JP5143566B2 - 癌特異的抗体および細胞表面タンパク質 - Google Patents
癌特異的抗体および細胞表面タンパク質 Download PDFInfo
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Description
本発明は、ヒト癌特異的結合タンパク質およびその全ての使用に関する。特に、本発明は、癌細胞上の抗原または分子に特異的な抗体または抗体断片に関し、ならびに本発明の結合タンパク質を含む免疫抱合体、およびその使用の方法に関する。本発明はまた、新規の癌関連抗原およびその使用に関する。
2000年に、世界中で推定2,200万人が癌を患い、かつ620万人の死亡がこの部類の疾患に原因があるとされた。毎年、1,000万を越える新しい症例があり、およびこの推定値は次の15年で50%増加すると予想されている(WHO, World Cancer Report. Bernard W. Stewart and Paul Kleihues, 編, IARC Press, Lyon, 2003(非特許文献1))。現在の癌治療は、侵襲的手術法、放射線療法、および化学療法に限られ、その全てが、潜在的に重篤な副作用、非特異的な毒性、ならびに/または人の身体像および/もしくは生活の質に対して精神的外傷を与える変化のいずれかを引き起こす。癌は、化学療法に対して不応性になる可能性があり、さらなる治療の選択肢および成功の可能性を減少させている。ある癌の予後が、その他の癌の予後よりも悪く、および中にはほぼ必ず致命的なものもある。さらに、比較的高い治療成功率のある癌の中には、その高い発生率が原因で依然として主要な死因のままであるものもある。
本発明者らは、乳癌、卵巣癌、前立腺癌、メラノーマ、肝臓癌、大腸癌、頸癌、頭頸部癌、膀胱癌、胃癌、膵臓癌および子宮内膜癌を含む、数種類の癌細胞に結合するヒト癌特異的抗体を調製した。重要なことに、本抗体は正常組織には有意に結合せず、そのことがそれらを癌治療および癌診断用の好適な候補にしている。
をそれぞれ含む、単離された軽鎖相補性決定領域1、2、および/または3;ならびにアミノ酸配列
をそれぞれ含む、単離された重鎖相補性決定領域1、2、および3を提供する。
をそれぞれ含む、軽鎖相補性決定領域1、2、および/または3をコードする単離された核酸配列;ならびにアミノ酸配列
をそれぞれ含む、重鎖相補性決定領域1、2、および/または3をコードする単離された核酸配列を提供する。
(1)対象から採取した被験試料を、本発明の結合タンパク質で、かつ癌細胞上の抗原に特異的に結合するタンパク質と接触させ、結合タンパク質‐抗原複合体を生成する工程;
(2)被験試料中の結合タンパク質‐抗原複合体の量を測定する工程;および
(3)被験試料中の結合タンパク質‐抗原複合体の量を対照と比較する工程。
(A)定義
本明細書において使用する場合、「全身に投与される」という用語は、免疫抱合体および/またはその他の癌治療薬剤が、注射(皮下、静脈内、筋肉内など)、経口投与、吸入、(局所クリームもしくは軟膏などのような)経皮投与もしくは局所適用、坐薬の適用、またはインプラントの手段によるなどの簡便な方法で、全身に投与されてもよいということを意味する。インプラントは、シアラスティック(sialastic)膜などの膜、または繊維を含む、多孔性物質、非多孔性物質、またはゼラチン様物質であることができる。坐薬は通常、0.5重量%〜10重量%の範囲の活性成分を含む。
(i)軽鎖相補性決定領域および重鎖相補性決定領域ならびに軽鎖可変領域および重鎖可変領域
本発明は、アミノ酸配列RASQDISNYLA(SEQ ID NO:1)を含む単離された軽鎖相補性決定領域1を提供する。本発明はまた、アミノ酸配列AASSLHS(SEQ ID NO:2)を含む単離された軽鎖相補性決定領域2を提供する。さらに、本発明は、アミノ酸配列LQYSTYPIT(SEQ ID NO:3)を含む単離された軽鎖相補性決定領域3を提供する。
をそれぞれ含む軽鎖相補性決定領域1、2、および/または3をコードする単離された核酸配列;ならびに、アミノ酸配列
をそれぞれ含む重鎖相補性決定領域1、2、および/または3をコードする単離された核酸配列を提供する。本発明はまた、図1で示した軽鎖可変領域をコードする単離された核酸配列(SEQ ID NO:7)、および図2で示した重鎖可変領域をコードする単離された核酸配列(SEQ ID NO:9)を提供する。
本発明の別の局面は、少なくとも1つの本発明の軽鎖相補性決定領域(すなわち、SEQ ID NO:1〜3のうちの1つもしくは複数)および/または少なくとも1つの本発明の重鎖相補性決定領域(すなわち、SEQ ID NO:4〜6のうちの1つもしくは複数)を含む、結合タンパク質、好ましくは抗体または抗体断片である。そのような結合タンパク質を通常、本明細書において、「本発明の結合タンパク質」、または好ましくは「本発明の抗体もしくは抗体断片」と称することができる。
をそれぞれ含む軽鎖相補性決定領域1、2、および3;ならびに、アミノ酸配列
