JP2012136528A - 癌(muc1)の診断および治療のための技術および組成物 - Google Patents
癌(muc1)の診断および治療のための技術および組成物 Download PDFInfo
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Abstract
【解決手段】ユビキチン化タンパク質、あるいはバロシン含有タンパク質に結合するFas関連因子1(Fas associated Factor 1)のポリペプチドフラグメント、および、癌を寛解するために有効な量の抗体またはその抗原結合断片を被検者に投与することを含む、MUC1の異常な発現を特徴とする癌を患う患者を治療する方法。
【選択図】図1
Description
1つのキットは、本発明が提供する抗体またはその抗原結合断片を含む。
1つのキットは、表面を有する第1物品、およびその表面に対して固定化された、あるいは固定化されるように適用されたペプチド配列を含む。ペプチド配列は細胞増殖を促進する、成長因子または変性酵素などの活性リガンドと相互作用する細胞表面受容体の一部分を含む。キット中には、活性リガンドの存在下に他の同じペプチド配列に直接または間接に結合するペプチド配列の能力に影響を与える候補薬剤も含まれる。前記一部分は活性リガンドと相互作用する細胞表面受容体を十分に含む。
本発明の他のキットは、細胞表面受容体の鎖間結合領域の分断後、細胞表面に付着して残存する細胞表面受容体の一部分に結合することが可能である種および該種に対して固定化されるか、あるいは固定化されるように適用されたシグナル伝達物質を含む。
本発明の他のキットは、物品(粒子である)および少なくとも、細胞増殖を促進する成長因子または変性酵素などの活性リガンドと相互作用する細胞表面受容体の一部分に対応する配列の断片であって、いかなる細胞からも検出され、前記物品に固定されるか、あるいは固定されるように適用される断片を含む。
1つの方法は細胞増殖を促進する成長因子などの活性リガンドと相互作用する細胞表面受容体の一部分であって、活性リガンドおよび該部分と相互作用する細胞表面受容体を十分に含む断片を含むペプチドを準備し、そして、該ペプチドに特異的に結合する抗体またはその抗原結合断片を生成することを含む。上記方法により産生する抗体またはその抗原結合断片も記載される。
癌を患うか、あるいは癌を発症する危険性を有する被検者を治療する本発明の他の方法は、細胞表面から細胞表面受容体の鎖間結合領域の開裂を減少させる物質を投与することを含む。
本発明の他の方法は被検者から得た試料中の細胞表面受容体の開裂部位を測定し、そして測定工程に基づいて、癌の徴候または癌の可能性を評価することを含む。
他の組成物はMGFRに特異的に結合する抗体またはその抗原結合断片を含む。
なおも他の実施態様では、N−末端にPSMGFRを含む単離タンパクまたはペプチドであって、配列番号1、2、3、6、または7に記載されるアミノ酸配列のいずれかも含まない単離タンパクまたはペプチドが記載される。
他の実施態様では、N−末端に配列番号7に記載されるアミノ酸配列を含む単離タンパクまたはペプチドが記載される。
他の実施態様では、配列番号2に記載されるアミノ酸配列を含む単離タンパクまたはペプチドが記載される。
他の実施態様では、配列番号60に記載されるアミノ酸配列を含む単離タンパクまたはペプチドが記載される。
他の実施態様では、配列番号64に記載されるアミノ酸配列を含む単離タンパクまたはペプチドが記載される。
他の実施態様では、配列番号65に記載されるアミノ酸配列に特異的に結合する抗体またはその抗原結合断片が記載される。
他の実施態様では、配列番号39に記載されるアミノ酸配列の固有領域に特異的に結合する抗体またはその抗原結合断片が記載される。
他の実施態様では、配列番号39に記載されるアミノ酸配列のN−末端と第104番のアミノ酸を架橋する領域に特異的に結合する抗体またはその抗原結合断片が記載される。
なおも別な実施態様では、配列番号7に記載されるアミノ酸配列を含む単離タンパクまたはペプチドが記載される。
なおも他の実施態様では、プロモーターに実施可能的に連結された上記した単離核酸分子のいずれかを含む発現ベクターが記載される。
他の実施態様では、上記した単離核酸分子のいずれかを含む発現ベクターにより形質移入または形質転換した宿主細胞が記載される。
他の実施態様では、プロモーターに実施可能的に連結された上記した単離核酸分子またはその相補体を含む発現ベクターが記載される。
なおも他の実施態様では、上記した単離核酸分子またはその相補体を含む発現ベクターにより形質移入または形質転換された宿主細胞が記載される。
「MUC1成長因子受容体」(MGFR)との用語は、細胞増殖を促進する、成長因子などの活性リガンドまたは開裂酵素などの変性酵素と相互作用するMUC1受容体の一部分を意味する機能的定義である。MUC1のMGFR領域は、以下に定義するように、細胞表面に最も近接していて、PSMGFRのほとんどあるいは全てとして定義される細胞外部分である。MGFRは未変性ペプチドおよび例えばリン酸化、グリコシル化などの酵素変性を受けたペプチドの両者を含む。本発明の効果は、細胞からIBRの部分または全ての放出を引き起こす腫瘍形成に関与する部位で、この部分がMUC1開裂時にリガンドに近づけられるというメカニズムと矛盾しない。
「繰り返し」との用語は、当該分野での通常の意味を有する。
