JP5784583B2 - セマフォリン3c(sema3c)阻害治療剤、方法及び用途 - Google Patents
セマフォリン3c(sema3c)阻害治療剤、方法及び用途 Download PDFInfo
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C07K2319/61—Fusion polypeptide containing an enzyme fusion for detection (lacZ, luciferase)
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Landscapes
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Description
他の態様としては、前立腺癌治療のためにSEMA3C阻害剤の使用を提供する。
他の態様としては、前立腺癌治療のためにSEMA3C阻害剤を提供する。
他の態様としては、生理学的に許容される担体と組み合わせて、SEMA3C阻害剤を含む医薬組成物を提供する。
他の態様としては、SEMA3C阻害剤及び前立腺癌の治療のために用いる説明を任意に含む、市販の包装を提供する。
他の態様としては、本明細書中に記載された単離された核酸及びアミノ酸を提供する。例えば、配列番号:2及び5-119である。
本明細書中、「全身送達」は、広い生物分布をもたらす脂質粒子又は担体の送達を言うが、生体におけるSEMA3C阻害剤(例えば、RNA干渉-RNAi(dsRNA);アンチセンスRNA(ssRNA);抗体(例えば、MAbs又はヒト化MAbs、細胞内抗体、又はそれらの断片;又はペプチド)である。投与のある技術としては、特定の薬剤であり、その他でないものの全身送達である。全身送達は、有用で、好ましくは治療効果があり、薬剤が全身のほとんどの部分にいきわたる用量である。広い生物分布を得るために、一般に血中での残存期間が、例えば薬剤が、投与から遠位にある疾患部位に到達するまでに、(例えば初回通過臓器(肝臓、肺等)又は急速な非特異的細胞結合により)急速に分解又は排出されないものであることを要する。
SEMA3Cの全身送達は当業者にとって知られた手段であり、例えば、静脈内、皮下及び腹腔内投与がある。ある態様としては、SEMA3Cの全身送達は、静脈内送達による。
例えば、SEMA3C阻害剤は、直接疾患部位、他の標的部位又は標的臓器例えば前立腺への注射により局所送達される。
用語「細胞内抗体」は、細胞内抗体を言い、細胞内において細胞内標的タンパク質に結合して働く。細胞内抗体送達は標的細胞における抗体発現の結果行われる(例えば、遺伝子治療を介する)。細胞内抗体の作製(engineering)方法は、当該分野において知られている(Marasco WA. Gene Ther. (1997)「細胞内抗体:ヒト免疫系を細胞内免疫のために反転する」 4(1):11-5)、単鎖抗体の使用を含み(scFvs)、免疫グロブリンVLドメインの超安定の修飾、細胞内環境の減少のための耐性抗体の選択、又はマルトース結合タンパク質との融合タンパク質又は他の安定した細胞内タンパク質の発現がある。
アミノ酸配列の類似性及び同一性は、BLAST(basic local alignment search tool) 2.0アルゴリズムを用いるBLASTP及びTBLASTNプログラムによりコンピュータを用いて行われる。アミノ酸配列の類似性及び同一性の特定のためのコンピュータ技術は、当該分野においてよく知られており、BLASTアルゴリズムは、ALTSCHUL et al. 1990, J Mol. Biol. 215: 403- 410 and ALTSCHUL et al. (1997), Nucleic Acids Res. 25: 3389-3402に用いられている。
アミノ酸の水治療法指標は、アミノ酸が水性環境(陰性値)又は疎水性環境(陽性値)を探す傾向の尺度である(KYTE&DOOLITTLE 1982. J Mol Biol 157:105-132)。水治療法指数は、標準アミノ酸については、アラニン(1.8), アルギニン(-4.5), アスパラギン(-3.5), アスパラギン酸(-3.5), システイン(2.5), グルタミン (-3.5), グルタミン酸 (-3.5), グリシン(-0.4), ヒスチジン(-3.2), イソロイシン(4.5), ロイシン(3.8), リジン(-3.9), メチオニン(1.9), フェニルアラニン(2.8), プロリン(-1.6), セリン(-0.8), スレオニン(-0.7), トリプトファン(-0.9), チロシン(-1.3)及びバリン(4.2)である。同様の水治療指数を有するアミノ酸は、ペプチド中において互いに置換することができる。
グループAは、ロイシン, イソロイシン, バリン, メチオニン, フェニルアラニン, セリン, システイン, スレオニン及び以下の側鎖を有する修飾アミノ酸:エチル, イソブチル, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHOHCH3及びCH2SCH3を含む。
グループBは、グリシン, アラニン, バリン, セリン, システイン, スレオニン及びエチル側鎖を有する修飾アミノ酸を含む。
グループCは、フェニルアラニン, フェニルグリシン, チロシン, トリプトファン, シクロヘキシルメチル及び置換ベンジル又はフェニル側鎖を有する修飾アミノを含む。
グループDは、グルタミン酸, アスパラギン酸、グルタミン酸又はアスパラギン酸 (例えば、メチル, エチル, n-プロピル, イソプロピル, シクロヘキシル, ベンジル、又は置換ベンジル)の置換又は無置換脂肪族, 芳香族又はベンジルエステル、グルタミン, アスパラギン, CO-NH-アルキル化グルタミン又はアスパラギン (例えば、メチル, エチル, n-プロピル、及びイソプロピル)及び-(CH2)3COOH側鎖を有する修飾アミノ酸、それらのエステル(置換又は無置換脂肪族, 芳香族又はベンジルエステル)、それらのアミド及びそれらの置換または無置換N-アルキルアミドである。
グループEは、ヒスチジン, リジン, アルギニン, N-ニトロアルギニン, p-シクロアルギニン, g-ヒドロキシアルギニン, N-アミジノシトルリン, 2-アミノグアニジノブタン酸、リジンの同族体、アルギニンの同族体及びオルニチンである。