をそれぞれ含む重鎖相補性決定領域1、2、および3を含む。本発明はまた、図1に示した軽鎖可変領域(SEQ ID NO:7)および/または図2に示した重鎖可変領域(SEQ ID NO:9)を含む結合タンパク質、好ましくは抗体または抗体断片を提供する。
PI=[(MF(Ab1+Ab2)−MFBgd)/(MFAb1−MFBgd)]×100
式中、PI=阻害率;MF(Ab1+Ab2)=Ab1+Ab2混合物について測定した蛍光中央値;およびMFBgd=PBS-5%FCSでのバックグラウンド蛍光中央値である。
(1)一定数の癌細胞に対して最大結合を生む最低濃度の本発明の結合タンパク質、好ましくは抗体または抗体断片(Ab1)と一定数の癌細胞をインキュベートし、かつAb1の蛍光中央値(MFAb1)を測定する工程;
(2)Ab1および癌細胞にAb2を加えることによって、2つまたはそれより多くの濃度の被験結合タンパク質(Ab2)を試験し、かつ蛍光中央値(MF(Ab1+Ab2))を測定する工程;
(3)バックグラウンド蛍光中央値(MFbgd)を測定する工程;
(4)PI=[(MF(Ab1+Ab2)−MFBgd)/(MFAb1−MFBgd)]×100である、PIを計算する工程;ならびに
(5)このPIと対照PI値を比較する工程、
ここで、対照PIとの統計的に有意な差を有するPIにより、被験結合タンパク質が癌細胞上の抗原に結合する能力があることが示される。
上記のように、本発明者らは、本発明の結合タンパク質が結合する抗原を同定した。新規の癌関連抗原は癌細胞の表面上に発現し、かつ正常細胞の表面上にはそれほど多くは発現しない。したがって、本発明は、本発明の結合タンパク質の1つと特異的に結合することができる単離されたタンパク質、ならびにその核酸配列および使用を含む。
本発明はまた、(2)エフェクター分子に連結された(1)本発明の結合タンパク質、好ましくは抗体または抗体断片を含む免疫抱合体を含む。ある態様において、本発明の結合タンパク質は癌細胞上の抗原または分子に結合する。
当業者は、軽鎖相補性決定領域および重鎖相補性決定領域、軽鎖可変領域および重鎖可変領域、抗体および抗体断片、本発明の免疫抱合体および新規の癌関連抗原などの、本発明のタンパク質を、幾つかの方法のうちの任意の方法で調製してもよいが、最も好ましくは組換え法を用いて調製するということを正しく理解すると考えられる。
本発明者らは、本発明の結合タンパク質が、グルコース輸送体8もしくはその変異体;SEQ ID NO:11〜20、好ましくは11、12、もしくは13によって定義されるアミノ酸配列の任意の1つを含むタンパク質;またはグルコース輸送体8の癌関連変異体に結合することを示した。本発明のある態様において、GLUT8の癌関連変異体は、SEQ ID NO:11、12、もしくは13の任意の1つによって定義されるアミノ酸配列、またはその変異体を含む。本発明の別の態様において、GLUT8の癌関連変異体は、N末端のジロイシンモチーフに改変を有するGLUT8を含む。本発明のさらなる態様において、N末端のジロイシンモチーフをジアラニンに改変する。
本発明の結合タンパク質は、癌細胞または癌細胞によって内在化された分子に選択的に結合し、かつ正常細胞にはそれほど結合しない。したがって、癌の診断において結合タンパク質を使用することができる。上記のように、本発明者らは、本発明の結合タンパク質がグルコース輸送体8もしくはその変異体;SEQ ID NO:11〜20によって定義されるアミノ酸配列の任意の1つを含むタンパク質;またはグルコース輸送体8の癌関連変異体に結合することを示した。本発明のある態様において、GLUT8の癌関連変異体は、SEQ ID NO:11、12、もしくは13の任意の1つによって定義されるアミノ酸配列、またはその変異体を含む。本発明の別の態様において、GLUT8の癌関連変異体は、N末端のジロイシンモチーフに改変を有するGLUT8を含む。本発明のさらなる態様において、N末端のジロイシンモチーフをジアラニンに改変する。
(1)対象から採取した被験試料を、本発明の結合タンパク質で、かつ癌細胞上の抗原に特異的に結合する結合タンパク質と接触させ、結合タンパク質‐抗原複合体を生成する工程;
(2)被験試料中の結合タンパク質‐抗原複合体の量を測定する工程;および
(3)被験試料中の結合タンパク質‐抗原複合体の量を対照と比較する工程。
(1)対象から採取した被験試料中の本発明の抗体の量を測定する工程;および
(2)被験試料中の本発明の抗体の量を対照と比較する工程。
本発明は、癌細胞の表面上に発現し、かつ正常細胞の表面上にはそれほど発現しない新規の癌関連抗原を提供する。したがって、インビボでの免疫反応を誘発するために新規の癌関連高原またはその断片を使用することを含む、癌を治療または抑制するための療法において新規の癌関連抗原を使用することができる。さらに、本発明は、癌を検出またはモニターするためにGLUT8の新規の癌関連変異体を使用することを含む。
