癌剤、または手術を、本発明の組成物と組み合わせることが望ましい場合がある。「抗癌」剤(「抗癌」因子)は、対象において、癌に負に作用することができ、例えば、そのような作用は、癌細胞を殺す、癌細胞においてアポトーシスを誘発する、癌細胞の増殖速度を低下させる、転移の出現率または数を減らす、腫瘍のサイズを小さくする、腫瘍の成長を阻害する、腫瘍または癌細胞への血液の供給を減らす、癌細胞または腫瘍に対する免疫応答を促進する、癌の進行を阻止または阻害する、あるいは、癌を有する対象の寿命を延ばすことによるものである。抗癌剤(抗癌因子)は、生物学的薬剤(生物学的作用因子)(生物療法)、化学療法剤、および放射線療法剤(放射線療法因子)を含む。より一般的には、これらの他の組成物は、細胞の増殖を止めるか阻害するのに効果的な組み合わせの量で供給されるだろう。このプロセスは、本発明のヒトラクトフェリン組成物および一つ以上の薬剤または複数の因子を同時に投与することを含みうる。これは、両剤(両因子)を含む単一の組成物または薬理学的製剤を投与することにより、あるいは、異なる二種の組成物または製剤(一方の組成物はヒトラクトフェリン組成物を含み、他方は第二の薬剤(因子)(類)を含む)を同時にまたはその効果が重なるよう十分に近い時期に投与することにより達成することができる。
また、癌の治療法には種々の化学薬品を用いた治療がある。以下に限定されるものではないが、化学療法剤の具体例には、抗生物質の化学療法剤、例えばドキソルビシン、ダウノルビシン、アドリアマイシン、マイトマイシン(ムタマイシンおよび/またはマイトマイシン-Cとしても知られる)、アクチノマイシンD(ダクチノマイシン)、ブレオマイシン、プリコマイシン(Plicomycin)、植物アルカロイド類、例えばタキソール、ビンクリスチン、ビンブラスチン、その他種々の薬剤、例えば白金系薬剤(例えばシスプラチン(CDDP))、エトポシド(VP16)、腫瘍壊死因子、およびアルキル化剤、例えばカルムスチン、メルファラン(アルケラン、L-フェニルアラニンマスタード、フェニルアラニンマスタード、L-PAM、またはL-サルコリシンとしても知られる)(ナイトロジェンマスタードのフェニルアラニン誘導体)、シクロホスファミド、クロラムブシル、ブスルファン(マイレランとしても知られる)、タキサン系薬剤(例えばドセタキセル)およびロムスチンがある。
放射線療法の作用因子およびファクターには、DNA損傷を誘発する放射線および波長があり、例えば、γ線照射、X線、UV照射、マイクロ波、電子射出、放射性同位体などがある。上記形態の放射線を局所的にできた腫瘍部位に照射することにより、治療を行うことができる。これらの因子のすべてが、DNA、DNAの前駆体、DNAの複製および修復、ならびに染色体の構築および維持に広範囲の損傷をもたらしうる。
癌の患者のおよそ60%が、予防的手術、診断用手術またはステージング手術、治療手術および緩和手術を含む、何らかの種類の外科手術をうけることになる。治療手術は、癌の治療であり、他の治療法、例えば、本発明の治療、化学療法、放射線療法、ホルモン療法、遺伝子治療、免疫療法および/またはその他の治療法と組合せて用いることができる。
意図するところによれば、治療上の効果を高めるため、他の生物学的な作用因子を本発明と組合せて用いることができる。以下に限定されるものではないが、それらのさらなる因子には、細胞表面の受容体およびGAP接合のアップレギュレーションに作用する因子、静細胞因子(静細胞剤)および分化因子、細胞接着の阻害剤、過剰増殖性細胞のアポトーシスインデューサーへの感受性を高める因子、またはその他の生物学的因子、さらには温熱療法のような生物療法が含まれる。
免疫療法は、一般に、癌細胞を標的にして破壊するため、免疫エフェクター細胞および分子を使用することによるものである。例えば、免疫エフェクターは、腫瘍細胞の表面にある何らかのマーカーに対して特異的な抗体とすることができる。抗体は、単独で治療のエフェクターとして働くことができ、あるいは、他の細胞を動員して実際に細胞の死滅をもたらすことができる。また、抗体は、薬剤または毒素(化学療法薬、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)と接合させることができ、そして、単にターゲティング剤として用いることができる。一方、エフェクターは、腫瘍細胞のターゲットと直接的または間接的に相互作用する表面分子を保持するリンパ球であってもよい。種々のエフェクター細胞には、細胞障害性T細胞およびNK細胞が含まれる。
