JP2005525995A - 新薬 - Google Patents
新薬 Download PDFInfo
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- JP2005525995A JP2005525995A JP2003522561A JP2003522561A JP2005525995A JP 2005525995 A JP2005525995 A JP 2005525995A JP 2003522561 A JP2003522561 A JP 2003522561A JP 2003522561 A JP2003522561 A JP 2003522561A JP 2005525995 A JP2005525995 A JP 2005525995A
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Abstract
Description
Kogermanら[Kogermanら、Oncogene 1997;15:1407−16]は、ヒトCD44標準アイソフォーム(hCD44s)を安定的に発現しているマウス線維肉腫細胞が、大きな皮下腫瘍においてhCD44s発現を喪失したことを見出した。これらの原発腫瘍由来のhCD44s陰性細胞を、二回目の腫瘍増殖のため新たなマウスの皮下に再導入したところ、得られた腫瘍は、hCD44s陽性腫瘍より有意に短い潜伏期間を有していた。
図面の簡単な記述
図1は組換えのGSTタンパク質及びGST−CD44タンパク質のSDS PAGEを示す。ゲルはクーマシーブリリアントブルーにより染色された。分子量マーカーが右側に示されている。
図2は組換えCD44ヒアルロン酸結合ドメインがヒアルロン酸と結合することを示す。a、野生型CD44HABDは、固定化されたHAと結合するが、R41A変異体、R78SY79S変異体又はR41AR78SY79S変異体は結合しない。b、CD44HABDはヒト大動脈内皮細胞のHAへの遊走を阻害するが、R41A HA非結合性変異体には効果がない。HA結合を阻止するCD44に対するモノクローナル抗体A3は、内皮細胞遊走も阻害する。
図3は組換えヒトCD44ヒアルロン酸結合ドメインがニワトリ絨毛尿膜におけるインビボの血管形成を阻止することを示す。a、血管形成がbFGFにより誘導された典型的な血管形成実験からのフィルターディスク及び関連CAM。b〜d、血管形成は血管枝ポイントの数;平均血管形成指数±SEMとして査定された。*(P<0.05)、有意な結果。
図4は組換えCD44ヒアルロン酸結合ドメインがニワトリCAMにおける黒色腫(SMMU−1、M21)及び肝細胞癌(HepG2)の増殖を阻害することを示す。
図5は組換えCD44ヒアルロン酸結合ドメインがCD44陰性黒色腫増殖を阻害することを示す。a、CD44HABD、CD44HABDR41AR78SY79S又は対照としてのGSTにより処理されたヌードマウスにおけるs.c.SMMU−1腫瘍の増殖曲線(各群n=8)。b、16日目の腫瘍重量(黒線は中央値を表している)。c、示されたようにして処理された16日目のマウスの代表的な写真。d、高倍率視野(HPF)1個当たりの腫瘍辺縁における血管密度。*(P<0.005)、**(0.05)有意な結果。
図6ではCD44−HABD融合タンパク質はヌードマウスにおけるヒト膵臓癌細胞の増殖を阻害する。GST−CD44HABD(四角)、GST−CD44HABDR41AR78SY79S(三角)又は対照としてのGST(菱形)により処理されたヌードマウスにおけるBxPC−3膵臓腺癌腫瘍(n=6〜7)(a)。b、実験終了時の平均BxPC−3腫瘍重量。グラフ内の値及びバーは平均±s.e.mを表す。アステリスクはP<0.05を示す。
図7では組換えCD44HABDは内皮細胞周期を特異的に阻止する。GST(黒)、GST−CD44HABD(薄い影)又はGST−CD44HABDR41AR78SY79S(濃い影)により処理された場合の、S期の細胞の割合。HUVEC、ヒト血管内皮細胞;CPAE、ウシ肺動脈内皮細胞;NHDF、正常ヒト皮膚線維芽細胞;MCF−7、ヒト乳癌細胞。
図8は内皮細胞増殖に対するCD44HABD欠失変異体の効果を示す。CD44HABD欠失変異体は、3mut CD44HABD(変異の位置は、太字で示されている、図8A)に由来し、組換えタンパク質は実施例1に記載されたようにして産生され精製された。ウシ肺内皮細胞(CPAE)が、10%血清を含有している培地中で示されたタンパク質(最終濃度それぞれ15μg/ml及び30μg/ml)により48時間処理された。細胞増殖は、顕微鏡写真(B)、又はMTT染色(Sigma)及び分光光度法(C)によりアッセイされた。