本発明のある態様は、好適な希釈剤または担体との混合物中の有効量のGLUT8の新規の癌関連変異体またはその断片を含む薬学的組成物である。本発明の別の態様は、好適な希釈剤または担体との混合物中のGLUT8の新規の癌関連変異体またはその断片をコードする有効量の単離された核酸を含む薬学的組成物である。本発明のさらなる局面は、好適な希釈剤または担体との混合物中のGLUT8の新規の癌関連変異体またはその断片をコードする核酸配列を含む有効量の組換え発現を含む薬学的組成物である。
上記のように、GLUT8の新規の癌関連変異体は癌細胞上には存在するが、正常細胞上にはそれほど存在しない。したがって、癌を抑制または治療するための治療法において、新規の癌関連抗原を使用することができる。さらに、対象における免疫反応を誘発するために、例えばワクチンとして、新規の癌関連抗原を使用することができる。
GLUT8の新規の癌関連変異体は癌細胞上に発現し、かつ正常細胞上にはそれほど発現せず、それゆえに、GLUT8の新規の癌関連変異体を癌の診断法として使用することができる。好ましい態様において、GLUT8の癌関連変異体は、SEQ ID NO:11、12、もしくは13の任意の1つによって定義されるアミノ酸配列、またはその変異体を含む。本発明の別の態様において、GLUT8の癌関連変異体は、N末端のジロイシンモチーフに改変を有するGLUT8を含む。本発明のさらなる態様において、N末端のジロイシンモチーフをジアラニンに改変する。
グルコース輸送体8は、糖輸送活性を有することが示されている。したがって、本発明は、癌細胞上または癌細胞内のグルコース輸送体8の癌関連変異体の活性を調節することによって、対象における癌を治療または抑制する方法を含む。
(a)グルコース輸送体8の癌関連変異体を発現する細胞を被験化合物と接触させる工程;および
(b)グルコース輸送体8の癌関連変異体の発現または機能を明らかにする工程;
(c)対照と比較したグルコース輸送体8の癌関連変異体の発現または機能の低下が、癌を抑制または治療するために有用な化合物であることを示す、グルコース輸送体8の癌関連変異体の発現または機能を対照と比較する工程。
実施例1:VB1-050モノクローナル抗体の作製
プールした癌患者試料の白血球からVB1-050モノクローナル抗体を作製した。モノクローナル抗体を作製するための融合相手としてSHFP-1を使用した。VB1-050はIgG1、κモノクローナル抗体である。
ハイブリドーマ細胞からメッセンジャーRNA(mRNA)を単離し、および第1鎖相補DNA(cDNA)を合成した。その後、cDNAを使用し、PCRによって抗体H鎖遺伝子および抗体L鎖遺伝子を単離した。H(γ)鎖アイソタイプおよびL(κ)鎖アイソタイプのコンセンサスフレームワーク領域に従って、PCRプライマーを設計した(注を参照)。PCR産物は個々にTOPO-pCR2.1ベクターにクローン化し、および大腸菌細胞内に形質転換した。TOPO-pCR2.1中にインサートを含む個々のクローンを単離し、および増殖させた。プラスミドDNAを精製し、およびシークエンシングした。
10×PCR緩衝剤 5μL
2mM dNTPs 5μL
50mM MgCl2 2μL
5'プライマー 20pmoL
3'プライマー 20pmoL
Taq DNAポリメラーゼ 2.5U
DNA鋳型 50ng
腫瘍細胞反応性および正常細胞反応性について、VB1-050をフローサイトメトリーで試験した。15の異なる種類の上皮癌を表す1つの腫瘍細胞株のパネルをスクリーニングした。VB1-050の結果を表2にまとめる。VB1-050は、全ての適応症について、>2.0というMF値を有したものの、最も強い反応性は、これらに限定されるわけではないが、乳癌細胞株、メラノーマ細胞株、および卵巣癌細胞株で観察された。比較すると、正常組織細胞株との反応性は、通常、癌細胞株で見られる反応性よりも低かった。乳癌細胞株および前立腺癌細胞株の場合、VB1-050の発現は、平均して癌細胞株上で>9倍であった。2つの例外は腎臓細胞株および肺細胞株であった;しかしながら、それらは対応する腫瘍細胞型よりもずっと低かった。MF値は、各々の適応症における全ての細胞株からの対照抗体に対する蛍光中央値の平均増加倍数の合計から計算された平均を示す。0値は、対照抗体と比較して、測定可能な反応性がないことを示す。
膜染色を示し、かつ染色用の最適な条件を明確にするための適切な組織フォーマットを評価するために、まず、フロー陽性の腫瘍細胞株SKBR-3に対してVB1-050を試験した。VB1-050は、全ての実験群において、強い核および/または核膜染色を示した。注目すべきことに、サイトスピンスライドは、約30%の無傷細胞で、細胞膜上における点状染色を示した。凍結切片上で、細胞質における染色(細胞の10%)の他、核/核膜染色(細胞の60%)に加え、同様の細胞膜染色が検出された(細胞の10%)。固定した細胞ペレットについて、本抗体は、核および核膜(細胞の70%)、ならびに細胞質(細胞の10%)を染色したが、非常に稀にしか細胞膜を染めなかった(細胞の3〜5%)。(サイトスピンスライド上の固定細胞の染色によって証明されているように)固定は抗原に影響を及ぼさないので、固定した細胞ペレットにおける細胞膜染色の明らかな損失は、凍結細胞と比べて、これらの細胞がより少ない膜の表面領域を有することによる可能性がある。凍結細胞で見られるより大きい膜領域は、もともと、凍結細胞を用いたより厚い切片のみならず、細胞質の萎縮の結果でもある。あるいは、固定後の処置(包埋など)によって、表面抗原が変化した可能性がある。