グループFは、セリン, スレオニン, システイン、-OH又は-SHを有する直鎖又は分岐のCl-C5アルキル側鎖で修飾されたアミノ酸を含む。
グループA-Fは、例示であり本発明を限定する意図ではない。
核酸分子は、適切なベクターに挿入される。適切なベクターは、以下に限られないが、レトロウイルスベクター, αウイルス, ワクチニア, アデノウイルス, アデノ随伴ウイルス, ヘルペスウイルス, 及び鶏痘ウイルスベクターを含む。ベクターは、好ましくは、天然又は工学的に真核細胞を形質転換する能力を有し、例えば、CHO-K1細胞がある。さらに、ベクターは、本発明の文脈において有用であり、「裸の(naked)」核酸ベクターである(すなわち、タンパク質、糖及び/又は脂質をほとんど又は全く包含しないベクター)であり、例えば、プラスミド又はエピソーム又はベクターは、他の分子と複合体を形成する。本発明の核酸とともに適切に結合される他の分子は、以下に限られないが、ウイルスコート、カチオン性脂質、リポソーム、ポリアミン、金粒子、及び標的分子、例えば、リガンド、受容体又は細胞分子を標的とする抗体がある。
そのような側鎖は当業者に知られており、脂肪族、単環芳香族、多環式芳香族, ヘテロ環, ヘテロ核, アミノ, アルキルアミノ, カルボキシル, カルボキサミド, カルボキシル エステル, グアニジン, アミジン, ヒドロキシル, アルコキシ, メルカプト-, アルキルメルカプト-, 又は他のヘテロ原子含有側鎖がある。他の合成アミノ酸は、αイミノ酸, 非αアミノ酸、例えばβ-アミノ酸, デス-カルボキシ又はデス-アミノ酸がある。アミノ酸の合成種は、当該分野における一般的方法を用いて行われ又は市販の業者から購入して行われ、例えば、RSPアミノ酸LLC(Shirley, MA)から購入した。
タンパク質又はタンパク質のアイソフォーム間において異なる、エピトープとしての使用のための特定のペプチドの使用のための選択又は特定は、配列比較を用いて行われる-当業者は、所望の選択性を有する抗体を産生するのに有用な適切なペプチド又はタンパク配列を特定することができるであろう。ポリクローナル抗体は、異なるB細胞株に由来する。それらは、それぞれ異なるエピトープを認識し、特定の抗体から分泌される免疫グロブリン分子の混合物である。これらの抗体は、典型的には適切な哺乳類、例えばマウス、ウサギ又はヤギの免疫化により生産される。大きな哺乳類はしばしば、血清の量を多く集められるので好ましい。抗原を哺乳類に注入する。これによりB-リンパ球を誘導し、抗原に特異的なIgGグロブリンを産生する。このIgGは、哺乳類の血清から精製される。対照的に、モノクローナル抗体は、単細胞株から得られる。アジュバントは、抗原の免疫反応を改善又は促進させるために用いられる。本発明の特定の態様としては、本発明のペプチドにから産生された又は結合する、抗体又は細胞内抗体を提供する。またそのような抗体又は細胞内抗体の使用の方法を提供する。
本明細書中、SEMA3C阻害剤とは、単離されたもの、又はトレーサー物質、リポソーム, 糖質担体, ポリマー担体、又は当業者にとって明らかな他の薬剤又は賦形剤との結合又は組合せである。他の態様としては、そのような化合物は、薬剤を含んでいてもよく、ここで、そのような化合物は、薬理学的に有効な用量が存在している。
用語「薬学的に許容される賦形剤」は、生理学的に混合可能な、溶媒、分散媒体, コーティング, 抗生物質, 抗菌剤又は抗真菌剤, 等張吸収遅延剤等のいかなる又はすべてのものであってよい。賦形剤は、静脈内, 腹腔内, 筋肉内, 皮下, くも膜下腔内, 局所投与又は経口投与に適切なものであればよい。賦形剤は、滅菌水溶液又は即時調製よう滅菌注射溶液のための分散体又は分散体であってよい。薬剤のそのような媒体の調製は、当該分野において知られている。
本明細書のSEMA3C阻害剤を含む組成物は、吸入による投与のために製剤化される。例えば、本明細書中のSEMA3C阻害剤は、エアロゾルとして賦形剤とともに組み合わされ、分散される。吸入製剤の例は、当該分野において知られている。SEMA3C阻害剤と組み合わされる他の薬剤は、取り込み又は代謝を補助するためのもの、又は宿主における分散の遅延、例えば放出制御製剤を含む。放出制御製剤の例は、当該分野において知られており、糖質又はポリマーマトリクス等におけるマイクロカプセル、糖質又はポリマーマトリクスエンボリズム(embolism)がある。製剤の製造方法についての他の方法は、例えば、「Remington’s Pharmaceutical Sciences」, (19th edition), ed. A. Gennaro, 1995, Mack Publishing Company, Easton, Pa. に記載されている。
同一組織型の癌は、通常同一組織を起源とし、生物学的特徴に基づいて異なるサブタイプに分かれる。癌の4つの一般的なカテゴリーは、癌(上皮組織由来), 肉腫(結合組織又は中胚葉組織由来), 白血病(血液形成組織由来)及びリンパ腫(リンパ組織由来)である。200以上の異なる型の癌が知られており、それぞれの生体の臓器及び組織に影響する。癌の定義を限定するものではない癌の具体例には、メラノーマ, 白血病, 星細胞腫, グリア芽腫, 網膜芽細胞腫, リンパ腫, 神経膠腫, ホジキンリンパ腫及び慢性リンパ性白血病がある。様々な癌によって影響される臓器及び組織は、膵臓, 乳房, 甲状腺, 卵巣, 子宮, 睾丸, 前立腺, 甲状腺, 下垂体, 副腎, 腎臓, 胃, 食道, 大腸又は直腸, 頭及び首, 骨, 神経系, 皮膚, 血液, 鼻咽頭組織, 肺, 尿路, 頚部, 膣, 外分泌腺及び内分泌腺がある。あるいは、癌は、多中心性であり初期部位がわからないことがある(CUPS)。
治療剤に耐性のある癌細胞は、当該方法には反応せず、増殖を続ける。感受性がある癌細胞は、治療剤によって、細胞が死滅し、癌が縮小し、全体として癌の成長を遅らせ(全身腫瘍組織量)、又は転移を阻害する。例えば、望ましくは、癌の縮小、全体としての癌の成長/癌の重量又は転移発生率が、約10%以上、例えば、約30%、約40%、約50%、約60%、約70%、約80%又はそれ以上であり、約2倍、約3倍、約4倍、約5倍、約10倍、約15倍、約20倍以上減少することである。モニタリングは、本明細書及び当業者に知られた数多くの病理的、臨床的及びイメージング方法がある。
