JP2006523607A - Cck−b/ガストリン受容体に対する免疫原性組成物および腫瘍の治療法 - Google Patents
Cck−b/ガストリン受容体に対する免疫原性組成物および腫瘍の治療法 Download PDFInfo
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Abstract
Description
本出願は、出願第09/076,372号の一部継続出願であり、1997年5月12日に出願された米国仮出願第60/046,201号の米国特許法第119条第(e)項に基づく優先権を主張する。
ガストリンは、テトラトリアコンタガストリン(G34)およびヘプタデカガストリン(G17)の2種の形で生じるペプチドホルモンであり、幽門洞(stomach antrum)にある、特殊化細胞のG細胞により合成および分泌される。ホルモンは循環血液中に分泌されて、胃の特定の細胞、すなわち腸クロム親和性細胞様(ECL)細胞および壁細胞に結合し、これが間接的または直接的に胃酸の分泌量(output)に影響を及ぼす。歴史的には、ガストリンホルモンは胃酸分泌の刺激を伴うものとされてきた(Edkins, J. S. 1905)。(本明細書中に記載される参照のための全引用は、特許請求の範囲に先立つ参照の項で提供される。)近年では、ガストリンは胃腸管内で栄養因子として作用する可能性があること(Johnson, L. 1997)、ならびに胃腸管癌(Watson et al. 1989, Dickinson, C. J. 1995)および肺の小細胞癌を始めとする非胃腸管癌(Rehfeld et al. 1989)の成長を促進し得ることの証拠が積み上げられてきた。ガストリンの翻訳後プロセシングにおいて、その5個のカルボキシ末端アミノ酸を介して高親和性でコレシストキニンB/ガストリン受容体に結合するのは、「成熟」カルボキシアミド化形である(Kopin et al. 1992)。CCK−B/ガストリン受容体(GR)は、Gタンパク質を介して、様々な遺伝子の発現を順に制御する細胞内シグナル伝達経路にカップリングした膜貫通タンパク質である。
GRを保持する腫瘍を治療するための異なるアプローチは、宿主の免疫系を、GRを標的とすることにより腫瘍を特異的に攻撃するように仕向けることである。
本発明の方法は、ヒトを始めとする動物のガストリンホルモン依存性腫瘍の治療に関し、ホルモンの成長促進効果を阻害するために受容体へのホルモンの結合を阻止するように、免疫された患者で腫瘍細胞上のCCK−B/ガストリン受容体(GR)に結合する抗体を産生する抗CCK−B/ガストリン受容体免疫原を患者に投与することを含む。GR免疫模倣ペプチドは、GRの外部から到達できる部分またはエピトープに対して向けられた抗体を産生するのに有利なように選択される。
免疫模倣エピトープを提供するために選択されたCCK−B/ガストリン受容体ペプチドを、標準的な固相ペプチド合成により調製した。免疫原をより特異的免疫応答を誘導する能力があるものにするため、カルボキシ末端にスペーサー配列SSPPPPC(配列表の配列番号3)を含有するGRE1およびGRE4のそれぞれを合成した。続いて、以下に記載されるように、方法A、方法B、または方法Cのいずれかにより、これらのペプチドを、架橋剤の一端にスクシンイミジルエステルおよび他端にマレイミドを含有するヘテロ二官能性架橋剤を用いて、スペーサーの末端ペプチドアミノ酸残基のシステインを介して、キャリアであるジフテリアトキソイド(「DT」)上に存在するアミノ基に抱合させた。
スペーサー有りまたは無しでDTと抱合したGRE1またはGRE4のいずれかを含有する本発明の免疫原を用いて、ウサギを免疫した。免疫原を以下のように調製した:抱合体を0.15Mリン酸ナトリウム緩衝食塩水(pH7.3)に溶解させ、濃度3.79mg/mlとした。抱合体溶液を30:70(wt:wt)の抱合体溶液対Montanide ISA703の比でMontanide ISA703アジュバント(Seppic, Inc.)に加え、次いで、混合物を、Silversonホモジナイザーを用いて8,000RPMで3分間ホモジナイズして、1mg/mlの抱合体を含有する乳濁液を形成した。