クリティカルおよび非クリティカル正常組織スクリーニングとは対照的に、細胞膜反応性が、全てではないが、幾つかの腫瘍組織で観察された。VB1-050は、大腸、前立腺、胃、卵巣、および肝臓の癌で、より頻繁に検出された。最も強い染色(2+)が、胃の腫瘍で一貫して検出された。通常、膜染色がある細胞の割合は、適応症および各々の適応症の範囲内の組織試料により変化した;しかしながら、大腸の腫瘍は、最も高い割合の細胞が染色されていることを実際に示した。表5を参照されたい。肺癌、直腸癌、皮膚癌、および子宮癌由来の組織標本では染色が検出されなかった。
VB1-050ならびに腫瘍細胞株A-375に対する強い反応性を示す2つの対照抗体(5E9およびMA-103)を用いて、VB1-050の内在化を評価した。代表的な実験を表6に示す。異なる温度でのVB1-050結合の結果は、内在化する抗体5E9と異ならなかった。37℃で60分後、膜に結合したVB1-050は細胞表面から消失し、蛍光中央値が61.8%減少していた。37℃でのインキュベーション時間の増加は、蛍光中央値のさらなる低下を伴ったが、より低い速度であった。120分までに、蛍光中央値は69.6%減少していた。細胞表面結合を示すフローヒストグラムを図3に例示する。
抗体-抗原複合体の形成に影響を及ぼす最も重要な要因は、その抗原に対する抗体の親和性である。この結合親和性は、これらの反応物の不変の特性であり、および会合/解離またはKA/KDの比率として測定される平衡定数(K)として表現される。所与の抗体について、観察される親和性の違いは、会合(KA)よりもむしろ解離(KD)に関連し、したがってVB1-050の親和性の尺度として、KDを選んだ。
1)VB6-050の人工的作製
PelB-VH845-CH-F-デ-ブーガニン/pSV73プラスミドのEcoRIおよびPvuIIによる消化から得られた、PelB-VH-PvuIIインサートを、同じ酵素で予め消化した(シグナルペプチド配列のないPelBリーダー、PelB(-S)を含む封入発現用に以前に人工的に作製された)PelB(-S)-VH050-CH-F-デ-ブーガニン/psV73ベクターにライゲートした。10Fコンピテント細胞をライゲーション反応物で形質転換し、およびアンピシリンプレート上で選択した。制限部位のマッピングによるコロニーのスクリーニングにより、どのクローンがPelB-VH050-CH-F-デ-ブーガニンインサートを含むのかを明らかにした。
VB6-050を含む形質転換したE104細胞を、37℃で30mLのTB培地(1%接種)を含む250mL振盪フラスコ中で増殖させ、および光学密度(O.D. 600nm)が2に達するまで、約5時間、225rpmで振盪した。この時、培養を最終濃度0.1%のL-(+)アラビノースで誘導し、および25℃で16時間インキュベートした。次に、14000rpmで5分間の遠心分離によって、上清を回収し、ならびに免疫毒素の存在および大きさを確認するために、非還元条件下で、抗λ軽鎖または抗ヒトκ軽鎖のいずれかを用いたウェスタンブロットによって解析した。
MCBを作製するために、25μg/mLのテトラサイクリンを含むLB寒天プレート由来の1個のコロニーを用いて、25μg/mLのテトラサイクリンを加えた5mLの2×YTに接種し、および37℃で絶えず振盪しながらインキュベートした。OD600が〜2に達した時、25μg/mLのテトラサイクリンを含む50mLの2×YT培地を含む250mL振盪フラスコに、1.25mLの種培養を接種し、および37℃でインキュベートした。OD600が1〜1.5に達した時、25mLの30%グリセロールを培養中に混合した。1.5mLのアリコートをクライオチューブに収納し、および−80℃で保存した。先に記載したように、発現について、3つの独立したバイアルを試験した。
TB培地を用いて、15LのCHEMAP発酵槽で、VB6-050のフェドバッチ発酵を行なった。OD600 20(ログ中期)で、飼料(50%グリセロール)および誘導剤(200g L-アラビノース)の混合物で培養を誘導した。誘導後30時間で、培養を採取し、および8000rpmで30分間、遠心分離し、その後、CM-セファロースカラムおよびキレート-セファロースカラム、続いてサイズ排除カラムを用いて精製した。簡潔に述べると、上清を、20mMリン酸ナトリウム pH 6.9±0.1で濃縮および透析濾過した。その後、透析濾過し、濃縮した上清を、20mM リン酸ナトリウム、25mM NaCl pH 6.9±0.1で平衡化したCM-セファロースカラム上に注いだ。カラムを、20mM リン酸ナトリウム、25mM NaCl pH 6.9±0.1で洗浄した。