本明細書中、用語「治療剤」又は「治療」は、癌細胞に該を与える少なくとも1つの薬剤を投与することを言う。本発明の使用のために適切な治療剤は、以下に限られないが、「化学療法剤」、「放射線治療剤」、「代替治療剤」及びそれらの組合せである。
アンドロゲン作用及びARの機能状態は、前立腺癌の進行の重要なメディエータとなる。高AR発現は、再発の可能性を減少させ、生存し、疾患の進行を低くすることと関連する(Heinlein and Chang 2004)。AR活性は、前立腺癌の成長及び生存に関係がある。アンドロゲン依存性及び非依存性前立腺癌細胞は、SEMA3Cの異なる上方制御をに応答する(Herman and Meadows 2007)。直接定義されていないものは、本発明の分野において関連して理解されるであろう。本明細書の至る所に存在する特定の用語を下に述べるが、専門家に追加のガイドとなるように組成、装置、方法等及びどのようにそれを用いるかを述べる。
本発明の開示は、前立腺がんの治療におけるSEMA3C阻害剤の使用において重要なサポートを提供する。本明細書は、高いSEMA3C mRNA及び分泌タンパク質レベルは、アンドロゲン感受性及びホルモン治療抵抗性前立腺癌細胞は、前立腺癌細胞におけるアンドロゲン耐性の上方制御を行うため、より進行した前立腺癌からの組織サンプルは、SEMA3Cが高い発現レベルを示すことと関係がある。さらに、本明細書において示すとおり、SEMA3C発現を阻害できるSEMA3Cに直接向けられた特定のRNA干渉化合物は、阻害により細胞増殖を抑制し、アポトーシスを前立腺がんにおいて誘導し、細胞増殖阻害は、SEMA3C非依存的に起こる。さらに、SEMA3Cは、前立腺癌細胞の増殖因子であることが示されている。前立腺癌異種移植マウスをSEMA3Cアンチセンスオリゴヌクレオチドで処置することにより癌体積を減少させ、PSA閾値を低下させたことを示す。 ペプチドは、SEMA3Cとそれを認識するタンパク質受容体又は他の結合パートナーとの相互作用を阻害する。前立腺癌細胞をそのようなペプチドで処置することにより、前立腺癌細胞増殖を低下させる。
本発明者は、性腺摘除耐性系統のLNCaPサブ細胞株及びアンドロゲン非依存性DU145細胞において、SEMA3C mRNAレベル、及び良性前立腺肥厚化BPH-1細胞、アンドロゲン感受性LNCaP細胞、C4-2細胞における分泌タンパク質レベルを測定した。アンドロゲン依存性DU145及びホルモン耐性C4-2細胞においては、アンドロゲン感受性 LNCaP及び非悪性BPH-1細胞よりも、6-ないし8-倍の濃度のSEMA3Cが発現することを見出し、これは良性前立腺肥厚化BPH-1細胞、アンドロゲン感受性LNCaP細胞、C4-2細胞におけるSEMA3C発現の増加がCRPCの進行に関連することをサポートしている(図 1)。
次に、臨床サンプルにおけるアンドロゲン切断によりSEMA3Cが上方制御されるかを決定するため、ホルモン未感作、ホルモン処置癌を<3ヶ月、3-6ヶ月、>6ヶ月及びCRPCにわけて、232のヒトCaP試料について、ネオアジュバントホルモン療法(neo-adjuvant hormone therapy)(NHT) 組織マイクロアレイについて免疫染色を行った。図4に示すとおり、男性から採取したCaP試料において、SEMA3Cは有意に上方制御され、NHT>6ヶ月及びCRPC標本において高SEMA3CがCRPC進行と関連があることを確認した。
SEMA3Cの機能的役割を特徴付けるため、SEMA3Cコード配列(配列番号:2)のヌクレオチド1-20位に対するASOをデザインした。定量的リアルタイムポリメラーゼ連鎖反応(qPCR)分析から、このSEMA3C標的ASOは、LNCaP、C4-2及びDU145細胞においてSEMA3C発現を有効に阻害することを見出した(図5)。さらに、SEMA3C mRNA及び分泌タンパク質をC4-2細胞においてASO用量依存的に阻害することを見出した(図5)。
サブG0/G1期 DNA割合分析をモニターしたところ、ASO処置により、LNCaP C4-2及びDU145細胞において、用量依存的に増殖阻害が見られ(図6)、及びアポトーシス誘導がなされた(図7A)。SEMA3C ASO誘導性アポトーシスは、DU145細胞において、(図7B)PARP開裂及びプロカスパーゼ3及びプロカスパーゼ8及びプロカスパーゼ9の減少と関連する。
標的特異性及びそれ以外に対する効果の問題は、機能的ゲノミクスにおけるASOの使用における重要な考慮事項である。ASO特異性をコントロールする最良で最も確実な方法は、標的の遺伝子又はタンパク質再構築を介してASOにより誘導されたフェノタイプを誘導することである。この目的を達成するため、LNCaP細胞にSEMA3Cを誘導するレンチウイルス、又は空のベクターをコントロールとして誘導し、条件培地を調製した。SEMA3C(SEMA3C CM)発現細胞からの条件培地は、DU145細胞誘導による細胞増殖阻害したが、空のベクターを誘導した細胞はしなかったことから、ASO処置によって誘導された細胞のSEMA3C ASOの標的特異性を示している(図8)。
SEMA3Cが真に刺激因子であるかを決定するため、SEMA3C CM 対 モック CMで処置し、生存細胞を直接計数することにより、細胞増殖をモニターした(図9E)。標記命題と一貫しており、SEMA3Cの過剰発現は、S相にある細胞割合に関連するLNCaP細胞成長を加速した(図9)。
LNCaP 異種移植癌を有する20の無胸腺ヌードマウスをPSA閾値が75 ng/mlとなるように性腺摘除し、SEMA3C ASO対スクランブルコントロール群にランダムに振り分けた。平均癌体積及びPSAは、いずれの群においても処置の最初においては、類似であった。性腺摘除の1日後、ASO 12.5 mg/kgを6週間、隔日で腹腔内 (i.p.)投与し、癌体積及びPSAレベルを1週間ごとにモニターした。図10に示すように、性腺摘除により、LNCaP癌体積及び血清PSAレベルは減少し、 測定期間中ずっと低いレベルであり、スクランブルコントロールで処置したものは、CRPCの増加に従い緩やかな増加を示した。副作用はSEMA3C ASO又はスクランブルコントロール処置のいずれにおいても見られなかった。