「切断された鎖間結合領域」(TPSIBR)はいくつかの腫瘍細胞の受容体開裂後に細胞表面から放出されるIBRのより小さな部分と定義する下記ペプチド配列(配列番号65参照)である。
当業者は、非ファミリーメンバーから目的の配列を選択的に区別する断片の能力を基にして、通常、固有アミノ酸配列を選択する方法に十分に精通している。通常、公知データベースのものと断片の配列を対比することは、必要なことである。
(a)配列番号37、38、39、40および41に記載されるMUC1切断型受容体アイソフォームをコードする核酸分子、または例えば、ヌクレオチド配列:配列番号42、43、44、45および46をそれぞれ含む、それらの機能的変異体またはその断片、および
(b)(a)の核酸分子に高ストリンジェントな条件下にハイブリダイズする核酸分子、
(c)(a)または(b)の核酸分子の欠失体、付加体または置換体、
(d)遺伝子コードの縮重によりコドン配列中において、(a)、(b)または(c)の核酸分子と異なった核酸分子、および
(e)(a)、(b)、(c)または(d)の相補体。
GTINVHDVETQFNQYKTEAASPYNLTISDVSVSHHHHHH(配列番号1)
GTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGAHHHHHH(配列番号2)
TINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGAHHHHHH(配列番号60)
VQLTLAFREGTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFHHHHHH(配列番号3)
SVVVQLTLAFREGTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGAHHHHHH(配列番号61)
HHHHHHGFLGLSNIKFRPGSVVVQLTLAFRE(配列番号4)
HHHHHHSVVVQLTLAFREG(配列番号62)
PDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSAHHHHH(配列番号5)
GTINVHDVETQFNQYKTEAASPYNLTISDVSVS(配列番号6)
GTINVHDVETQFNQYKTEAASRYNLTISDVSVSDVPFPFSAQSGA(配列番号36)
TINVHDVETQFNQYKTEAASRYNLTISDVSVSDVPFPFSAQSGA(配列番号63)
GTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGA(配列番号7)
TINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGA(配列番号64)
GFLGLSNIKFRPGSVVVQLTLAFRE(配列番号8)
SVVVQLTLAFREG(配列番号65)
PDTRPAPGSTAPPAHGVTSAPDTRPAPGSTAPPAHGVTSA(配列番号9)
SVVVQLTLAFREGTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGA(配列番号66)
ムチン1前駆体、Genbank寄託番号:P15941(下記表1)
G TINVHDVETQ FNQYKTEAAS RYNLTISDVS VSDVPFPFSA QSGAGVPGWG IALLVLVCVL VALAIVYLIALAVCQCRRKN YGQLDIFPARDTYHPMSEYP TYHTHGRYVP PSSTDRSPYE KVSAGNGGSS LSYTNPAVAA ASANL
(配列番号37)
GFLGLSNIKFRPGSVV VQLTLAFREG TINVHDVETQ FNQYKTEAAS RYNLTISDVS VSDVPFPFSA QSGAGVPGWG IALLVLVCVL VALAIVYLIA LAVCQCRRKN YGQLDIFPARDTYHPMSEYP TYHTHGRYVP PSSTDRSPYEKVSAGNGGSS LSYTNPAVAA ASANL
(配列番号38)
ATTTPASKSTPFSIPSHHSDTPTTLASHSTKTDASSTHHSTVPPLTSSNHSTSPQLSTGVSFFFLSFHISNLQFNSSLEDPSTDYYQELQRDISEMFLQIYKQGGFLGLSNIKFRPGSVVVQLTLAFREGTINVHDVETQFNQYKTEAASRYNLTISDVSVSDVPFPFSAQSGAGVPGWGIALLVLVCVLVALAIVYLIALAVCQCRRKNYGQLDIFPARDTYHPMSEYP TYHTHGRYVPPSSTDRSPYEKVSAGNGGSSLSYTNPAVAAASANL
(配列番号39)
GSGHASSTPGGEKETSATQRSSVPSSTEKNAFNSSLEDPSTDYYQELQRDISEMFLQI YKQGGFLGLSNIKFRPGSVVVQLTLAFREGTINVHDMETQFNQYKTEAASRYNLTI SDVSVSDVPFPFSAQSGAGVPGWGIALLVLVCVLVALAIVYLIALAVCQCRRKNYG QLDIFPARDTYHPMSEYPTYHTHGRYVPPSSTDRSPYEKVSAGNGGSSLSYTNPAV AATSANL
(配列番号40)