本発明の好ましい態様を例示するために、以下に実施例を記載する。当業者に明らかなとおり、以下の実施例に開示する技術は、本発明者が見出した本発明の実施に際しうまく機能する技術を表し、従って、その実施の好ましい形態を構成するとみなすことができる。しかし、ここに開示する具体例には数多くの変更を加えることができ、それでもなお本発明の精神および範囲から逸脱することなく、よく似たまたは同類の結果が得られることは、本明細書の開示に照らして、当業者には明らかなことである。
rhLFによる腫瘍増殖の阻害
ヒト扁平上皮細胞癌(O12)を用いた。該細胞を無胸腺ヌードマウスの右側腹に注射した。腫瘍内(49匹、1回あたり0.05μg〜125μgの用量で7回)、静脈内(7匹、125μg/1回の用量)、または経口(7匹、20mg/1回の用量)のいずれかでrhLFを投与した。対照動物はビヒクルのみで処置した。rhLFを対照動物には投与しなかった。定着腫瘍を形成させるべく腫瘍細胞を接種して11日後から、rhLFを1日2回で5日間(静脈内の群)または8日間(その他のすべての群)投与した。
腫瘍の種類に対するrhLFの評価
広範囲にわたる種類の腫瘍細胞を無胸腺ヌードマウスの右側腹に注射する。動物には、rhLF、本来のhLF、またはウシLFのいずれかを経口投与する。対照動物はビヒクルのみで処理する。対照動物にはrhLFを投与しない。定着腫瘍を形成させるべく腫瘍細胞を接種して約11日後から、1、5、7、もしくは14日間または8日間、1日1回または2回、rhLFを投与するか、あるいは、標準的または公開された投薬法で一般に行われるような他の時期にrhLFを投与する。
rhLFおよびbLFの経口投与の効果
組換えヒトラクトフェリンおよびウシラクトフェリンをマウスに経口投与し、そして、小腸におけるIL-18の産生を測定した。
インビボでのNK活性における経口rhLFの効果
Balb/cナイーブマウスにrhLFまたはプラセボを1日1回、3日間、経口投与した(表4参照)。
rhLF経口投与のGM-CSFに対するインビボでの効果
組換えヒトラクトフェリンまたはプラセボをマウスに経口投与し、GM-CSFの小腸における産生を測定した。
hLFの化学療法との組合せ
ネズミ扁平上皮癌細胞株(SCCVII)を、免疫担当C3Hマウスの頸部皮膚を介して口底に注射した(0日目)。腫瘍細胞の移植後5日で(5日目)、頸下部において皮膚の切開を行い、外科的解剖により腫瘍が定着したことを確認した。腫瘍をキャリパスで三次元的に測定した。
化学療法との組合せhLFの用量依存
実施例6に記載するように、ネズミ扁平上皮癌細胞株(SCCVII)を、免疫担当C3Hマウスの頸部皮膚を介して口底に注射した(0日目)。最初の移植後5日目で、腫瘍をベースラインとして測定し、次いで、シスプラチン単独(8日目、i.p.、5mg/kg)またはシスプラチン+3種の用量の経口rhLF(毎日、胃管栄養法により5日目から11/12日目にかけて7〜8日間)のいずれかで処置した。11/12日目で動物をと殺し、そして腫瘍を測定した。図3に示すように、シスプラチン単独を摂取した動物と比較して、rhLFとシスプラチンの両方を摂取した動物では、用量に依存する腫瘍増殖阻害があった。
hLFのドセタキセルとの組合せ
実施例7に記載するように、ネズミ扁平上皮癌細胞株(SCCVII)を、免疫担当C3Hマウスの頸部皮膚を介して口底に注射した(0日目)。最初の移植後5日目で、腫瘍をベースラインとして測定し、次いで、経口プラセボ単独(1日1回、5日目から12日目まで、6匹)、プラセボとドセタキセル(i.v.ボーラス31.3mg/kgドセタキセル、8日目、9匹)、またはドセタキセル+経口rhLF(200mg/kg、胃管栄養法により1日1回、5日目から12日目まで投与、9匹)のいずれかで処置した。14日目に動物をと殺し、そして腫瘍を測定した。プラセボと比較して、ドセタキセル単独は、腫瘍増殖の阻害を引き起こし、そして、rhLFとドセタキセルとの組合せは、さらなる増殖阻害を引き起こした。阻害およびp値(片側検定)を表9に示す。