LNCaP細胞を、条件培地において調製した。安定的にレンチウイルスを誘導させた全長SEMA3C (FL)発現遺伝子、切断SEMA3C (SDH)又は空のベクターを発現させ、LNCaP細胞増殖を3H-チミジン取り込みによりモニターした。切断SEMA3C(SDH)存在下培養したLNCaP細胞は、全長SEMA3C (FL)又はSEMA3Cなし(空のベクター)に比べて、有意に細胞増殖を低下させた(図11)。この試験において用いられた切断SEMA3Cは、SEMA3CからのSEMAドメインを含み、配列番号:3に対応する。
全長セマフォリン3Cの過剰発現は、平板効率を促進し、LNCaP細胞の軟寒天培地における細胞増殖を促進したのに対し、SEMAドメイン単独では、軟寒天培地におけるコロニー形成を減少させた(図12)。軟寒天培地を、細胞アンカリング非依存的細胞増殖の可能性を測定するために行い、細胞の形質転換を検出する、最も重要で最もよく用いられるアッセイにおり行い、SEMAドメインがアンカリング非依存的細胞増殖の阻害に作用しうることを示した。
セマフォリン3Cは、インフレームでヒト胎盤分泌アルカリホスファターゼと融合させ、生じるAPSema3Cと呼ばれるAP融合タンパク質とし、ホスファターゼ活性アッセイによる細胞表面受容体結合のモニターに用いた(図13)。
APSema3C 融合タンパク質のDU145細胞への特異的結合は、SEMAドメイン:Fc 融合タンパク質、全長Sema3C又はマウス抗Sema3Cモノクローナル抗体のいずれかを加えて競合したが、ラット抗マウスIgG2b(コントロール)は競合しなかった。
天然シグナルペプチドを含む全長セマフォリン3Cをセマフォリン3C cDNA NM_006379 (Origene cDNA clone SC116160, Origene, Rockville, MD)を、PCRのテンプレートとし、PCRにより増幅させた。PCR増幅のため、NheI及びBglII抑制部位を含むセマフォリン3C-特異的5’-及び3’-プライマーを用いた。生成したPCR産物を、pAPtag-5ベクター(GenHunter Corporation社, Nashville, TN)のNhe1/BglII部位にライゲーションにより、インフレームでホスファターゼとクローンした。最終構築物をDNA配列分析で確認した。セマフォリン3C AP融合タンパク質の発現を、全細胞溶解物及び培地から抗セマフォリン3C (N-20)抗体又はTHE(登録商標)抗Hisモノクローナル抗体(Genescript Corp. NJ.)を用いてウエスタンブロット法により確認した。
DU145細胞により結合アッセイは、基本的にFlanaganら、1990の文献に記載された方法により行った。結合アッセイの前日、DU145細胞(20,000/ウェル)を96ウェル組織培養プレートの成長培地(DMEM含有10% FBS)に播種した。コンフルエントになってから48時間後、セマフォリン3C-AP 発現293T細胞から、条件培地を収穫した。結合バッファーHBHA(20mM HEPES, 150 mM NaCl, 0.1% アジド, 5g/L BSA, 5mM CaCl2, 1mM MgCl2)において、条件培地を2倍個の連続希釈した。続いて、成長培地を細胞から除き、細胞をHBHAバッファーで一度洗浄し、連続希釈したセマフォリン-AP CMに置き換えた。細胞を室温で90分間培養した。プレートは、HBHAで10分以上かけて7回洗浄した。細胞を氷で30分間固定した(60% アセトン, 3% ホルムアルデヒド)。細胞ホスファターゼを65℃水浴で20分間でプレートをフローティングさせて不活性化した。続いて、AP活性をAPバッファー(100mM Tris pH 9.5, 100mM NaCl, 5mM MgCl2)で調製したNBT/BCIPによって検出する前に、さらに細胞を3回HBHAで洗浄した。プレートを暗室で終夜インキュベートし、プレートリーダーにおいて光学密度(550-562nm)を測定した。
セマフォリン3C (NM_006379, Origene clone SC116160, Origene, Rockville,MD))のその野生型シグナルペプチド(アミノ酸s (1-495)を含有するSEMAドメインを、Age1及びBglII抑制部位含有セマフォリン3C-特異的5’及び3’プライマーを用いてPCRにより増幅した。SEMAドメインはそれゆえヒトIgG1工学によるFcとインフレームにより、抑制部位特異的DNAライゲーションによりpFUSE-hIgG1e1-Fc1 (Invivogen, San Diego,CA)と結合した。最終cDNA構築物をDNAシークエンシングにより確認した。続いて、最終融合構築物をHEK 293T細胞にトランスフェクトさせ、安定的に発現するクローンをゼオシン(10 μg/ml) (Invitrogen, Missisauga, On)において抗生物質選択により選択した。SEMAドメイン:Fc(SD:FC) 融合タンパク質の発現は、ウエスタンブロット法により抗hIgG:96ウェルプレートを用いて確認した。条件培地からの約1,000のクローンを、モノクローナル抗ヒトIgG1Fc特異的抗体を捕捉剤(clone GG7, 5μg/ml) (Sigma, St. Louis, MO)及びヤギ抗ヒトIgG(Fc-特異的)ペルオキシダーゼ(1:30,000, Sigma, St. Louis, MO)を二次抗体としてとして用いて、間接ELISAによりスクリーニングした。テトラメチルベンジジン(TMB)を用いて行った。プレートを60分間暗室でインキュベートし、続いてプレートリーダーで450 nmで読んだ。高レベルのSEMAドメイン:Fc 融合タンパク質を分泌するクローンが特定され、続くすべての実験において用いた。条件培地からSEMAドメイン:Fc 融合タンパク質をさらに精製し、タンパク質A/Gアフィニティークロマトグラフィーにより、Amicon Ultra遠心分離フィルター10,000 MWCO を用いて70倍に濃縮した。
SEMA3Cによる細胞の処置は、DU145及びPC3細胞におけるMET及びRONチロシンキナーゼ受容体を活性化し、及びSEMA3C処置はLNCaP細胞におけるEGFRを活性化する(図14)。セマフォリンはプレキシン受容体に結合し、活性化し、プレキシンは細胞外ドメインを介してMET及びEGFRと相互作用することが示されている。さらに、細胞をSD:Fc融合タンパク質で処置すると、METのSEMA3C誘導性リン酸化をブロックする(図15)。