LDPRVRTSAPDTRPAPGSTAPQAHGVTS (APDTRPAPGSTAPPAHGVTS) 25APDTRP APGSTAPPAHGVTSAPDNRPALGSTAPPVHNVTSASGSASGSASTLVHNGTSARAT TTPASKSTPFSIPSHHSDTPTTLASHSTKTDASSTHHSSVPPLTSSNHSTSPQLSTGVSFFFLSFHISNLQFNSSLEDPSTDYYQELQRDISEMFLQIYKQGGFLGLSNIKFRPGSVVVQLTLAFREGTINVHDVETQFNQYKTEAASRYNLTISDVSVSDVPFPFSAQSGAGVPGWGIALLVLVCVLVALAIVYLIALAVCQCRRKNYGQLDIFPARDTYHPMSEYPTYH THGRYVPPSSTDRSPYEKVSAGNGGSSLSYTNPAVAAASANL
(配列番号41)
MTPGTQSPFFLLLLLTVLT (配列番号47)
MTPGTQSPFFLLLLLTVLT VVTA (配列番号58)
MTPGTQSPFFLLLLLTVLT VVTG (配列番号59)
寄託番号:XP_002485
HHHHHHSSSSGSSSSGSSSSGGRGDSGRGDS (配列番号12)
acgggcacgg ccggtaccat caatgtccac gacgtggaga cacagttcaa tcagtataaa acggaagcag cctctcgata taacctgacg atctcagacg tcagcgtgag tgatgtgcca tttcctttct ctgcccagtc tggggctggg gtgccaggct ggggcatcgc gctgctggtg ctggtctgtg ttctggttgc gctggccatt gtctatctca ttgccttggc tgtctgtcag tgccgccgaa agaactacgg gcagctggac atctttccag cccgggatac ctaccatcct atgagcgagt accccaccta ccacacccat gggcgctatg tgccccctag cagtaccgat cgtagcccct atgagaaggt ttctgcaggt aacggtggca gcagcctctc ttacacaaac ccagcagtgg cagccgcttc tgccaacttg tagggcacgt cgccgctgag ctgagtggcc agccagtgcc attccactcc actcaggttc ttcaggccag agcccctgca ccctgtttgg gctggtgagc tgggagttca ggtgggctgc tcacagcctc cttcagaggc cccaccaatt tctcggacac ttctcagtgt gtggaagctc atgtgggccc ctgaggctca tgcctgggaa gtgttgtggg ggctcccagg aggactggcc cagagagccc tgagatagcg gggatcctga actggactga ataaaacgtg gtctcccact g
(配列番号42)
acggccggtt ttctgggcct ctccaatatt aagttcaggc caggatctgt ggtggtacaa ttgactctgg ccttccgaga aggtaccatc aatgtccacg acgtggagac acagttcaat cagtataaaa cggaagcagc ctctcgatat aacctgacga tctcagacgt cagcgtgagt gatgtgccat ttcctttctc tgcccagtct ggggctgggg tgccaggctg gggcatcgcg ctgctggtgc tggtctgtgt tctggttgcg ctggccattg tctatctcat tgccttggct gtctgtcagt gccgccgaaa gaactacggg cagctggaca tctttccagc ccgggatacc taccatccta tgagcgagta ccccacctac cacacccatg ggcgctatgt gccccctagc agtaccgatc gtagccccta tgagaaggtt tctgcaggta acggtggcag cagcctctct tacacaaacc cagcagtggc agccgcttct gccaacttgt agggcacgtc gccgctgagc tgagtggcca gccagtgcca ttccactcca ctcaggttct tcaggccaga gcccctgcac cctgtttggg ctggtgagct gggagttcag gtgggctgct cacagcctcc ttcagaggcc ccaccaattt ctcggacact tctcagtgtg tggaagctca tgtgggcccc tgaggctcat gcctgggaag tgttgtgggg gctcccagga ggactggccc agagagccct gagatagcgg ggatcctgaa ctggactgaa taaaacgtgg tctcccactg
(配列番号43)