ウサギに、0.1mgのGRE1−DTまたはGRE4−DT抱合体のいずれかからなる0.1mlの免疫原を筋肉内注射した。各ウサギに0週および4週で免疫原を注射した。実験の6週および8週で、各ウサギから血液を採取した。各血液試料から血清を調製して、抗GR抗体の存在を測定するアッセイに用いるまで、−20℃で貯蔵した。
固相ELISAを用いて、各免疫化ウサギのペプチド1およびペプチド4に対して産生した抗血清の反応または交差反応についてスクリーニングした。ポリスチレン96ウェルプレート(IMMULON II, Dynatech)を、25μl/ウェルで、0.1Mグリシン−HCl緩衝液(pH9.5)中10μg/mlの、ウシ血清アルブミン(BSA)に結合したペプチド1(「GRE1−BSA」)またはBSAに結合したペプチド4(「GRE4−BSA」)抗原でコーティングすることによりELISAを行った。プレートを4℃で一晩インキュベートし、続いて緩衝液中洗浄した。
ロダル・グリーン(rhodal green)標識化ヘプタガストリン(RG−G7)の結合および内部移行は、AR42J細胞、HepG2、およびC170HM2細胞で見られた。ガストリンはこれらの細胞の細胞質中に取り込まれた。結合もまた、ガストリン受容体を安定して形質移入されたNIH3T3細胞で見られたが、形質移入されていないNIH3T3では見られなかった。形質移入された細胞において、ガストリンは細胞膜に結合するようであった。ガストリン取り込みを示すAR42J細胞を固定化して、Alexa−546抱合化GRE1抗体を用いてガストリン受容体を染色したところ、ガストリンおよびガストリン受容体の同時発現が見られた。ガストリン受容体は、これらの細胞の膜上および細胞質中で検出された。
腫瘍細胞株、AR42J、C170HM2、およびHepG2において、生きた腫瘍細胞への抗GRE1抗体の添加は、細胞の細胞質中および核中への抗体の結合および内部移行をもたらした。抗GRE1抗体のF(ab)およびF(ab)2フラグメントもまた、これらの腫瘍細胞株からの生きた細胞とともにインキュベートすると、細胞質および核中への取り込みが見られた。これらの細胞株によるFITC結合無関連抗体(ウサギ抗マウスIg、F(ab)2フラグメント)の取り込みは見られなかった。抗GRE1抗体の取り込みは、形質移入されていないNIH3T3細胞でも、正常リンパ球でも見られなかったが、野生型および切断型のヒトガストリン/CCK−B受容体で形質移入されたNIH3T3細胞では見られた。抗GRE1抗体は、形質移入されたNIH3T3細胞の膜に結合するようであったが、これらの細胞の細胞質または核中には取り込まれなかった。これは、GRを正常に暴露する腫瘍細胞株で見られるものと異なるパターンの取り込みであった。
C170HM2腫瘍異種移植片を、細胞の腹腔内注射により開始した。3種の異なる細胞接種を用いて、3つのレベルの腫瘍量を産生させた。0日目からGRE1抗血清を尾静脈注射で受動的に投与した。40日目に治療を終了した。
評価された初期パラメーターは、肝臓中の平均腫瘍数であり、これは図21に示される。正常ウサギ抗血清処置された対照は、増加する細胞接種の群にまとめられる。図21からわかるように、対照群において、肝臓あたりの平均腫瘍数は、1〜3であった。GRE1抗血清処置群において、肝臓あたりの平均腫瘍数は、3種の細胞接種全てについて1未満であり、3つの実験全てについて有意であった(接種1、n=18、p=0.003、接種2、n=12、p=0.0001、および接種3、n=20、p=0.0068、マン・ホイットニー分析)。
図22は、3つの増加する細胞接種について、左側のパネルに、正常ウサギ血清処置された対照の平均腫瘍重量を示す。この図はまた、GRE1抗血清での処置に続くヌードマウスの平均腫瘍重量も示す。平均肝臓腫瘍重量は、3種の細胞接種全てで60%減少し、これは3つの実験全てについて有意であった(接種1、p=0.0016、接種2、p=0.0084、および接種3、p=0.0001、マン・ホイットニー分析)。