「ヒアルロン酸結合ドメイン」は、以後、habdと呼ばれる。
国際公開第94/09811号は、炎症の治療又は癌転移の検出におけるCD44の使用を記載している。著者らは、CD44が炎症状態においてアップレギュレートされていること、及びCD44ペプチドがT細胞活性化を阻害し得ることを示している。CD44による転移の阻害に関するデータ又は請求項は提示されておらず、腫瘍増殖又は血管形成を阻害するためのCD44の使用は、特許請求の範囲に記載されていない。国際公開第99/45942号は、癌及び血管形成依存性疾患を阻害するためのCD44を含むHA結合性のタンパク質及びペプチドの使用を開示している。この公報は、B16マウス黒色腫の肺転移及びルイス肺癌を阻害するため、軟骨リンクタンパク質の38kDa断片であるメタスタチン、並びにこの断片に由来するHA結合ペプチドを使用している。HA結合ペプチドの場合、ニワトリCAMにおけるB16黒色腫の増殖及びHAへの内皮細胞遊走が阻害された。いずれの公報においても、HA結合ペプチドの使用は、ヒアルロン酸との結合能と直接関係がある。
a)CD44ヒアルロン酸結合ドメイン又はその断片を含む分子を準備する工程;
b)可能性のある結合パートナーを前記分子と接触させる工程;及び
c)前記可能性のある結合パートナーに対する前記分子の効果を決定する工程、を含む、CD44ヒアルロン酸結合ドメイン、並びにそのアナログ、変異体及び組換えバリアントを含む分子の結合パートナーのスクリーニング方法に関する。
(I)
a)HABD、HABDアナログ又はそれらの変異体の、細胞、細胞溶解物、細胞画分、組織、生物、動物、又は生物もしくは動物の一部とのインキュベーション。
b)例えば、アフィニティカラム、ゲル電気泳動、及び抗体又はタンパク質染色又は同位体又はHABDもしくはHABDに接続されたタグを検出するその他の手段を使用した任意の検出による、HABD結合パートナーの精製及び検出。
c)ゲル電気泳動(例えば、2D電気泳動)における局在化、質量分析、配列決定、抗体又はその他の同定手段の使用によるHABD結合パートナーの同定。
d)インビトロもしくはインビボの、同定された結合パートナーに対するHABDの効果の決定、又は前記可能性のある結合パートナーのその他の相互作用剤の効果の決定。
e)細胞増殖及び/又は血管形成の新規の阻害剤を設計するための同定されたHABD結合パートナーの使用。
(II)
a)DNA、cDNA、ファージ、ペプチド、タンパク質、細胞もしくは生物のライブラリーの遺伝学的スクリーニングのベイトとしてのHABDの使用、又はHABD、そのアナログもしくは変異体をベイトとして使用した、合成ペプチド、タンパク質、多糖、脂質、ヘパラン硫酸もしくはプロテオグリカンのライブラリーのスクリーニング。
b)選択マーカーによるHABD結合パートナーの検出。
c)配列決定、ハイブリダイゼーション、制限分析、抗体、又はライブラリー内の段階的な排除、又はその他の同定手段によるHABD結合パートナーの同定。
d)インビトロ又はインビボの、同定された結合パートナーに対するHABDの効果の決定、又は前記可能性のある結合パートナーのその他の相互作用剤の効果の決定。
e)細胞増殖及び/又は血管形成の新規の阻害剤を設計するための同定されたHABD結合パートナーの使用。
実施例1−GST融合タンパク質としての野生型及び変異型のヒトCD44 HA結合ドメインの構築及び精製
ヒトCD44標準アイソフォームcDNA[Stamenkovicら、EMBO J 1991;10:343−8]を使用して、オリゴヌクレオチド5’CGCGAATTCCAGATCGATTTGAATATG3’(配列番号:13)(内部EcoRI切断部位を含有している)及び5’CGCGAGCTCCTTCTAACATGTAGTCAG3’(配列番号:14)(内部SacI切断部位を含有している)により、アミノ酸21〜132をカバーするヒアルロン酸結合ドメインをPCR増幅した。得られたPCR増幅産物を、pGEX−KGベクター[Guan及びDixon、Anal Biochem 1991;192:262−7]へクローニングした。CD44HABDヒアルロン酸非結合性変異体の作製は、製造業者のプロトコル(Quickchange(登録商標)、Stratagene)に従い、部位特異的突然変異誘発により実施した。突然変異誘発オリゴ対R41A(5’GAGAAAAATGGTGCCTACAGCATCTCTCGG−3’(配列番号:15)、5’AGATGCTGTAGGCACCATTTTTCTCCACG−3’(配列番号:16))及びR78SY79S(5’GACCTGCAGCTCTGGGTTCATAG3’(配列番号:17)、5’ATGAACCCAGAGCTGCAGGTCTC3’(配列番号:18))を、それぞれR41A変異及びR78S、Y79S変異の野生型CD44HABDへの導入のため使用した。