次に、結合したVB6 Fab-デ-ブーガニン融合体を、20mM リン酸ナトリウム、150mM NaCl pH7.5±0.1で溶出した。CM-セファロース溶出物を、最終濃度0.25% triton-X100にまで調整し、および荷電したキレートセファロースカラムに注いだ。その後、キレートセファロースカラムを、20mM リン酸ナトリウム、150mM NaCl、0.25% triton-X100 pH7.5±0.1で始まり、次に20mM リン酸ナトリウム、150mM NaCl pH7.5±0.1、次に20mM リン酸ナトリウム、150mM NaCl、10mm イミダゾールpH7.5±0.1という3つの異なる洗浄緩衝液で洗浄した。結合したVB6 Fab-デ-ブーガニン融合体を、20mM リン酸ナトリウム、150mM NaCl、250mM イミダゾールpH7.5±0.1で溶出し、および2mL分画ごとに回収した。各々の分画についてA280nmにおける吸収を決定し、および物質を含む分画をプールし、ならびに〜80%の純度を得るために、サイズ排除カラムS200上に注いだ。処置の各工程での試料を、抗κ抗体を用いたウェスタンブロットによって解析した。サイズ排除カラム後の純度を、コロイダルブルー染色によって確認した。
ヒトメラノーマA-375細胞株、ヒトT細胞Daudi細胞株、ヒト卵巣SK-OV-3細胞株、ヒト膵臓Panc-1細胞株、ヒト乳房SKBR-3細胞株およびMB-435S細胞株、ならびにヒト大腸Colo-320細胞株を、ATCCのプロトコル通りに、それらのそれぞれの培地中で増殖させた。90%を越える生存率で、30〜40%コンフルエンシーの時に、細胞を採取した。
フローサイトメトリーを用いて、抗原陽性細胞株、SKBR-3、A-375、およびSK-OV-3、ならびに抗原陰性細胞株、Panc-1、Colo-320、およびDaudiをそれぞれ使用して、精製したVB6-050が結合特性を保持することを示した。抗デ-ブーガニン抗体を用いて、結合を検出した。簡潔に述べると、試験すべき構築物を、氷上で1.5時間、0.45×106個の腫瘍細胞とインキュベートした。洗浄後、細胞表面に結合した反応性を、氷上で1時間、ウサギ抗デ-ブーガニン(1/100)で検出した。細胞を洗浄し、および氷上で30分間、FITCがコンジュゲートした抗ウサギIgGとインキュベートした。その後、細胞を洗浄し、フローサイトメトリーによるFab結合の評価のために、ヨウ化プロピジウムを含むPBS 5%FCSで再懸濁した。
抗原陽性細胞を10〜750μg/mLの範囲にまで濃度を増加させたVB6-050とインキュベートすることにより、飽和曲線を作成した。先に記載したように、フローサイトメトリーによって、結合したFab-デ-ブーガニンを検出した。その後、飽和点に対応する濃度のFab-デ-ブーガニンを、濃度を増加させたもとのIgG抗体の存在下で、抗原陽性細胞とインキュベートした。結合したFab-デ-ブーガニンの減少を、フローサイトメトリーによって測定した。4B5 IgGを陰性対照として使用した。
MTSアッセイによって、VB6-050の細胞毒性を測定した。簡潔に述べると、抗原陽性細胞および抗原陰性細胞を、ウェル当たり1000細胞で播き、および37℃で3時間、インキュベートした。その後、様々な濃度のVB6-050およびデ-ブーガニンを細胞に添加し、5日後に、細胞の生存率を決定した。
1)pING3302発現ベクター中のVB6-050の人工的作製および小規模発現
Fab-デ-ブーガニンタンパク質を産生する最初の試みとして、ベクターを、デ-ブーガニンに融合したFd部分および軽鎖という、2つの別々の構築物として人工的に作製した。PelBリーダー配列中のペプチドシグナル、PelB(-S)の欠失により、各々の鎖の発現を封入体の中へと導いた。しかしながら、Fd-デ-ブーガニンタンパク質の封入体中への発現の欠如およびVB6-845の可溶性発現の成功によって、VB6-050可溶性Fab-デ-ブーガニン構築物を人工的に作製し直すことが合理化された。人工的に作製し直す時間を最小限にするために、および実現可能性に基づき、制限酵素を用いて、Fd-F-デ-ブーガニンおよびVL-CL断片をペプチドシグナルのあるPelBリーダー配列と接続した。
VB6-050を15リットル発酵槽から精製した。各カラムの回収率を評価するために、精製処理の各工程由来のアリコートをウェスタンブロットで解析した(図7A)。免疫ブロットを抗ヒトκ軽鎖とインキュベートした。濃縮および透析濾過工程の濾液中に検出可能な産物は観察されなかった(図7A、それぞれレーン2および4)。1/10希釈した、透析濾過した物質をCM-セファロースカラムに充填した(図7A、レーン5)。ウェスタンブロット解析により、CM溶出物(図7A、レーン8)は全長VB6-050および分解したVB6-050と考えられる断片を含むことが示された。ニッケルカラムのフロースルー、レーン9、は、VB6-050およびその他の産物の大部分がカラムに結合したこと示している。その後、Ni2+溶出物、レーン13をSEC 200サイズ排除上に注ぎ、分解した断片からの無傷のVB6-050の分離を可能にした(図7A、レーン14、および図7B、レーン2)。
