JP6283411B2 - Dll4とvegfに特異的に結合する新規二重標的タンパク質とこれの用途 - Google Patents
Dll4とvegfに特異的に結合する新規二重標的タンパク質とこれの用途 Download PDFInfo
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Description
リンカーヌクレオチド(配列番号19):GGTGGAGGTGGCAGCGGTGGTGGCGGCAGTC CCGGTGGCGGCTCC
具体的には、(a)前記形質転換体を培養して、二重標的タンパク質を生産する工程;及び(b)前記(a)工程で生産された二重標的タンパク質を回収する工程を含む、DLL4に特異的に結合するタンパク質及びVEGF(Vascular endothelial growth factor)に特異的に結合する抗体を含む二重標的タンパク質の製造方法であってもよい。
さらに他の態様として、本発明は、前記二重標的タンパク質を含む癌治療用組成物を提供する。
本発明において、用語「薬学的に許容可能な担体」とは、生物体を刺激せずに投与化合物の生物学的活性および特性を阻害しない担体または希釈剤をいう。液状溶液に製剤化される組成物において許容される薬学的担体としては、滅菌および生体に適したものであって、生理食塩水、滅菌水き、リンゲル液、緩衝食塩水、アルブミン注射溶液、デキストロース溶液、マルトデキストリン溶液、グリセロール、エタノール、およびこれらの成分のうち1成分以上を混合して使用することができ、必要に応じて、抗酸化剤、緩衝液、静菌剤などの他の通常の添加剤を添加してもよい。また、希釈剤、分散剤、界面活性剤、結合剤、及び潤滑剤を付加的に添加して水溶液、懸濁液、乳濁液などのような注射用剤形、丸薬、カプセル、顆粒または錠剤に製剤化することができる。
製剤化する場合には、通常用いる充鎮剤、増量剤、結合剤、湿潤剤、崩壊剤、界面活性剤等の希釈剤または賦形剤を用いて調剤される。経口投与のための固形製剤には、錠剤、丸剤、散剤、顆粒剤、カプセル剤などが含まれ、このような固形製剤は、前記化合物に少なくとも一つ以上の賦形剤、例えば、デンプン、カルシウムカーボネート(calcium carbonate)、スクロース(sucrose)またはラクトース(lactose)、ゼラチン等を混ぜて調製される。また、単純な賦形剤以外にマグネシウムステアレート、タルクのような潤滑剤も用いられる。経口のための液状製剤には、懸濁剤、内容液剤、油剤、シロップ剤等が該当し、よく使用される単純希釈剤である水、リキッドパラフィン以外に種々の賦形剤、例えば湿潤剤、甘味制、芳香剤、保存剤等が含まれる。非経口投与のための製剤には滅菌された水溶液、非水性溶剤、懸濁剤、油剤、凍結乾燥製剤、座薬が含まれる。非水性溶剤、懸濁剤としては、プロピレングリコール(propylene glycol)、ポリエチレングリコール、オリーブ油のような植物性油、エチルオレートのような注射可能なエステル等が用いられる。座薬の基剤としては、ウィテプゾール(witepsol)、マクロゴール、ツイン(tween)61、カカオ脂、ラウリン脂、クリセロゼラチン等が用いられる。
前記二重標的タンパク質は、薬学的に許容可能な担体をさらに含む薬学的組成物を癌が発症したか、発症の疑いがある個体に投与する工程を含む癌を治療する方法であってもよく、使用できる担体及び癌は、前述した通りである。前記個体は、牛、豚、羊、鶏、犬、ヒトなどを含む哺乳動物、鳥類などを含んでもよく、本発明の組成物の投与によって癌が治療されている個体は、制限せず含んでもよい。
さらに他の態様として、本発明は、前記二重標的タンパク質を含む癌診断用組成物を提供する。
本発明において、用語「診断」とは、病理状態の存在または特徴を確認することを意味する。本発明の目的上、診断は、癌を発症したか否かを確認することである。
本発明のDLL4、モノクローナル抗体、ベクター、形質転換体等は、前述した通りである。
さらに他の態様として、本発明は、前記二重標的タンパク質を、がんが疑われる個体に投与する工程を含む、癌の治療方法を提供する。
実施例1−1:DLL4抗原の製造