hLFの放射線療法との組合せ
ネズミ扁平上皮癌細胞株(SCCVII)を、免疫担当C3Hマウスの頸部皮膚を介して口底に注射した(0日目)。腫瘍細胞移植後5日(5日目)で、頸下部において皮膚の切開を行い、外科的解剖により腫瘍が定着したことを確認した。腫瘍をキャリパスで三次元的に測定した。
hLFのヒトにおける経口投与
四カ国(アルゼンチン、ブラジル、チリ、米国)における複数の医療センターで行った二つの異なる研究において、標準的な化学療法が不成功に終わったある範囲の種類にわたる転移性癌のヒト患者に組換えヒトラクトフェリンを経口投与した。rhLFを、1日あたり1.5〜9グラムの用量で2回に分けて14日おきに14のサイクルで投与した。
ヒトにおける経口hLFでの組合せ治療
組換えヒトラクトフェリンをヒト患者に経口投与し、単独でまたは標準的な抗癌投薬法と組合せて腫瘍の増殖を阻害する。
経口rhLFの投与後の免疫刺激
Balb/cナイーブマウスにrhLFまたはプラセボを1日1回、3日間、経口投与した。1日後(4日目)、マウスをと殺し、そして脾臓を採取した。磁気ビーズ細胞選別アッセイ(MACS抗NK-DX5)を用いてNK細胞を分離し、カウントした。次に、乳酸脱水素酵素(LDH)放出試験を用いて、YACターゲットに対するNK活性についてインビトロで細胞を試験した。
静脈内投与の効果
組換えラクトフェリン、ウシラクトフェリンおよび天然のラクトフェリンを、動物、好ましくはラットに、静脈内投与し、そして、IL-18、IL-1、IL-2、IL-4、IL-5、IL-10、IL-12およびIFN-ガンマの血漿、血清および血液内細胞における産生を測定する。
静脈内rhLFの他の薬剤との組合せ化学療法
試験すべき腫瘍細胞を、無胸腺ヌードマウスの右側腹に注射する。動物にrhLFを単独でまたは他の抗癌投薬法と組合わせて、実施例13のように静脈内投与する。対照動物をビヒクルのみで処置する。対照動物にはrhLFを投与しない。実施例13に記載した試験において最適と判断される投薬計画を用いてrhLFを投与する。標準的または公知の投薬法を用いて抗癌治療を行う。定着腫瘍を形成させるべく腫瘍細胞を接種してから約11日後に治療を開始するか、あるいは、標準的または公知の投薬法で一般に行われるような他の時期に治療を開始する。
hLFのヒトにおける静脈内投与
腫瘍増殖を阻害するため、組換えラクトフェリンを患者に静脈内投与する。
静脈内hLFによる組合せ治療
組換えラクトフェリンを患者に静脈内投与し、単独でまたは標準的な抗癌投薬法と組合せて腫瘍の増殖を阻害する。
腫瘍内rhLFの活性
O12ヒト口腔咽頭扁平上皮細胞癌の腫瘍細胞を無胸腺ヌードマウスの右側腹に注射した。組換えヒトラクトフェリンおよびビヒクル対照を腫瘍内注射により投与した。各動物には、異なる濃度のrhLFを50μLで投与した。該50μLは、異なる方向および角度(ほぼS/N/E/W)からの約12.5μLの4回の注射に分け、該用量が腫瘍のいたるところに確実に一様に分配(ファンニング)されるようにした。
腫瘍内rhLF後の免疫刺激
正常なC3H/HeJマウスに、実施例17記載の方法により、二種類のマウス腫瘍のうちのいずれかを移植した。使用した腫瘍はSCCVIIおよびRIFマウス腫瘍細胞株であった。マウスにおいて腫瘍を定着させた後、1用量あたり250または500μgのrhLFまたはビヒクル対照物を、毎日、4日間、腫瘍内に注射した。最後の腫瘍内注射の後24時間で動物をと殺し、その血液をリンパ球の集団について調べた。循環リンパ球の数は、プラセボ処置対照動物に対し34%〜56%増加した(表14)。
hLFの他の薬剤との組合せ化学療法
試験すべき腫瘍細胞を、無胸腺ヌードマウスの右側腹に注射する。動物にrhLFを単独でまたは他の抗癌投薬法と組合わせて、実施例1または実施例17記載のように腫瘍内投与する。対照動物をビヒクルのみで処置する。対照動物にはrhLFを投与しない。標準的または公知の投薬法を用いて抗癌治療を行う。定着腫瘍を形成させるべく腫瘍細胞を接種してから約11日後に治療を開始するか、あるいは、標準的または公知の投薬法で一般に行われるような他の時期に治療を開始する。
hLFの腫瘍内投与
腫瘍増殖を阻害するため、組換えラクトフェリンを患者に腫瘍内投与する。