VB6-050について、各抗体のプロファイリングデータに基づいて、抗原陽性細胞株および抗原陰性細胞株を選択した。結合したFab-デ-ブーガニンを、抗ブーガニン抗体を用いたフローサイトメトリーによって検出した。予期した通り、抗原陰性細胞とのインキュベーション後、フローサイトメトリーによって、結合は検出されなかった。対照的に、抗原陽性細胞株で結合したFab-デ-ブーガニンが検出された。さらに、抗原陽性細胞株を、0〜500μg/mLの範囲にまで及ぶ、様々な濃度のFab-デ-ブーガニンタンパク質とインキュベートし、および結合活性をフローサイトメトリーによって決定した。滴定曲線を作成した(図8)。Lineweaver-Burk法によってKDを決定するために、決定した蛍光中央値の逆数を抗体濃度の逆数の関数としてプロットした。直線を作成し、曲線の傾きからKDを計算した。解離定数KDを以下の方程式により決定した:1/F=1/fmax+(KD/Fmax)(1/VB6)、式中、F=バックグラウンドを差し引いた蛍光中央値、およびFmaxはプロットから計算した(表7)。Fab-デ-ブーガニンについての飽和点を飽和曲線から決定し、および元の抗体との競合アッセイに用いた。0〜1000μg/mLの範囲にまで量が増加するその対応する元のIgGの存在下で、飽和点、250μg/mLのVB6-050を抗原陽性細胞とインキュベートした。結合したVB6-050を、抗ブーガニン抗体を用いたフローサイトメトリーによって検出した。予期した通り、元のIgGはFab-デ-ブーガニンタンパク質の結合と競合した。結合したFab-デ-ブーガニンの50%を阻害するのに必要なIgGの濃度を、180μg/mLと決定した(表7)。
抗原陰性細胞株および抗原陽性細胞株を、1nM〜1μMまでの異なる濃度のVB6-050とインキュベートした。インキュベーション5日後、計算されたVB6-050のIC50は、400nMであった(図9)(表7)。対照的に、抗原陰性細胞株では、IC50を決定することができなかった。
Hybridomics and Immunomine(商標)プラットフォームから選択された、VB1-050 IgGを、フューリンで切断可能なリンカーを介してVH-CHドメインと遺伝的に接続されたデ-ブーガニンを含む可溶性Fab-デ-ブーガニン融合タンパク質として人工的に作製した。データは、IgGに由来するFab-デ-ブーガニンフォーマットが可溶性発現に好適であり、容易な後続処理をもたらすことを裏付けている。ひとたび精製されれば、フローサイトメトリーのデータによって、VB6フォーマットのプロファイリングデータが元のIgGと一致することが示され、特異性および選択性が保存されていることを示唆している。さらに、IgGはVB6融合タンパク質と競合し、両断片が同じ抗原に結合したことを示している。計算されたVB6フォーマットの親和性は、IC50 >280nMにまで至るマイクロモルの範囲にあった。
VB1-050Agの予備的な特徴付け
VB1-050は、脱グリコシル化によって、58.62%(P値0.008)の結合の増加を示した。脱グリコシル化により観察されたこの抗原の結合の増加は、グリカン部分が細胞表面上の抗原性部位を部分的に隠す可能性があること、および脱グリコシル化が抗原の同定において必須の工程である可能性があることを示唆する。
4つの陽性細胞株、MCF-7、MDA-MB-435S、A-375、HepG2、ならびに3つの陰性細胞株、Panc-1、Daudi、およびC-33Aの各々由来の等量の膜調製物をN-グリカナーゼで脱グリコシル化し、かつプロテアーゼ阻害剤の存在下、インビボ条件を模倣する条件で、各々40μgのVB1-050および4B5-IgGと共に振動させた。免疫複合体を遠心分離し、RIP-A溶解緩衝液で洗浄し、および0.2M グリシン pH 2.5で溶出した。
上述の全ての細胞株由来の免疫沈降物を、還元および非還元条件の試料調製に供し、その後、SDS-PAGEおよびウェスタンブロッティングによって解析した。結果として得られたブロットを、4B5-IgGおよびVB1-050を同時に、ならびにHRPにコンジュゲートした対応する2次抗体を用いて調べ、化学発光によって免疫沈降したタンパク質を可視化した。全ての細胞株で、1D-PAGEにより、VB1-050免疫沈降物から、〜50kDaに1本のバンドが検出され、および2D-PAGEによって、何ら結果が得られなかった。4B5-IgGではバンドが検出されなかった。従来のアプローチにより、異なる形で発現した抗原が何ら示されなかったので、抗原同定のための別の方法を検討した。
HepG2、MCF-7、Panc-1およびC-33AのPF2D分画
膜調製物から予め分画したVB1-050免疫沈降物から、高速遠心分離によって、全ての粒子状物質を取り除いた。澄んだ上清を開始緩衝液で平衡化し、および1次元目にクロマトフォーカシングカラムで分画した。pH=7.4〜7.6で溶出するピーク分画を、1:4の比にして、溶媒A(0.1% TFA)で平衡化し、および微量のTFAを含む0〜100%の勾配のアセトニトリルによって、HPRPカラムで分画した。