核外膜タンパク質を、実験物の2/3からのC170HM2異種移植片から調製した。GRE1抗血清を用いて、これらをウエスタンブロット法により分析した。図23は、ウエスタンブロット法の写真であり、正常ウサギ血清処置した異種移植片において、2本の免疫反応性バンドが74および50kDaに存在し、前者のバンドが最も強力な免疫反応性を示したことを示している。GRE1抗血清処置した異種移植片において、2本の免疫反応性バンドと一緒に、対照異種移植片またはin vitroで増殖した細胞には見られない中間バンドが存在する。50kDaバンドが最も強力な免疫反応性を示す。このことは、GRE1抗血清処置した異種移植片において、より多くの割合のGRが内部移行した形で存在する可能性があることを示している。
図24は、ヌードマウスの肝臓に浸潤するC170HM2異種移植片の顕微鏡図を示す。腫瘍は一般に、それが肝臓に浸潤する時に肝細胞を押しつぶす生きた先行縁を有する壊死中心で構成される。in situeハイブリッド形成法により可視化された陽性細胞を用いて、Tunel法によりC170HM2腫瘍の生きた先行縁でアポトーシスの程度を測定した。図25は、アポトーシス細胞が、GRE1抗血清処置した異種移植片の生腫瘍細胞に存在したが、正常ウサギ血清処置した腫瘍に存在しなかったことを示す。
各ペプチドによる抗体結合の阻害割合は、GRE−11で84%、GRE1で57%、GRE1+GRE6(混合)で49%、およびGRE6で4%であった。
方法:ラット(BDIX株)に、GRE1または対照免疫原で7回免疫化を与えた(−4、−3、−2、0、1、4、7週目に注射した)。
結果は、以下を示す:
GRE1での免疫化は治療上有効であった。GRE1免疫化の化学療法との併用は、単独でのいずれの治療にも勝って、顕著に有効性を向上させた。
Claims (20)
- システイン末端で免疫原性キャリアに抱合された、
KLNRSVQGTGPGPGASLAAC(配列番号2)、
CCGKLNRSVQGTGPGPGASL(配列番号5)、
MELLKLNRSVQGC(配列番号8)、
RDBDLGEADVWRASSC(配列番号9)、
WERRSGGNWAGDWGDSPFSSC(配列番号10)、
MELLKLNRSVQGTGPGPGASLC(配列番号11)、
MELLKLNRSVQGTGPGPGASLSSPPPPC(配列番号12)、
ELLKLNRSVQGTGPGPGASLC(配列番号13)、
LLKLNRSVQGTGPGPGASLC(配列番号14)、
LKLNRSVQGTGPGPGASLC(配列番号15)、
KLNRSVQGTGPGPGASLC(配列番号16)、
ELLKLNRSVQGSSC(配列番号17)、および
GTGPGPGASLC(配列番号18)、
の合成配列からなる群より選択されるガストリン受容体ペプチドエピトープ(GRE)を含む免疫原。 - 免疫原性キャリアに抱合された配列番号5、11、12、13、14、15、16、17、および18からなる群より選択されるGREを含む免疫原。
- 免疫原性キャリアに抱合されたMELLKLNRSVQGC(配列番号8)からなるGREを含む免疫原。
- 免疫原性キャリアに抱合された配列番号9または配列番号10のアミノ酸配列からなるGREを含む免疫原。
- 請求項1〜4のいずれか1項に記載の免疫原、および薬学的に許容可能なキャリアまたはアジュバントを含む免疫原性組成物。
- 配列番号2、5、6、9、10、11、12、13、14、15、16、17、および18により同定される配列からなる群より選択されるガストリン受容体免疫模倣ペプチドと結合する能力がある抗体。
- 前記抗体がモノクローナル抗体である、請求項6に記載の抗体。
- 前記抗体がマウス抗体、ヒト化抗体、またはヒト抗体である、請求項7に記載の抗体。
- 請求項7または8に記載の抗体を1つまたは複数含む組成物。
- 配列番号2、5、8〜17、または18として同定されるアミノ酸配列からなるガストリン受容体エピトープに特異的である免疫血清または上清から調製される抗体を含む、ガストリン刺激性悪性増殖または前悪性増殖を阻止または治療する組成物。
- 配列番号9または配列番号10として記載されるアミノ酸配列からなる腫瘍ガストリン受容体エピトープに特異的である免疫血清または上清から調製される抗体を含む、ガストリン刺激性悪性増殖または前悪性増殖を阻止または治療する組成物。