ヒトDLL4の細胞外ドメインの抗原は、アールアンドディシステム社から提供されたヒトDLL4タンパク質(Cat:1506−D4/CF)を使用した。このDLL4抗原タンパク質は、Accession No.Q9NR61のDLL4アミノ酸配列の27番目〜524番目のアミノ酸を含む。前記タンパク質C−末端にヒスチジン−タグ(10−His tag)が結紮されている。
多様性を持つヒト由来scFv(single−chain variable fragment)ライブラリ細胞2.7×1010個を2X YT CM[Tryptone(CONDA,1612.00)17g、イースト抽出物(CONDA,1702.00)10g、NaCl(sigma,S7653−5kg)5g、クロラムフェニコール(sigma,C0857)34μg/mL)]、2%グルコース(sigma,G5400)及び5mM MgCl2(sigma,M2393)を含む培地(3L)で37℃で2〜3時間培養した後(OD600=0.5〜0.7)、ヘルパーファージ(helper phage)を感染させ2X YT CMK(2X YT CM、カナマイシン(sigma,K1876)70μg/mL、1mM IPTG(ELPISBIO,IPTG025))培地に30℃で16時間培養した。培養した細胞を遠心分離(4500rpm、15分、4℃)した後、上澄み液に4%PEG(Fluka,81253)6000と3%NaCl(sigma,S7653)を添加してよく溶かした後、氷で1時間反応させた。再度遠心分離(8000rpm、20分、4℃)した後、ペレットにPBSを添加して溶かした後、遠心分離(12000rpm、10分、4℃)して、ライブラリファージを含む上澄み液を新しいチューブに入れ、4℃で保管した。
ヒトDLL4結合する抗DLL4抗体を選別するために、ヒトDLL4抗原に対するパニングを3回(round)進行した。
前記実施例1−3で作製されたヒトDLL4と結合するscFvの形態の抗体をリンカーを利用して、アバスチンIgG形態と連結して、ヒトVEGFとも結合することができる二重標的タンパク質の発現ベクターを製造した(図1B)。
抗DLL4、抗VEGF二重標的タンパク質に対してELISAベースの溶液発色試験を使用して二重標的タンパク質の結合力を評価した。96ウェルプレート(Nunc−Immuno Plates,NUNC,Rochester,NY)を4℃で一晩50ng/mL濃度のhVEGF(R&D systems,cat:293−VE)と200ng/mL濃度のrhDLL4(R&D systems,cat:1506−D4/CF)でウェル当り100μLずつコーティングした後、非特異的結合部位をBSAで2時間遮断させた。96ウェルマイクロタイタープレート上で抗体を128nMおよび64nMで1/5ずつ希釈を行って、hDLL4及びhVEGFタンパク質でコーティングされたプレートに100μLずつ接種した後、2時間恒温処理して0.05%ツイン20(tween 20)を含むPBSで5回洗浄した。プレートに結合された抗体を検出するためにHRPが接合された抗Fab抗体(Pierce,cat:31414)を1:40000で希釈して洗浄された96ウェルプレートに処理した後、1時間37℃で反応させた後、比色用基質(3,3’,5,5’−Tetramethylbenzidine;Sigma−Aldrich)を使用して発色させ、酵素反応を0.5mol/L硫酸で中止させた。吸光度は、SpectraMax190(molecular Devices)機器を利用して、450nmの波長で測定した。
前記実施例1で分離精製された二重標的タンパク質(二重抗体)をアバスチン−DLL4 BsAbと命名し、分離精製された抗体の抗原に対する親和度を次のように分析した。アバスチン−DLL4 BsAb二重標的抗体のDLL4とVEGFの結合能の差を調べるためにBIACOREアッセイを実施した。
前記アバスチン−DLL4 BsAb二重標的抗体について、ELISA−ベースの溶液競争実験を介して中和効果を評価した。96ウェルマイクロタイタープレート(Nunc−Immuno Plates,NUNC,Rochester,NY)にPBSで希釈された500ng/mL濃度のhNotch−1−hFcタンパク質(R&D systems)をウェル当り100μLずつ添加した後、4℃で一晩コーティングした後、BSAで2時間処理して、非特異的結合部位を遮断させた。
複数の不連続的な配列で構成された、しかし立体構造的に単一である分子表面を形成する構造的エピトープを究明するために、架橋反応と質量分析による架橋化反応の位置を確認するための手法を使用した。