HPRPカラムについて得られたグロマトグラフィーのプロファイルをProteoVue(商標)ファイルにインポートし、DeltaVue(商標)での最終的な解析用に許容されるフォーマットに形式を合わせた。陽性(HepG2およびMCF-7)細胞株および陰性(Panc-1およびC-33A)細胞株の両方からの抗原分画について解析を組み合わせ、細胞株の各々から包括的な膜タンパク質マップを作成するために、ProteoVue(登録商標)ソフトウェアを用いて形式を合わせた。その後、DeltaVue(商標)ソフトウェアで、異なる形で調節されているタンパク質の比較プロファイリングを作成した。両細胞株からの分画のクロマトグラフィーのプロファイルを、ピークからバンドのパターンへと変換し、異なる発現の領域がより容易に分かるようにした。より良い解像度および解析のために、陽性細胞株において異なる形で発現した特定のピーク/バンドに焦点を当てることができた。各実験で得られた陽性および陰性のプロットを重ね合わせることにより、タンパク質の過剰発現が陽性細胞株(HepG2およびMCF-7)でのみ見られることが示され、ならびにこれらの分画をペプチド抽出の目的のために使用した。
20時間のペプチド抽出処置において、シークエンシング等級のトリプシンによるトリプシン消化を行ない、20〜50nL/分という作業流速のナノソースが装備された、QSTAR Pulsar-I(ESI-qTOF-MS/MS)で解析されるペプチドの抽出が最終的にもたらされた。ペプチドをイオン化し、およびそれらのそれぞれの質量にまでさらに純化された、2つ、3つ、または4つの電荷を帯びた分子として検出する。同定したタンパク質のデノボシークエンシングも、可能なら何時でも行なった。それが正しい抗原であることを確かめるために、陽性細胞株および陰性細胞株の両方からペプチドを抽出した。質量スペクトルから抽出したペプチド質量を用いて、MASCOT検索エンジンを通じてアクセス可能であるタンパク質データベース上で得られたMOWSEスコアにより、抗原を直接同定した。
ペプチド解析を2つの方法で行なった:
・タンパク質のIDを得るために、回収され、かつそれらの正確な質量にまで再構築された全てのペプチドを、ペプチド質量フィンガープリンティング工程で直接使用した。
・「y」イオンおよび「b」イオンを用いて、それらの1次構造を演繹する、さらなるMS/MSイオン断片化のために、豊富にあり、かつよくイオン化されるペプチドを選択した。その後、タンパク質IDに関するタンパク質データベースで、これらの配列を相同性について検索した。
1Nは適応症あたりの試験した細胞株の数を示す。2MF:値は、各々の適応症における全ての細胞株からの対照抗体に対する蛍光中央値の平均増加倍数の合計から計算した平均を示す。0値は、対照抗体と比べて計測可能な反応性がないことを示す。aは、AntiCancer社から提供された同所性モデルを示す。bは、GFP(緑色蛍光タンパク質)-トランスフェクタントとして入手可能な細胞株を示す。cHer2/neu−、ER+。dHer2/neu、ER−、p53wt、raswt。eHer2/neu−、ER−、p53mt、raswt。fアンドロゲン反応性。gアンドロゲン非反応性。
10〜3+の規模でスコアを評価し、0=染色なし、および1+未満だが、0よりも大きいものを微量とした。1+〜3+の等級は、増加した染色の強度を表し、強い濃褐色の染色を3+とした。通常、6人の異なる患者の1つの標本をスクリーニングした。6人未満の患者がスクリーニングされた場合というのは、中心が欠けていたか、または染色されるべき組織を代表しなかったかのいずれかを示す。括弧内の値は、スコア付けされた範囲における染色された細胞の割合を示す。2隣接する正常組織のみを用いた。35つのうち4つは、隣接する正常組織標本であった。
*0〜3+の規模でスコアを評価し、0=染色なし、および1+未満だが、0よりも大きいものを微量とした。1+〜3+の等級は、増加した染色の強度を表し、強い濃褐色の染色を3+とした。通常、8人の異なる患者の2つの標本をスクリーニングした。8人未満の患者がスクリーニングされた場合というのは、中心が欠けていたか、または染色されるべき組織を代表しなかったかのいずれかを示す。括弧内の値は、スコア付けされた範囲における染色された細胞の割合を示す。
0〜3+の規模でスコアを評価し、0=染色なし、および1+未満だが、0よりも大きいものを微量とした。1+〜3+の等級は、増加した染色の強度を表し、強い濃褐色の染色を3+とした。通常、8人の異なる患者の2つの標本をスクリーニングした。8人未満の患者がスクリーニングされた場合というのは、中心が欠けていたか、または染色されるべき組織を代表しなかったかのいずれかを示す。頭頸部癌には、咽喉、口唇、喉頭、口腔、扁桃腺、および歯肉表面の腫瘍が含まれていた。括弧内の値は、スコア付けされた範囲における染色された細胞の割合を示す。太字にされた癌の適応症は、VB1-050反応性を示す。