セマフォリン3Cで刺激する24時間前に、等価細胞密度のDU145又はPC3細胞のいずれかを6-ウェルプレートに播種した。細胞刺激をまずPBSで洗浄し、セマフォリン3C CMを20mM HEPES含有PBSで1:10に希釈又は希釈せずに再構成した。細胞を30分以上かけて刺激した。示した時間において氷冷PBSで洗浄し、ただちに、1mM バナジン酸ナトリウム及び1mM モリブデン酸ナトリウムを加えたコンプリートプロテアーゼ阻害剤を含有するRIPAバッファーで溶解させた。溶解細胞は、かき集め、マイクロチューブに移し、プレートから収穫した。全細胞溶解物(WCL)を遠心分離し、残骸を除いた。WCL(20μg)由来のタンパク質を8% SDS-PAGEで分離し、さらにウエスタンブロット法でMETオンコタンパク質のリン酸化の変化を分析した。
等密度のDU145又はLNCaP細胞を10 cm 組織培養プレートにおいて成長培地に播種した。24時間後、刺激の60時間前に血清フリーの培地に培地を換えた。細胞を、37℃、5% CO2存在下、20mM HEPES含有PBSによる1:10希釈のセマフォリン3Cでモック処置又は刺激した。10分後、細胞を1mM バナジン酸ナトリウム及び1mM モリブデン酸ナトリウムを加えたRIPAバッファーで溶解させた。細胞溶解物を、プレートから細胞溶解物をかき集めて、収穫し、残骸を除くために遠心分離した。全細胞溶解物を続いて、30μL タンパク質Aアガロースビーズにより30分間前処置した。500μLの容積における細胞溶解物(1000μg)を1.0μg/ml, DU145細胞において、抗ホスホチロシン(クローン4G10, Upstate,Temecula CA)、抗MET(C-28)又は抗RON(Santa Cruz, LaJolla CA)で免疫沈降させた。 LNCaP細胞は、抗EGFR 抗体(528, 2.0 μg/ml)、(Santa Cruz Biotechnology, Inc., LaJolla CA)において同様に免疫沈降される。細胞溶解物を抗体と4℃において終夜免疫沈降させた。免疫複合体は、続いて2時間、4℃において適切なタンパク質A/Gアガロースビーズとインキュベートさせた。免疫沈降物を遠沈し、3回PBSで洗浄し、最終ビーズペレットを30 μLサンプルバッファーにおいて5分間煮沸し、サンプルを8%SDS-PAGEにより、続いてウエスタンブロット法で分離した。ウエスタンブロット法は、製造業者が指示するように以下の抗体を用いてプローブした:抗ホスホMET(Y1234/1235)、抗MET、抗pEGFR(tyr1148)、(Cell signaling, Pickering, ON)、抗Ronβ(C-20)、抗EGFR(528)、(Santa Cruz Biotechnology, Inc, LaJolla CA)、抗ホスホチロシン(clone 4G10, Upstate,Temecula CA)。
SEMA3Cに対するモノクローナル抗体によりLNCaP細胞を処置したところ、LNCaP細胞増殖を阻害した(図16)。LNCaP細胞を、48-ウェル組織培養プレートに500細胞/ウェルの密度で、成長培地(RPMI + 10% FBS)に播種した。24時間後、10 μg/ml抗マウスセマフォリン3C 又は抗マウスIgGκ(Bethyl Laboratories, Montgomery, TX) 抗体を含む、1% 血清にRPMI を加えた(R&D Diagnostics, MN)成長培地で置換した。細胞増殖を、CyQuant 細胞増殖アッセイキット(Invitrogen,Mississauga, ON)を用いてモニターした。細胞増殖を、第4日に、CyQuant 細胞増殖アッセイキット(Invitrogen, Missisauga, ON)を用いてモニターした。簡単に述べると、細胞をトリプシンを用いて収穫し、V底96ウェルプレートに移し、1400 RPMで4分間遠沈した。上清を緩やかにタッピングして除き、細胞をPBSで1回洗浄した。続いて細胞を遠沈し、洗浄バッファーを除去した。プレートは、即時に-80℃で凍結させ、30分以上の後、CyQuantアッセイを行った。蛍光を、485 nmで励起させ、527nmでの発行をフルオロスキャンAscent FL, (Thermo Labsystems,Helsinki, Finland)で測定した。
前に述べた発明は、図及び例とともに理解を明確にする目的で詳細に記載されているが、本発明の理解に詳しい当業者は、添付の請求の範囲の精神及び範囲から離れることなく変更及び修飾をなしうることを理解するであろう。
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配列番号:1 -全長ヒトSEMA3C-751アミノ酸
MAFRTICVLVGVFICSICVKGSSQPQARVYLTFDELRETKTSEYFSLSHHPLDYRILLMDEDQDRIYVGSKDHILSLNINNISQEALSVFWPASTIKVEECKMAGKDPTHGCGNFVRVIQTFNRTHLYVCGSGAFSPVCTYLNRGRRSEDQVFMIDSKCESGKGRCSFNPNVNTVSVMINEELFSGMYIDFMGTDAAIFRSLTKRNAVRTDQHNSKWLSEPMFVDAHVIPDGTDPNDAKVYFFFKEKLTDNNRSTKQIHSMIARICPNDTGGLRSLVNKWTTFLKARLVCSVTDEDGPETHFDELEDVFLLETDNPRTTLVYGIFTTSSSVFKGSAVCVYHLSDIQTVFNGPFAHKEGPNHQLISYQGRIPYPRPGTCPGGAFTPNMRTTKEFPDDVVTFIRNHPLMYNSIYPIHKRPLIVRIGTDYKYTKIAVDRVNAADGRYHVLFLGTDRGTVQKVVVLPTNNSVSGELILEELEVFKNHAPITTMKISSKKQQLYVSSNEGVSQVSLHRCHIYGTACADCCLARDPYCAWDGHSCSRFYPTGKRRSRRQDVRHGNPLTQCRGFNLKAYRNAAEIVQYGVKNNTTFLECAPKSPQASIKWLLQKDKDRRKEVKLNERIIATSQGLLIRSVQGSDQGLYHCIATENSFKQTIAKINFKVLDSEMVAVVTDKWSPWTWASSVRALPFHPKDIMGAFSHSEMQMINQYCKDTRQQHQQGDESQKMRGDYGKLKALINSRKSRNRRNQLPES