抗原タンパク質ヒトデルタ様リガンド4(human DLL4,hDLL4,R&D Systems)と実施例1−3のMLCK2抗体をモル比が2:1となるように混合した後、K200クロスリンカー(CovalXAG.)を終濃度0.2mg/mLとなるように入れた。この混合物を室温で3時間反応させて抗原−抗体複合体を作製した後、Ultraflex II MALDI ToF(Bruker Daltonics)装置を利用して反応生成物の分子量を分析した。図6に示すように、クロスリンカーを使用しない対照実験に比べてクロスリンカーを使用した場合、ヒトDLL4とMLCK2抗体との間の1:1及び2:1複合体が形成されたことが分かった。一方、ヒトDLL4もしくはMLCK2抗体単独でクロスリンカーと反応させた場合には、いかなる多量体や複合体も検出されなく、このことから、前記ヒトDLL4及びMLCK2抗体複合体の形成が相互特異的な反応であることを知ることができた。
架橋されたペプチド切片を区分するために、重水素で標識されていないd0−DSS(disuccinimidyl suberate)と12個の重水素で標識されたd12−DSSを1:1で混合して、DMFで溶かして、2mg/mL溶液を作った。この溶液を、ヒトDLL4:MLCK2=2:1混合溶液に終濃度0.2mg/mLになるように入れて、常温で3時間架橋化反応をさせた。反応物は、効果的な分解反応のためにDTT(dithiothreitol)とヨードアセトアミド(iodoacetamide)を利用して、還元およびアルキル化をさせて変性させて、トリプシン、アルファ−キモトリプシン、ASP−Nプロテアーゼなどのタンパク質加水分解酵素をそれぞれ使用して断片化をさせた。生成された断片化反応物は、Ultimate 3000 nano−liquidクロマトグラフィシステム(Dionex)とLTQ Orbitrap XL質量分析器(Thermo)で質量分析して、得られた質量分析データは、Xquest(バージョン2.0)ソフト、Stavrox(バージョン2.1)ソフトを用いて架橋化されたペプチドの対を分別した。その結果、表5に示されたように、hDLL4とMLCK2との間の架橋化されたペプチドの対を検出することができた。
ヒトDLL4のアラニン置換突然変異体のパネルを、以下のように製造したが、これらのパネルでは、ヒトDLL4細胞外タンパク質の領域の64番(Histidine、ヒスチジン)、65番(phenylalanine、フェニルアラニン)、および69番(Valine、バリン)アミノ酸をそれぞれのアミノ酸をアラニン(Alanine)で置換した。アラニン置換突然変異体のための発現ベクターは、前記実施例1−1に示すようにDLL4細胞外ドメインの特定領域に対する抗原の製造に使用したベクターを利用した。具体的に、前記ベクターは、ヒトDLL4特定領域のアミノ酸27〜アミノ酸251の遺伝子を含むベクターであり、この領域は、Notch1受容体と結合すると知られている「DSL(デルタ/セレート(Serrate)/lag−2)」ドメインと称されるモチーフを含有する。
DLL4とVEGFに結合する二重抗体の血管内皮細胞(HUVEC)の増殖に対する影響を分析するために、血管内皮細胞(HUVEC,Human umbilical vein endothelial cell)をLonza社から購入して実験に使用した。
DLL4とVEGFに結合する二重抗体のDLL4/NotchおよびVEGF/VEGFRシグナル伝達経路抑制活性を調べるために、実施例4と同様の方法でHUVECを利用した。実験前日6ウェルプレート(BD)に組換えヒトDLL4(rhDLL4,recombinant human DLL4,R&D systems)を1mg/mLでCarbonate緩衝溶液を使用して希釈させた後、1mL/ウェルで添加した後、4℃で一夜静置させた。rhDLL4を処理しない対照実験群では、Carbonate緩衝溶液単独で1mL/ウェルで処理して同様に4℃で一夜静置させた。翌日、4℃の冷蔵庫からDLL4がコーティングされたプレートを取り出し、PBSで1回洗浄した後、EGM−2培地を各ウェルに1mLずつ処理して、各ウェル毎に抗体(アバスチン:20mg/mL、DBZ:0.08mM、DLL4単独抗体:20mg/mL、Oncomed社DLL4単独抗体:20mg/mL、アバスチン−DLL4 BsAb二重抗体:26mg/mL)を処理した。