acggccgcta ccacaacccc agccagcaag agcactccat tctcaattcc cagccaccac tctgatactc ctaccaccct tgccagccat agcaccaaga ctgatgccag tagcactcac catagctcgg tacctcctct cacctcctcc aatcacagca cttctcccca gttgtctact ggggtctctt tctttttcct gtcttttcac atttcaaacc tccagtttaa ttcctctctg gaagatccca gcaccgacta ctaccaagag ctgcagagag acatttctga aatgtttttg cagatttata aacaaggggg ttttctgggc ctctccaata ttaagttcag gccaggatct gtggtggtac aattgactct ggccttccga gaaggtacca tcaatgtcca cgacgtggag acacagttca atcagtataa aacggaagca gcctctcgat ataacctgac gatctcagac gtcagcgtga gtgatgtgcc atttcctttc tctgcccagt ctggggctgg ggtgccaggc tggggcatcg cgctgctggt gctggtctgt gttctggttg cgctggccat tgtctatctc attgccttgg ctgtctgtca gtgccgccga aagaactacg ggcagctgga catctttcca gcccgggata cctaccatcc tatgagcgag taccccacct accacaccca tgggcgctat gtgcccccta gcagtaccga tcgtagcccc tatgagaagg tttctgcagg taacggtggc agcagcctct cttacacaaa cccagcagtg gcagccgctt ctgccaactt gtagggcacg tcgccgctga gctgagtggc cagccagtgc cattccactc cactcaggtt cttcaggcca gagcccctgc accctgtttg ggctggtgag ctgggagttc aggtgggctg ctcacagcct ccttcagagg ccccaccaat ttctcggaca cttctcagtg tgtggaagct catgtgggcc cctgaggctc atgcctggga agtgttgtgg gggctcccag gaggactggc ccagagagcc ctgagatagc ggggatcctg aactggactg aataaaacgt ggtctcccac tg
(配列番号44)
acaggttctg gtcatgcaag ctctacccca ggtggagaaa aggagacttc ggctacccag agaagttcag tgcccagctc tactgagaag aatgctttta attcctctct ggaagatccc agcaccgact actaccaaga gctgcagaga gacatttctg aaatgttttt gcagatttat aaacaagggg gttttctggg cctctccaat attaagttca ggccaggatc tgtggtggta caattgactc tggccttccg agaaggtacc atcaatgtcc acgacgtgga gacacagttc aatcagtata aaacggaagc agcctctcga tataacctga cgatctcaga cgtcagcgtg agtgatgtgc catttccttt ctctgcccag tctggggctg gggtgccagg ctggggcatc gcgctgctgg tgctggtctg tgttctggtt gcgctggcca ttgtctatct cattgccttg gctgtctgtc agtgccgccg aaagaactac gggcagctgg acatctttcc agcccgggat acctaccatc ctatgagcga gtaccccacc taccacaccc atgggcgcta tgtgccccct agcagtaccg atcgtagccc ctatgagaag gtttctgcag gtaatggtgg cagcagcctc tcttacacaa acccagcagt ggcagccact tctgccaact tgtaggggca cgtcgcc
(配列番号45)
ctcgacccac gcgtccgctc gacccacgcg tccgcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccacg gtgtcacctc ggccccggac accaggccgg ccccgggctc caccgccccc ccagcccatg gtgtcacctc ggccccggac aacaggcccg ccttgggctc caccgcccct ccagtccaca atgtcacctc ggcctcaggc tctgcatcag gctcagcttc tactctggtg cacaacggca cctctgccag ggctaccaca accccagcca gcaagagcac tccattctca attcccagcc accactctga tactcctacc acccttgcca gccatagcac caagactgat gccagtagca ctcaccatag ctcggtacct cctctcacct cctccaatca cagcacttct ccccagttgt ctactggggt ctctttcttt ttcctgtctt