- 前記抗体は細胞毒性物質に抱合される、請求項10または11に記載の組成物。
- 前記細胞毒性物質は、毒素または放射性物質を含む、請求項12に記載の組成物。
- 前記毒素は、コレラ毒素、ジフテリア毒素、またはリシンであり、そして前記放射性物質は、125ヨウ素、131ヨウ素、99イットリウム、または111インジウムである、請求項13に記載の組成物。
- (i)患者から生検標本を得る工程と、
(ii)該標本を免疫血清または上清から調製した抗GR抗体に暴露させる工程であって、該抗体は配列番号2、5、8〜17、または18として記載されるアミノ酸配列からなるガストリン受容体ペプチドエピトープに特異的である、暴露させる工程と、
(iii)比色法、化学発光(chemiluminescent)法、蛍光法、放射分析法、またはシンチグラフィー法により、結合抗体を検出する工程を含む、生検でガストリン受容体を診断する方法。 - 以下、比色分子、化学発光(chemiluminescent)分子、または放射性分子を含む検出可能な分子と結合した抗GR抗体の投与、および画像化技法による抗体複合体の画像化を含む、患者のガストリン応答性悪性腫瘍または前悪性腫瘍を検出する方法。
- (i)化学療法薬または放射性物質を保有するように改変されていてもよい、治療上有効量の動物抗GRE11抗体、ヒト抗GRE11抗体、もしくはヒト化抗GRE11抗体を投与すること、および
(ii)治療上有効量のガストリンG17免疫原を投与すること、および/または
(iii)治療上有効量の動物抗G17抗体、ヒト抗G17抗体、もしくはヒト化抗G17抗体を投与することを含む、ガストリン応答性腫瘍に罹病している患者を治療する方法。 - 前記抗体は、単独のモノクローナル種または異なるモノクローナル種の混合である、請求項17に記載の方法。
- 請求項6に記載の抗体を含有するリポソーム小胞懸濁液を含む、リポソーム組成物。
- (i)請求項1または2に記載のガストリン受容体エピトープに対する免疫原、および/または
(ii)請求項6に記載の抗体、および
(iii)5FU(+ロイコボリン)、ゲムシタビン、イリノテカン(irinotecan)、タキサン、オキシプラチン(oxiplatin)、カルボプラチン、シスプラチン、カンプトテシン/カンプトサール、ビンクリスチン、ビンブラスチン、ルベテカン(rubitecan)、シクロホスファミド、ドキシルビシン(doxirubicin)、マイトマイシンC、エトポシド、およびノスカピンからなる群より選択される化学療法薬、の投与の組み合わせを含む、癌を治療する方法。
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- 2003-12-17 EP EP03799994A patent/EP1572742A2/en not_active Withdrawn
- 2003-12-17 AU AU2003299713A patent/AU2003299713A1/en not_active Abandoned
- 2003-12-17 WO PCT/US2003/040449 patent/WO2004056862A2/en active Application Filing
- 2003-12-17 JP JP2004562279A patent/JP2006523607A/ja active Pending
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AU2003299713A8 (en) | 2004-07-14 |
WO2004056862A2 (en) | 2004-07-08 |
EP1572742A2 (en) | 2005-09-14 |
WO2004056862A3 (en) | 2005-03-17 |
US20040001842A1 (en) | 2004-01-01 |
AU2003299713A1 (en) | 2004-07-14 |
CA2507637A1 (en) | 2004-07-08 |
CA2507637C (en) | 2015-08-11 |
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