最終培養液の量は2mLであるため、抗体処理を2倍にして、常温で20分間静置した。抗体処理時間の間パッセージ#2〜#5(passage#2〜#5)の75Tプレートで培養されたHUVECを取り出して培地除去後、単一細胞化させた。遠心分離過程を介して細胞を洗浄し、新鮮なEGM−2培地を使用して再浮遊させて、細胞の数をカウントして5×105cells/mLに希釈した後、それぞれのウェルに1mLずつ接種して、37℃、5%CO2インキュベーターで一日中培養した。0.2%FBSが含まれたEBM−2最小培地を準備して、一日中培養されたHUVECの各ウェルから培地を除去して、PBS1回洗浄した後、0.2%FBSが含まれたEBM−2最小培地を2mL処理した。また、それぞれのウェルに前日処理した同じ濃度の抗体(アバスチン:20mg/mL、DBZ:0.08mM、DLL4単独抗体:20mg/mL、Oncomed社DLL4単独抗体:20mg/mL、アバスチン−DLL4 BsAb二重抗体:26mg/mL)を処理し、37℃、5%CO2インキュベーターで一日中培養した。抗体が処理されたHUVECの各ウェルにhVEGF(R&D systems)を100ng/mLで処理して、37℃、5%CO2インキュベーターで5分間反応させた後、プレートを取り出して、直ちに培地を捨て、PBSで1回洗浄した後、細胞溶解緩衝液(1%NP−40,20mM Tris,137mM NaCl,10%Glycerol,2mM EDTA,1mM Sodium orthovanabate,1x Protease & phosphatase inhibitor coctail)を準備し、それぞれのウェルに150mLを添加した後、満遍なく広がるように振った。
報告された文献によると、SCHヒト胃がん細胞株(human gastric cancer)は、アバスチンの耐性を持っていると開示されており、SCH細胞株を用いたヌードマウス異種移植モデル(nude mouse xenograft model)で二重抗体の抗癌効能試験を行った。
A549細胞株をヌードマウスに接種した後、アバスチン(2.5mg/kg/week)を3ヶ月間処理してアバスチン処理後にも腫瘍の大きさが減らず、腫瘍が成長するアバスチン投与に耐性を持ったA549癌細胞を確保した。この腫瘍を剥ぎ取った後、アバスチン耐性A549細胞をEx−vivo培養を行って、二重ターゲット抗体の効能分析のために使用した。
図12に示すように、アバスチンに対して耐性を有する肺癌細胞株に対して、本発明の二重標的タンパク質が抗癌効果を著しく増加させることをin vivo実験で確認した。
Claims (19)
- 配列番号21で表されるDLL4タンパク質のアミノ酸配列で58番〜65番のアミノ酸配列、及び110番〜115番のアミノ酸配列を含むDLL4の立体構造エピトープを認知する、DLL4に特異的に結合するタンパク質、並びにVEGFに特異的に結合する抗体を含む、二重標的タンパク質であって、
前記DLL4に特異的に結合するタンパク質は、配列番号2で表される重鎖CDR1;配列番号3で表される重鎖CDR2;及び配列番号4で表される重鎖CDR3を含む重鎖可変領域、並びに配列番号5で表される軽鎖CDR1;配列番号6で表される軽鎖CDR2;及び配列番号7で表される軽鎖CDR3を含む軽鎖可変領域を含む、前記二重標的タンパク質。 - 前記二重標的タンパク質は、DLL4に特異的に結合するタンパク質及びVEGFに特異的に結合するIgG形態の抗体が、リンカーで連結された形態であることを特徴とする請求項1に記載の二重標的タンパク質。
- 前記リンカーは、非ペプチドリンカーまたはペプチドリンカーであることを特徴とする請求項2に記載の二重標的タンパク質。
- 前記ペプチドリンカーは、配列番号18で表されるペプチドであることを特徴とする請求項3に記載の二重標的タンパク質。
- 前記DLL4に特異的に結合するタンパク質は、配列番号8で表される重鎖アミノ酸配列及び配列番号9で表される軽鎖アミノ酸配列を含むことを特徴とする請求項1に記載の二重標的タンパク質。