5’-AUGGCAUUCCGGACAAUUUG-3’
MAFRTICVLVGVFICSICVKGSSQPQARVYLTFDELRETKTSEYFSLSHHPLDYRILLMDEDQDRIYVGSKDHILSLNINNISQEALSVFWPASTIKVEECKMAGKDPTHGCGNFVRVIQTFNRTHLYVCGSGAFSPVCTYLNRGRRSEDQVFMIDSKCESGKGRCSFNPNVNTVSVMINEELFSGMYIDFMGTDAAIFRSLTKRNAVRTDQHNSKWLSEPMFVDAHVIPDGTDPNDAKVYFFFKEKLTDNNRSTKQIHSMIARICPNDTGGLRSLVNKWTTFLKARLVCSVTDEDGPETHFDELEDVFLLETDNPRTTLVYGIFTTSSSVFKGSAVCVYHLSDIQTVFNGPFAHKEGPNHQLISYQGRIPYPRPGTCPGGAFTPNMRTTKEFPDDVVTFIRNHPLMYNSIYPIHKRPLIVRIGTDYKYTKIAVDRVNAADGRYHVLFLGTDRGTVQKVVVLPTNNSVSGELILEELEVFKNHAPITTMKISSKK
1 ggactgcgaa aggagcaggg ttgcggagct agggctccag cctgcggccg cgcattcttg
61 cgtctggcca gccgcgagct ctaagggtcg gccccgcccg gtccgccccc gcggctccct
121 gccaggctct cgcgggcgcg ctcggggtgg ggcctcgcgg ctggcggaga tgcggccggg
181 gctgcgcggt ggtgatgcga gcctgctggg cggcgcgccg gggcagccgg agccgcgcgc
241 cgcggcgctg taatcggaca ccaagagcgc tcgcccccgg cctccggcca ctttccattc
301 actccgaggt gcttgattga gcgacgcgga gaagagctcc gggtgccgcg gcactgcagc
361 gctgagattc ctttacaaag aaactcagag gaccgggaag aaagaatttc acctttgcga
421 cgtgctagaa aataaggtcg tctgggaaaa ggactggaga cacaagcgca tccaaccccg
481 gtagcaaact gatgactttt ccgtgctgat ttctttcaac ctcggtattt tcccttggat
541 attaacttgc atatctgaag aaatggcatt ccggacaatt tgcgtgttgg ttggagtatt
601 tatttgttct atctgtgtga aaggatcttc ccagccccaa gcaagagttt atttaacatt
661 tgatgaactt cgagaaacca agacctctga atacttcagc ctttcccacc atcctttaga
721 ctacaggatt ttattaatgg atgaagatca ggaccggata tatgtgggaa gcaaagatca
781 cattctttcc ctgaatatta acaatataag tcaagaagct ttgagtgttt tctggccagc
841 atctacaatc aaagttgaag aatgcaaaat ggctggcaaa gatcccacac acggctgtgg
901 gaactttgtc cgtgtaattc agactttcaa tcgcacacat ttgtatgtct gtgggagtgg
961 cgctttcagt cctgtctgta cttacttgaa cagagggagg agatcagagg accaagtttt
1021 catgattgac tccaagtgtg aatctggaaa aggacgctgc tctttcaacc ccaacgtgaa
1081 cacggtgtct gttatgatca atgaggagct tttctctgga atgtatatag atttcatggg
1141 gacagatgct gctatttttc gaagtttaac caagaggaat gcggtcagaa ctgatcaaca
1201 taattccaaa tggctaagtg aacctatgtt tgtagatgca catgtcatcc cagatggtac
1261 tgatccaaat gatgctaagg tgtacttctt cttcaaagaa aaactgactg acaataacag
1321 gagcacgaaa cagattcatt ccatgattgc tcgaatatgt cctaatgaca ctggtggact
1381 gcgtagcctt gtcaacaagt ggaccacttt cttaaaggcg aggctggtgt gctcggtaac
1441 agatgaagac ggcccagaaa cacactttga tgaattagag gatgtgtttc tgctggaaac
1501 tgataacccg aggacaacac tagtgtatgg catttttaca acatcaagct cagttttcaa
1561 aggatcagcc gtgtgtgtgt atcatttatc tgatatacag actgtgttta atgggccttt
1621 tgcccacaaa gaagggccca atcatcagct gatttcctat cagggcagaa ttccatatcc
1681 tcgccctgga acttgtccag gaggagcatt tacacccaat atgcgaacca ccaaggagtt
1741 cccagatgat gttgtcactt ttattcggaa ccatcctctc atgtacaatt ccatctaccc