1mg ml−1の高分子量ヒアルロン酸(Sigma)を含むPBSを使用して、室温(RT)で一夜、マキシソープ(Maxisorp)(Nunc)プレートをコーティングした。ウェルをPBSで洗浄し、RTで2時間2%BSAによりブロッキングした。PBSで希釈された精製されたタンパク質をウェルに添加し、RTで1時間インキュベートした。PBS−Tによる3回の洗浄の後、マウス抗GST抗体B−14(Santa Cruz Biotechnology)をRTで1時間インキュベートした後、さらに洗浄し、HRP結合ヤギ抗マウス二次抗体(Dako)と共にRTで1時間インキュベートした。HA結合をOPD発色性基質(Sigma)により可視化し、吸光度を450nmで読み取った。図2Aに示されるように、野生型CD44融合タンパク質は、濃度依存的にHAと結合するが、変異体はそうでなかった。
10日齢ニワトリ胚を、[Brooksら、J Clin Invest 1995;96:1815−22]に記載されたようにして調製した。血管形成アッセイのため、100ng ml−1 VEGF(Sigma)、100ng ml−1 TGFα(Sigma)又は1μg ml−1 bFGF(Gibco Lifetech)を含浸させたフィルターディスクを、CAM上に置いた後、毎日、10μgのCD44HABD、CD44HABDR41AR78SY79S、又は対照としてのGST及びPBS(各群n=6)を異所的に添加した。72時間後、フィルターディスク及び周囲のCAM組織を、解剖顕微鏡において解剖し、血管形成を定量した。血管形成を、フィルターディスク直下のCAMエリア内の血管分枝点の数として査定した。
SMMU−1ヒト黒色腫細胞は、原発腫瘍から最初に単離されたものであり、CD44陰性である(Guoら、Cancer Res 1994;54:1561−5)。HepG2ヒト肝細胞癌を、10%ウシ胎仔血清及び50mgml−1ゲンタマイシンを含有しているRPMI1640中で増殖させた。SMMU−1細胞及びM21細胞は、10%ウシ胎仔血清及び50μgml−1ゲンタマイシンを含有しているDMEM中で増殖させた。細胞をトリプシン処理によりプレートから剥離し、10日齢ニワトリ胚のCAM上に100万個の細胞を播いた。腫瘍を、ヒト又はニワトリのいずれか起源の融合タンパク質10μgを含むPBS 100μl、又は媒体単独により2日毎に処理した。7日後、腫瘍を切除し、湿重量を決定した。図4に示されるように、テストされた腫瘍細胞系全ての腫瘍増殖が、有意に阻害された。
1×106個のSMMU−1細胞を、6週齢雌BALB/cABomヌードマウス(M&B)の背部に皮下注射した。翌日、マウスに、体重1kg当たり2.4mgのGST−CD44HABD、GST−CD44HABDR41AR78SY79S又はGST単独を含むPBS 100μlを、腫瘍の近位に皮下注射した。その処理を2日毎に繰り返し、2週間後に動物を屠殺し、腫瘍を解剖し、重量に関して分析し、組織分析用に調製した。CD44HABD又は非HA結合性変異体CD44HABDR41AR78SY79Sによるマウスの皮下処理は、GST処理対照と比較して、腫瘍増殖を有意に低下させた(図5a、c、全ての時点においてP<0.05)。16日目にマウスを屠殺した場合、CD44HABD及びCD44HABDR41AR78SY79Sにより処理されたマウスは、GST処理マウスより平均して45%小さい腫瘍負荷(それぞれ47%及び43%)を有していた(図5b)。