ttcacatttc aaacctccag tttaattcct ctctggaaga tcccagcacc gactactacc aagagctgca gagagacatt tctgaaatgt ttttgcagat ttataaacaa gggggttttc tgggcctctc caatattaag ttcaggccag gatctgtggt ggtacaattg actctggcct tccgagaagg taccatcaat gtccacgacg tggagacaca gttcaatcag tataaaacgg aagcagcctc tcgatataac ctgacgatct cagacgtcag cgtgagtgat gtgccatttc ctttctctgc ccagtctggg gctggggtgc caggctgggg catcgcgctg ctggtgctgg tctgtgttct ggttgcgctg gccattgtct atctcattgc cttggctgtc tgtcagtgcc gccgaaagaa ctacgggcag ctggacatct ttccagcccg ggatacctac catcctatga gcgagtaccc cacctaccac acccatgggc gctatgtgcc ccctagcagt accgatcgta gcccctatga gaaggtttct gcaggtaacg gtggcagcag cctctcttac acaaacccag cagtggcagc cgcttctgcc aacttgtagg gcacgtcgcc gctgagctga gtggccagcc agtgccattc cactccactc aggttcttca ggccagagcc cctgcaccct gtttgggctg gtgagctggg agttcaggtg ggctgctcac agcctccttc agaggcccca ccaatttctc ggacacttct cagtgtgtgg aagctcatgt gggcccctga ggctcatgcc tgggaagtgt tgtgggggct cccaggagga ctggcccaga gagccctgag atagcgggga tcctgaactg gactgaataa aacgtggtct cccactg
(配列番号46)
acaggttctg gtcatgcaag ctctacccca ggtggagaaa aggagacttc ggctacccag agaagttcag tgcccagctc tactgagaag aatgctgtga gtatgaccag cagcgtactc tccagccaca gccccggttc aggctcctcc accactcagg gacaggatgt cactctggcc ccggccacgg aaccagcttc aggttcagct gccacctggg gacaggatgt cacctcggtc ccagtcacca ggccagccct gggctccacc accccgccag cccacgatgt cacctcagcc ccggacaaca agccagcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccacggtgt cacctcggcc ccggacacca ggccggcccc gggctccacc gcccccccag cccatggtgt cacctcggcc ccggacaaca ggcccgcctt gggctccacc gcccctccag tccacaatgt cacctcggcc tcaggctctg catcaggctc agcttctact ctggtgcaca acggcacctc tgccagggct accacaaccc cagccagcaa gagcactcca ttctcaattc ccagccacca ctctgatact cctaccaccc ttgccagcca tagcaccaag actgatgcca gtagcactca ccatagctcg gtacctcctc tcacctcctc caatcacagc acttctcccc agttgtctac tggggtctct ttctttttcc tgtcttttca catttcaaac ctccagttta attcctctct ggaagatccc agcaccgact actaccaaga gctgcagaga gacatttctg aaatgttttt gcagatttat aaacaagggg gttttctggg cctctccaat attaagttca ggccaggatc tgtggtggta caattgactc tggccttccg agaaggtacc atcaatgtcc acgacgtgga gacacagttc aatcagtata aaacggaagc agcctctcga tataacctga cgatctcaga cgtcagcgtg agtgatgtgc catttccttt ctctgcccag tctggggctg gggtgccagg ctggggcatc gcgctgctgg tgctggtctg tgttctggtt gcgctggcca ttgtctatct cattgccttg gctgtctgtc agtgccgccg aaagaactac gggcagctgg acatctttcc agcccgggat acctaccatc ctatgagcga gtaccccacc