1801 aatccacaaa aggcctttga ttgttcgtat tggcactgac tacaagtata caaagatagc
1861 tgtggatcga gtgaacgctg ctgatgggag ataccatgtc ctgtttctcg gaacagatcg
1921 gggtactgtg caaaaagtgg ttgttcttcc tactaacaac tctgtcagtg gcgagctcat
1981 tctggaggag ctggaagtct ttaagaatca tgctcctata acaacaatga aaatttcatc
2041 taaaaagcaa cagttgtatg tgagttccaa tgaaggggtt tcccaggtat ctctgcaccg
2101 ctgccacatc tatggtacag cctgtgctga ctgctgcctg gcgcgggacc cttattgcgc
2161 ctgggatggc cattcctgtt ccagattcta cccaactggg aaacggagga gccgaagaca
2221 agatgtgaga catggaaacc cactgactca atgcagagga tttaatctaa aagcatacag
2281 aaatgcagct gaaattgtgc agtatggagt aaaaaataac accacttttc tggagtgtgc
2341 ccccaagtct ccgcaggcat ctatcaagtg gctgttacag aaagacaaag acaggaggaa
2401 agaggttaag ctgaatgaac gaataatagc cacttcacag ggactcctga tccgctctgt
2461 tcagggttct gaccaaggac tttatcactg cattgctaca gaaaatagtt tcaagcagac
2521 catagccaag atcaacttca aagttttaga ttcagaaatg gtggctgttg tgacggacaa
2581 atggtcccca tggacctggg ccagctctgt gagggcttta cccttccacc cgaaggacat
2641 catgggggca ttcagccact cagaaatgca gatgattaac caatattgca aagacactcg
2701 gcagcaacat cagcagggag atgaatcaca gaaaatgaga ggggactatg gcaagttaaa
2761 ggccctcatc aatagtcgga aaagtagaaa caggaggaat cagttgccag agtcataata
2821 ttttcttatg tgggtcttat gcttccatta acaaatgctc tgtcttcaat gatcaaattt
2881 tgagcaaaga aacttgtgct ttaccaaggg gaattactga aaaaggtgat tactcctgaa
2941 gtgagtttta cacgaactga aatgagcatg cattttcttg tatgatagtg actagcacta
3001 gacatgtcat ggtcctcatg gtgcatataa atatatttaa cttaacccag attttattta
3061 tatctttatt caccttttct tcaaaatcga tatggtggct gcaaaactag aattgttgca
3121 tccctcaatt gaatgagggc catatccctg tggtattcct ttcctgcttt ggggctttag
3181 aattctaatt gtcagtgatt ttgtatatga aaacaagttc caaatccaca gcttttacgt
3241 agtaaaagtc ataaatgcat atgacagaat ggctatcaaa agaaatagaa aaggaagacg
3301 gcatttaaag ttgtataaaa acacgagtta ttcataaaga gaaaatgatg agtttttatg
3361 gttccaatga aatatgttgg ggttttttta agattgtaaa aataatcagt tactggtatc
3421 tgtcactgac ctttgtttcc ttattcagga agataaaaat cagtaaccta ccccatgaag
3481 atatttggtg ggagttatat cagtgaagca gtttggttta tattcttatg ttatcacctt
3541 ccaaacaaaa gcacttactt tttttggaag ttatttattt tagactcaaa gaatataatc
3601 ttgcactact cagttattac tgtttgttct cttattccct agtctgtgtg gcaaattaaa
3661 caatataaga aggaaaaatt tgaagtatta gacttctaaa taaggggtga aatcatcaga
3721 aagaaaaatc aaagtagaaa ctactaattt tttaagagga atttataaca aatatggcta
3781 gttttcaact tcagtactca aattcaatga ttcttccttt tattaaaacc agtctcagat
3841 atcatactga tttttaagtc aacactatat attttatgat cttttcagtg tgatggcaag
3901 gtgcttgtta tgtctagaaa gtaagaaaac aatatgagga gacattctgt ctttcaaaag
3961 gtaatggtac atacgttcac tggtctctaa gtgtaaaagt agtaaatttt gtgatgaata
4021 aaataattat ctcctaattg tatgttagaa taattttatt agaataattt catactgaaa
4081 ttattttctc caaataaaaa ttagatggaa aaatgtgaaa aaaattattc atgctctcat