腫瘍内hLFによる組合せ治療
組換えラクトフェリンを患者に腫瘍内投与し、単独でまたは標準的な抗癌投薬法と組合せて腫瘍の増殖を阻害する。
ヒトにおけるhLFの局所投与
腫瘍増殖を阻害するため、組換えラクトフェリンをゲル製剤で患者に投与する。
局所hLFによる組合せ治療
組換えラクトフェリンをゲル製剤で患者に投与し、単独でまたは標準的な抗癌投薬法と組合せて腫瘍の増殖を阻害する。
本明細書に記載するすべての特許および刊行物は、本発明に関し、当業者の技術水準を示すものである。すべての特許および刊行物は、引用することによって、その内容が具体的かつ個々に本明細書に記載されたものとする。
米国特許第5,629,001号
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本発明およびその利点を詳細に説明してきたが、勿論、添付の特許請求の範囲に規定する本発明の精神および範囲から逸脱することなく、さまざまな変更、置換、および改変を施すことができる。さらに、本願の範囲は、本明細書に記載した特定の態様のプロセス、装置、製品、組成物、手段、方法および工程に限定されるものではない。本発明の開示から当業者には明らかなように、本明細書に記載した対応する態様と実質的に同じ機能を果たすか、または実質的に同じ結果をもたらす、既存のまたは将来開発されるプロセス、装置、製品、組成物、手段、方法または工程を、本発明に従って用いることができる。従って、そのようなプロセス、装置、製品、組成物、手段、方法または工程もまた、添付の特許請求の範囲に包含するものとする。
Claims (10)
- 固形癌としての肺癌を治療する為の癌治療薬であって、ヒトラクトフェリンを該癌治療薬の有効成分として含有する経口医薬組成物を含む癌治療薬。
- 前記ヒトラクトフェリンが、前記経口医薬組成物において、薬学的に許容される担体中に分散されている、請求項1記載の癌治療薬。
- 該ヒトラクトフェリンが組換えヒトラクトフェリンである、請求項1または2記載の癌治療薬。
- 前記ヒトラクトフェリンを該癌治療薬の有効成分として含有する経口医薬組成物に、さらに化学療法用薬剤を組合せてなる、請求項1から3までのいずれかに記載の癌治療薬。
- 前記化学療法用薬剤が、白金系の薬剤を含む、請求項4記載の癌治療薬。
- 前記白金系の薬剤がシスプラチンである、請求項5記載の癌治療薬。
- 前記ヒトラクトフェリンを該癌治療薬の有効成分として含有する経口医薬組成物の投与が、シスプラチン投与前あるいはシスプラチン投与と同時に行われる、請求項6記載の癌治療薬。
- 前記化学療法用薬剤が、タキサン系の薬剤を含む、4から7までのいずれかに記載の治療薬。
- 前記タキサン系の薬剤が、ドセタキセルである、請求項8記載の癌治療薬。
- 前記ヒトラクトフェリンを該癌治療薬の有効成分として含有する経口医薬組成物の投与が、ドセタキセル投与前あるいはドセタキセル投与と同時に行われる、請求項9記載の癌治療薬。
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JP (2) | JP4685443B2 (ja) |
CN (2) | CN100467059C (ja) |
AT (1) | ATE519499T1 (ja) |
AU (2) | AU2003239393A1 (ja) |
CA (1) | CA2484656A1 (ja) |
CY (1) | CY1111999T1 (ja) |
DK (1) | DK1507554T3 (ja) |
HK (2) | HK1080722A1 (ja) |
PT (1) | PT1507554E (ja) |
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JPWO2018079701A1 (ja) * | 2016-10-28 | 2019-09-19 | 株式会社Nrlファーマ | ラクトフェリン活性を有するタンパク質を含む、抗ガン治療補助剤 |
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- 2003-05-09 US US10/434,769 patent/US7901879B2/en not_active Expired - Fee Related