1代表的な実験を示す。2陰性対照、マウス骨髄腫IgGまはたヒトIgG(4B5)を上回るMF増加。3腫瘍細胞の細胞表面からのMFの減少の割合。4(−)氷上で120分間インキュベートした細胞。
Claims (27)
- SEQ ID NO:11、12もしくは13のアミノ酸配列を含む癌細胞の表面上に発現するグルコース輸送体8の癌関連変異体を含む、単離されたタンパク質。
- SEQ ID NO:11のアミノ酸配列からなる、請求項1記載の単離されたタンパク質。
- 請求項1または2記載のタンパク質をコードする、単離された核酸分子。
- 請求項3記載の核酸分子を含む、組換え発現ベクター。
- 請求項4記載の組換え発現ベクターを含む、宿主細胞。
- SEQ ID NO:7に示される軽鎖可変領域、およびSEQ ID NO:9に示される重鎖可変領域を含む結合タンパク質。
- 結合タンパク質が抗体または請求項1または2記載の単離されたタンパク質に結合する抗体断片であり、抗体断片が、Fab、Fab'、F(ab')2、scFv、dsFv、ds-scFv、二量体、ミニボディ(minibodies)、ダイアボディ(diabodies)、もしくはそれらの多量体、または二重特異性抗体断片である、請求項6記載の結合タンパク質。
- 細胞毒性があるか、細胞増殖抑制性があるか、またはそうでなければ癌細胞が分裂および/もしくは転移する能力を抑制もしくは低下させる癌治療薬(2)に連結している、癌細胞上に発現するグルコース輸送体8抗原に結合する請求項6もしくは7記載の結合タンパク質(1)を含む、免疫抱合体。
- 結合タンパク質が、SEQ ID NO:7によって規定される軽鎖可変領域、および/またはSEQ ID NO:9によって規定される重鎖可変領域を含む、請求項8記載の免疫抱合体。
- 癌治療薬が細胞毒素である、請求項8または9記載の免疫抱合体。
- 細胞毒素がリボソーム不活性化ポリペプチドである、請求項10記載の免疫抱合体。
- 細胞毒素が、ジェロニン(gelonin)、ブーガニン(bouganin)、サポリン、リシン、リシンA鎖、ブリオジン(bryodin)、ジフテリア、レストリクトシン(restrictocin)、および緑膿菌外毒素Aまたはそれらの機能的変異体からなる群より選択される、請求項10記載の免疫抱合体。
- 細胞毒素が改変されたブーガニンまたはその機能的変異体である、請求項10記載の免疫抱合体。
- 細胞毒素がアミノ酸252〜608からなる緑膿菌外毒素Aの切断型またはその機能的変異体である、請求項10記載の免疫抱合体。
- 薬学的に許容される賦形剤、担体、緩衝剤、または安定剤を伴う、請求項8〜14のいずれか一項記載の免疫抱合体を含む組成物。
- 癌を治療または抑制するための医薬の製造のための、請求項8〜14のいずれか一項記載の有効量の免疫抱合体の使用。
- 同時的、個別的、もしくは連続的な癌の治療または抑制のための医薬の製造のための1つまたは複数のさらなる癌治療薬剤の使用をさらに含む、請求項16記載の使用。
- 請求項8〜14のいずれか一項記載の有効量の免疫抱合体および癌を治療または抑制するためのその使用法を含む、癌を治療または抑制するためのキット。
- 以下の工程を含む、対象における癌細胞を検出またはモニターする方法:
対象から採取した被験試料を、癌細胞上の抗原に特異的に結合する請求項6記載の結合タンパク質と接触させ、結合タンパク質‐抗原複合体を生成する工程;
被験試料中の結合タンパク質‐抗原複合体の量を測定する工程;および
被験試料中の結合タンパク質‐抗原複合体の量を対照と比較する工程。 - 癌細胞上の抗原に結合する請求項6記載の結合タンパク質およびその使用説明書を含む、癌を診断するためのキット。
- 直接的にまたは間接的に、検出可能なシグナルを生成する標識(2)に連結された癌細胞上の抗原に結合する、請求項6記載の結合タンパク質(1)を含む、診断薬。
- 薬学的に許容される希釈剤または担体と混合した請求項1または2記載の有効量のタンパク質を含む、薬学的組成物。
- 薬学的に許容される希釈剤または担体と混合した請求項3記載の有効量の単離された核酸配列を含む、薬学的組成物。
- 薬学的に許容される希釈剤または担体と混合した請求項4記載の有効量の組換え発現ベクターを含む、薬学的組成物。
- アジュバントをさらに含む、請求項22〜24のいずれか一項記載の薬学的組成物。
- 請求項22〜25のいずれか一項記載の薬学的組成物およびその使用に関する説明書を含むキット。
- 以下の工程を含む、対象における癌細胞を検出またはモニターする方法:
対象由来の細胞内のmRNA量を検出する工程;および
mRNA量を対照と比較する工程であって、mRNAがSEQ ID NO:11、12、もしくは13のアミノ酸配列を含むグルコース輸送体8の癌関連変異体タンパク質をコードする、工程。
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