1×106個のBxPC−3(ATCC,Manassas,Virginia)細胞を、6〜8週齢雌BALB/cABomヌードマウス(M&B,Ry,Denmark)の背部に皮下注射した。腫瘍結節が出現した時点で、マウスに、腫瘍の近位に、20μg(BxPC−3)又は50μg(SMMU−1)のGST−CD44HABD、GST−CD44HABDR41AR78SY79S又はGSTを含むPBS 100μlを皮下注射により与え始めた。その処理を2日毎に繰り返し、対照腫瘍の大部分が直径25mmに達した時点で、動物を屠殺した。腫瘍体積を、式(幅2×長さ)×0.52を使用して計算した。実験終了時、腫瘍を解剖し、重量に関して分析し、組織分析用に調製した。BxPC−3細胞は、徐々に増殖する腫瘍を与えた。GSTで処理された対照は、マウスが屠殺された52日目に、0.267±0.042gという平均重量に達した(図6a〜b)。GST−CD44HABD又はGST−CD44HABDR41AR78SY79Sによるマウスの処理は、BxPC−3腫瘍増殖を有意に阻害し、対照と比較してそれぞれ60%(0.108±0.028g)及び70%(0.085±0.017g)平均腫瘍重量を低下させた(P<0.05;n=6)。
細胞周期分析のため、対数増殖期の初代ヒト血管内皮細胞(HUVEC)、ウシ肺動脈内皮(CPAE)細胞、初代ヒト線維芽細胞(NHDF)、MCF−7細胞又はSMMU1細胞を、30μg/ml GST−CD44HABD、GST−CD44HABDR41AR78SY79S、GST又はPBSの存在下で48時間インキュベートした。細胞を30μg/mlブロモデオキシウリジン(BrdU)により60分間パルス処理し、採集し、氷冷エタノールで固定した。次いで、細胞を、1:50希釈の抗BrdU mAb G3G4(Developmental Studies Hybridoma Bank,University of Iowa,Iowa)によりBrdUに関して染色した後、ヨウ化プロピジウムによる染色と平行して、フルオレセインイソチオシアネート結合ヤギ抗マウス抗体(Jackson Immunoresearch,West Grove,Pennsylvania)により染色した。次いで、細胞周期分布を、FACScanフローサイトメーター(Becton Dickinson,Franklin Lakes,New Jersey)により分析した。
内皮細胞増殖の阻害にとって重要なCD44HABD内の領域の分析を開始するため、いくつかのCD44の欠失変異体をPCRを使用して作成した。三重変異体CD44HABDを鋳型として使用した。CD44HABDに特異的なオリゴヌクレオチドを、ベクター特異的なプライマーと共にPCR増幅に使用し、産物をライゲートさせ、CD44HABDのaa21〜60、21〜100又は93〜132をそれぞれ産生するベクターを得た。wt CD44HABD及び3mut CD44HABDの配列が、欠失変異体21〜100、21〜60及び93〜130と共に図8Aに示されており、その配列は、配列番号23(21〜100)、配列番号24(21〜60)及び配列番号25(93〜132)として表に記載されている。内皮細胞増殖の阻害に関与しているCD44HABD中央ドメインの配列は、配列番号26に示されている。全ての組換えタンパク質が、実施例1に記載されたようにして細菌において産生され、精製された。
配列番号15〜18は変異型プライマーの配列である。
配列番号19〜22はRT−PCR−プライマーの配列である。
配列番号23〜25は欠失変型体の配列である。
Claims (21)
- 血管形成及び/又は内皮細胞増殖の阻害と関係がある状態を治療するための医薬品の製造のためのCD44ヒアルロン酸結合ドメイン(CD44−HABD)の非HA結合性バリアント、並びにそれらのアナログ、組換えバリアント及び変異型バリアント又はその断片を含む分子の使用。
- CD44−HABDがそれを非HA結合性にする変異を少なくとも1個含む請求項1に記載の使用。
- (1個以上の)変異がF34A、F34Y、K38R、K38S、R41A、Y42F、Y42S、R46S、E48S、K54S、Q65S、K68S、R78K、R78S、Y79F、Y79S、N100A、N100R、N101S、Y105F、Y105S、S112R、Y114F、F119A及びF119Y、好ましくはR41A、R78S、Y79Sより選択される請求項2に記載の使用。
- CD44ヒアルロン酸結合ドメインは少なくとも55%、より好ましくは少なくとも65%、最も好ましくは少なくとも75%という配列番号:2の配列との相同性を有する請求項1〜3のいずれかに記載の使用。
- 組換えバリアントがCD44−HABD部分とGST部分とを有し、CD44−HABD部分が非HA結合性型である請求項1〜4のいずれかに記載の融合タンパク質の使用。