4141 atatatttta aaaacactac ttttgctttt ttatttacct tttaagacat tttcatgctt
4201 ccaggtaaaa acagatattg taccatgtac ctaatccaaa tatcatataa acattttatt
4261 tatagttaat aatctatgat gaaggtaatt aaagtagatt atggcctttt taagtattgc
4321 agtctaaaac ttcaaaaact aaaatcattg tcaaaattaa tatgattatt aatcagaata
4381 tcagaatatg attcactatt taaactatga taaattatga taatatatga ggaggcctcg
4441 ctatagcaaa aatagttaaa atgctgacat aacaccaaac ttcatttttt aaaaaatctg
4501 ttgttccaaa tgtgtataat tttaaagtaa tttctaaagc agtttattat aatggtttgc
4561 ctgcttaaaa ggtataatta aacttctttt ctcttctaca ttgacacaca gaaatgtgtc
4621 aatgtaaagc caaaaccatc ttctgtgttt atggccaatc tattctcaaa gttaaaagta
4681 aaattgtttc agagtcacag ttccctttat ttcacataag cccaaactga tagacagtaa
4741 cggtgtttag ttttatacta tatttgtgct atttaattct ttctattttc acaattatta
4801 aattgtgtac actttcatta cttttaaaaa tgtagaaatt cttcatgaac ataactctgc
4861 tgaatgtaaa agaaaatttt ttttcaaaaa tgctgttaat gtatactact ggtggttgat
4921 tggttttatt ttatgtagct tgacaattca gtgacttaat atctattcca tttgtattgt
4981 acataaaatt ttctagaaat acactttttt ccaaagtgta agtttgtgaa tagattttag
5041 catgatgaaa ctgtcataat ggtgaatgtt caatctgtgt aagaaaacaa actaaatgta
5101 gttgtcacac taaaatttaa ttggatattg atgaaatcat tggcctggca aaataaaaca
5161 tgttgaattc cccaaaaaaa aaaaaaaaa
Claims (18)
- 生物学的有効量の、
(a)SEMA3Cタンパク質または該タンパク質の断片に特異的に結合する、抗体、抗体誘導体または抗体断片、
(b)配列番号:3に示すアミノ酸配列からなるペプチドであるSEMA3Cペプチド、または
(c)SEMA3C遺伝子に特異的なRNAi分子またはアンチセンスRNA分子から選ばれるRNA分子
の1またはそれ以上から選ばれるSEMA3C阻害剤を含む、前立腺癌を治療するための医薬組成物。 - 該生物学的有効量が、前立腺癌細胞の細胞死を引き起こす又は前立腺癌細胞の細胞増殖を阻害するのに十分な用量である、請求項1に記載の医薬組成物。
- 該前立腺癌が、アンドロゲン受容体(AR) 陽性前立腺癌である請求項1又は2に記載の医薬組成物。
- さらに担体を含む請求項1〜3のいずれかに記載の医薬組成物。
- 該抗体、抗体誘導体または抗体断片が、以下の:ポリクローナル抗体;モノクローナル抗体;またはそれらの断片;または細胞内抗体の1つ以上から選択される請求項1に記載の医薬組成物。
- RNA分子が、配列番号:4から選択される15〜50個の連続ヌクレオチドを含む、請求項1に記載の医薬組成物。
- RNA分子が、配列番号:4から選択される17〜30個の連続ヌクレオチドを含む、請求項1に記載の医薬組成物。
- RNA分子が、配列番号:4から選択される19〜25個の連続ヌクレオチドを含む、請求項1に記載の医薬組成物。
- RNA分子が、配列番号:2又は配列番号:5〜119の1つ以上のヌクレオチドを含む請求項1に記載の医薬組成物。
- 前立腺癌の治療剤の製造のための、
(a)SEMA3Cタンパク質または該タンパク質の断片に特異的に結合する、抗体、抗体誘導体または抗体断片、
(b)配列番号:3に示すアミノ酸配列からなるペプチドであるSEMA3Cペプチド、または
(c)SEMA3C遺伝子に特異的なRNAi分子またはアンチセンスRNA分子から選ばれるRNA分子
の1またはそれ以上から選ばれるSEMA3C阻害剤の使用。 - 前立腺癌の治療のための、
(a)SEMA3Cタンパク質または該タンパク質の断片に特異的に結合する、抗体、抗体誘導体または抗体断片、
(b)配列番号:3に示すアミノ酸配列からなるペプチドであるSEMA3Cペプチド、または
(c)SEMA3C遺伝子に特異的なRNAi分子またはアンチセンスRNA分子から選ばれるRNA分子
の1またはそれ以上から選ばれるSEMA3C阻害剤。 - 該前立腺癌が、アンドロゲン受容体(AR)陽性前立腺癌である請求項10に記載の使用。
- 該抗体、抗体誘導体または抗体断片が、ポリクローナル抗体;モノクローナル抗体;及びそれらの断片;または細胞内抗体の1つ以上から選択される請求項10に記載の使用。
- RNA分子が配列番号:4から選択される15〜50個の連続ヌクレオチドを含む請求項10に記載の使用。
- RNA分子が配列番号:4から選択される17〜30個の連続ヌクレオチドを含む請求項10に記載の使用。
- RNA分子が配列番号:4から選択される19〜25個の連続ヌクレオチドを含む請求項10に記載の使用。
- RNA分子が配列番号:2又は配列番号:5〜119の1つ以上のヌクレオチドを含む請求項10に記載の使用。
- RNA分子がセンス鎖及びアンチセンス鎖を有する二本鎖領域を含む請求項14〜17のいずれかに記載の使用。
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