- 前記VEGFに特異的に結合する抗体は、配列番号10で表される重鎖CDR1;配列番号11で表される重鎖CDR2;及び配列番号12で表される重鎖CDR3を含む重鎖可変領域、並びに配列番号13で表される軽鎖CDR1;配列番号14で表される軽鎖CDR2;及び配列番号15で表される軽鎖CDR3を含む軽鎖可変領域を含むことを特徴とする請求項1に記載の二重標的タンパク質。
- 前記VEGFに特異的に結合する抗体は、配列番号16で表される重鎖アミノ酸配列及び配列番号17で表される軽鎖アミノ酸配列を含むことを特徴とする請求項1に記載の二重標的タンパク質。
- 前記VEGFに特異的に結合する抗体は、ベバシズマブであることを特徴とする請求項7に記載の二重標的タンパク質。
- 配列番号1で表される重鎖アミノ酸配列および配列番号20で表される軽鎖アミノ酸配列を含むことを特徴とする請求項1に記載の二重標的タンパク質。
- 前記DLL4に特異的に結合するタンパク質は、全長抗体、Fab’、F(ab’)2、Fab、Fv、rIgGまたはscFv形態であることを特徴とする請求項1に記載の二重標的タンパク質。
- 請求項1から請求項10のいずれかに記載の二重標的タンパク質をコードするポリヌクレオチド。
- 請求項11に記載のポリヌクレオチドを含む発現ベクター。
- 請求項12に記載の発現ベクターが導入された形質転換体。
- (a)請求項13に記載の形質転換体を培養して、二重標的タンパク質を生産する工程;及び
(b)前記(a)工程で生産された二重標的タンパク質を回収する工程を含む、DLL4に特異的に結合するタンパク質及びVEGFに特異的に結合する抗体を含む二重標的タンパク質の製造方法。 - 請求項1から請求項10のいずれかに記載の二重標的タンパク質を含む組成物。
- 請求項1から請求項10のいずれかに記載の二重標的タンパク質を含む癌治療用薬学組成物。
- 前記癌は、食道癌、胃癌、大腸癌、直膓癌、口腔癌、咽頭癌、喉頭癌、肺癌、結腸癌、乳癌、子宮頸部癌、子宮内膜癌、卵巣癌、前立腺癌、睾丸癌、膀胱癌、腎臓癌、肝臓癌、膵臓癌、骨癌、結合組織癌、皮膚癌、脳腫瘍、甲状腺癌、白血病、ホジキン病、リンパ腫及び多発性骨髄血液癌よりなる群から選ばれることを特徴とする請求項16に記載の組成物。
- 請求項1から請求項10のいずれかに記載の二重標的タンパク質を含む、癌診断用組成物。
- 癌の治療用医薬の製造における、請求項1から請求項10のいずれかに記載の二重標的タンパク質の使用。
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- 2014-07-08 WO PCT/KR2014/006090 patent/WO2015005632A1/ko active Application Filing
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CA2917402C (en) | 2019-10-22 |
KR101673389B1 (ko) | 2016-11-08 |
EP3020731A1 (en) | 2016-05-18 |
KR20150007241A (ko) | 2015-01-20 |
US10184010B2 (en) | 2019-01-22 |
JP2016531097A (ja) | 2016-10-06 |
AU2014287984A1 (en) | 2016-02-04 |
ES2742855T3 (es) | 2020-02-17 |
CA2917402A1 (en) | 2015-01-15 |
TR201910592T4 (tr) | 2019-08-21 |
EP3020731B1 (en) | 2019-06-12 |
RU2648154C2 (ru) | 2018-03-22 |
PL3020731T3 (pl) | 2019-11-29 |
WO2015005632A1 (ko) | 2015-01-15 |
RU2016104057A (ru) | 2017-08-15 |
CN105518028A (zh) | 2016-04-20 |
CN105518028B (zh) | 2019-08-13 |
US20160159929A1 (en) | 2016-06-09 |
AU2014287984B2 (en) | 2016-09-22 |
EP3020731A4 (en) | 2017-02-22 |
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