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- 2003-05-09 EP EP10010751A patent/EP2286827A1/en not_active Withdrawn
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- 2003-05-09 CN CNB038163853A patent/CN100467059C/zh not_active Expired - Fee Related
- 2003-05-09 AU AU2003273182A patent/AU2003273182B8/en not_active Ceased
- 2003-05-09 JP JP2004506847A patent/JP4685443B2/ja not_active Expired - Fee Related
- 2003-05-09 AT AT03755357T patent/ATE519499T1/de active
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- 2010-12-09 US US12/964,327 patent/US8242079B2/en not_active Expired - Fee Related
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Also Published As
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HK1083203A1 (en) | 2006-06-30 |
CN1668326A (zh) | 2005-09-14 |
AU2003273182B8 (en) | 2009-05-07 |
US8242079B2 (en) | 2012-08-14 |
US20100137208A1 (en) | 2010-06-03 |
AU2003239393A1 (en) | 2003-11-11 |
EP1507554B1 (en) | 2011-08-10 |
US20040009895A1 (en) | 2004-01-15 |
US7901879B2 (en) | 2011-03-08 |
US20040082504A1 (en) | 2004-04-29 |
CN1668325A (zh) | 2005-09-14 |
HK1080722A1 (en) | 2006-05-04 |
PT1507554E (pt) | 2011-11-21 |
JP2011079858A (ja) | 2011-04-21 |
AU2003273182A1 (en) | 2003-12-12 |
DK1507554T3 (da) | 2011-11-21 |
WO2003094952A1 (en) | 2003-11-20 |
EP2286827A1 (en) | 2011-02-23 |
WO2003099323A1 (en) | 2003-12-04 |
US20120276126A1 (en) | 2012-11-01 |
CN100467059C (zh) | 2009-03-11 |
CY1111999T1 (el) | 2015-11-04 |
CA2484656A1 (en) | 2003-12-04 |
JP5156084B2 (ja) | 2013-03-06 |
CN100467060C (zh) | 2009-03-11 |
ATE519499T1 (de) | 2011-08-15 |
AU2003273182B2 (en) | 2009-04-23 |
EP1507554A1 (en) | 2005-02-23 |
EP1507554A4 (en) | 2007-05-09 |
US20110076295A1 (en) | 2011-03-31 |
JP2005533029A (ja) | 2005-11-04 |
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