- CD44ヒアルロン酸結合ドメインの非HA結合性バリアントを含む分子が、ヒトCD44−HABD(配列番号:2)、イヌCD44−HABD(配列番号:4)、ニワトリCD44−HABD(配列番号:6)、ヒトCD44−HABD−R41A(配列番号:8)、ヒトCD44−HABD−R78SY79S(配列番号:10)CD44−HABD−R41AR78SY79S(配列番号:12)、CD44−HABD(21−100)(配列番号:23)及びCD44−HABD(61−100)(配列番号:26)を含む群より選択され、これらの配列がこれらの配列を非HA結合性にする少なくとも1個の修飾をさらに含む請求項1〜5のいずれか一項に記載の使用。
- 分子がヒト、イヌ、ニワトリ、霊長類の動物、ラット又はマウスを起源とする分子である請求項1〜6のいずれか一項に記載の使用。
- 治療される状態が、黄斑変性症、糖尿病性網膜症及び網膜低酸素状態のような失明又は視覚障害を引き起こす眼疾患、慢性関節リウマチのような慢性炎症の状態、乾癬、アテローム性動脈硬化症、再狭窄、並びに癌の増殖及び転移、並びに乳房、前立腺、結腸、肺、皮膚、肝臓、脳、卵巣、精巣、骨格、上皮、内皮、膵臓、腎臓、筋肉、副腎、腸、内分泌腺、口腔、頭部及び頸部、又はその他の固形組織起源の癌、又は任意の型の白血病、及び血管腫のようなあらゆる型の癌疾患及び腫瘍より選択される請求項1〜7のいずれか一項に記載の使用。
- 内皮細胞のターゲティングのためのCD44ヒアルロン酸結合ドメイン並びにそのアナログ、組換えバリアント及び変異型バリアント又は断片を含む分子の使用。
- 分子が化学療法特性及び/又は遺伝子治療特性を示す部分をさらに含む請求項9に記載の使用。
- CD44−HABD部分、GST部分及び/又は化学療法特性を示す部分を含む組換え分子であって、CD44−HABD部分は、F34A、F34Y、K38R、K38S、R41A、Y42F、Y42S、R46S、E48S、K54S、Q65S、K68S、R78K、R78S、Y79F、Y79S、N100A、N100R、N101S、Y105F、Y105S、S112R、Y114F、F119A、F119Y、好ましくはR41A、R78S、Y79Sより選択される変異型のうちの少なくとも1個により変異されている組換え分子。
- CD44−HABD部分が配列番号:2、配列番号:4、配列番号:6、配列番号:8、配列番号:10、配列番号:12、配列番号:23、配列番号:26のアミノ酸配列のうちのいずれか1個の修飾されたバリアントにより規定される請求項11に記載の組換え分子。
- CD44−HABD部分が修飾型であるヌクレオチド配列:配列番号:1、配列番号:3、配列番号:5、配列番号:7、配列番号:9、配列番号:11のうちのいずれかと少なくとも55%の相同性、好ましくは65%の相同性、より好ましくは75%の相同性を有する配列、最も好ましくは修飾型であるヌクレオチド配列:配列番号:1、配列番号:3、配列番号:5、配列番号:7、配列番号:9、配列番号:11のうちのいずれかである配列によりコードされる請求項11又は12に記載の組換え分子。
- 医学的使用のための請求項11〜13のいずれか一項に記載の組換え分子。
- 請求項1〜14のいずれか一項に記載の分子の少なくとも1個を少なくとも1個の薬学的に許容される担体又は賦形剤との混合物として、又はそれらと共に含む薬学的組成物。
- 請求項1〜14のいずれか一項に記載の分子の薬学的な用量を投与することを含む患者における腫瘍又はその他の疾患の治療方法。
- 以下の工程を含む請求項1〜14のいずれか一項に記載の分子の結合パートナーのスクリーニング方法:
a)CD44ヒアルロン酸結合ドメインを含む分子を準備する;
b)可能性のある結合パートナーを前記分子と接触させる;及び
c)前記可能性のある結合パートナーに対する前記分子の効果を決定する。 - 可能性のある結合パートナーがタンパク質、糖タンパク質、プロテオグリカン、ヘパラン硫酸、脂質、グリカン、配糖体及び糖類を含む群より選択される請求項17に記載の方法。
- 可能性のある結合パートナーが受容体分子、受容体分子の一部、細胞表面受容体分子もしくは受容体分子ではない細胞表面に位置する分子と結合する分子である請求項17又は18に記載の方法。
- 請求項17〜19のいずれか一項に記載の方法により見出された請求項1〜14のいずれか一項に記載の分子の結合パートナー。
- 請求項1〜14のいずれか一項に記載の分子と請求項20に記載の可能性のある結合パートナーを別々のバイアルに含む請求項17〜19のいずれか一項に記載の方法を実施するためのキット。
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