taccacaccc atgggcgcta tgtgccccct agcagtaccg atcgtagccc ctatgagaag gtttctgcag gtaacggtgg cagcagcctc tcttacacaa acccagcagt ggcagccgct tctgccaact tgtagggcac gtcgccgctg agctgagtgg ccagccagtg ccattccact ccactcaggt tcttcaggcc agagcccctg caccctgttt gggctggtga gctgggagtt caggtgggct gctcacagcc tccttcagag gccccaccaa tttctcggac acttctcagt gtgtggaagc tcatgtgggc ccctgaggct catgcctggg aagtgttgtg ggggctccca ggaggactgg cccagagagc cctgagatag cggggatcct gaactggact gaataaaacg tggtctccca ctg
(配列番号48)
コロイド調製/実施例にて用いる薬物スクリーニング方法
本発明の特定の実施例および実施態様において、コロイド粒子の表面に自己組織化単分子層(SAM)を作製して使用する。コロイドはSAMで誘導体化されており、国際公開公報番号WO00/43791、2000年7月27日公開、表題「神経変性疾患における異常タンパク凝集の迅速かつ高感受性検出」、(参照により本明細書に組み入れられる)に記載されている方法と同様の方法で、薬物スクリーニングのために調製された。
本実施例は、MUC1受容体への二量体化の影響を示す。本実施例において、MUC1受容体のMGFR領域に対して生成された本発明の2価抗体への細胞の暴露は、様々な濃度において、MUC1腫瘍細胞に提示されたメカニズムに一致する増強した細胞増殖(もしくはその欠失)をもたらすことが示されている。2価抗体は配列表に示されるvar−PSMGFRもしくはnat−PSMGFRのいずれかに対して生じた(すなわち、2つのMGFRに同時に結合する能力を有する1つの抗体が産生された)。MUC1腫瘍細胞(T47D)は本抗体に露呈され、細胞増殖は抗体の濃度の関数として研究された。成長因子/受容体−抗体応答の典型的な成長/応答曲線が観察された。特に、細胞のほんの一部分のみが抗体に露呈されるのに十分に低い濃度では、細胞増殖は低かった。1つの抗体が隣接したMGFRに結合することのできる十分に高い抗体濃度では、細胞増殖が最大であった。高過剰の抗体において、各抗体は隣接したMGFRを二量体化するよりも、むしろ1つのMGFRにしか結合せず、増殖が減少した。
MUC1受容体へのリガンドを同定する試みにおいて、合成のHis−var−PSMGFRペプチド、GTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGAHHHHHH(配列番号2)、MUC1受容体の一部分の代表であり、鎖間結合領域の開裂後、細胞表面に付着したまま残存するものであるが、これをNTA−Niビーズ(カタログ番号1000630;Qiagen GmbH, Germanyより市販)に負荷し、プロテアーゼ阻害剤PMSF(フェニルメチルスルホニルフルオライド)の存在下(図4)もしくは非存在下(図5)で細胞可溶化液とともにインキュベートした。T47D細胞から得た可溶化液を用いたが、これはこの乳房腫瘍細胞株が、MUC1とMUC1リガンドを過剰発現することが知られているからである。T47D細胞を培養し、その後1分間超音波処理して細胞を可溶化した。可溶化液をPSMGFRペプチド提示ビーズと混合し、1時間、断続的に混合しながら氷上でインキュベートした。ネガティブコントロールとして、無関係のペプチドHHHHHHRGEFTGTYITAVT(配列番号13)をNTA−Niビーズに付着させ、同じように処理した。両セットのビーズを、pH7.4のリン酸緩衝液で2回洗浄した。結合タンパク種は、250mMイミダゾールも含む100μLリン酸緩衝液を3回添加することにより溶出した。両方のペプチドについて、最初の溶出液の一部分を除去して、別個の試料として流すために貯蔵し、一方、残部をさらなる2回の溶出液と組み合わせて、TCA(トリクロロ酢酸)−滴定で濃縮した(Chen, L.ら、 Anal. Biochem. Vol 269; pgs 179-188; 1999)。溶出液を、12%SDSゲルに流した、図4参照。その後、ゲルを銀染色した(Schevchenko, Aら、Anal. Chem., Vol. 68; pg 850-858; 1996)。レーンに次のように負荷した:(左から右へ)(1)Benchmarkプレ染色タンパクラダー(Gibco);(2)MUC1ペプチドからの第1溶出液;(3)TCA濃縮試料の1/10;(4)ブランク;(5)TCA濃縮試料の9/10;(6)第1溶出液のネガティブコントロールペプチド;(7)ネガティブコントロールペプチドから得たTCA濃縮試料の1/10;(8)0.5ピコモルBSA(標準として);(9)ネガティブコントロールペプチドから得たTCA濃縮試料の9/10;(10)銀染色SDSページ標準(BioRadカタログ番号1610314)。図4を参照して、レーン2と6(コントロール)を比較すると、MUC1のPSMGFRペプチドが、3つのペプチドに別々に結合したことを見ることができる:見かけ分子量が17kDで流れる第1固有ペプチド;見かけ分子量23kDで流れる第2ペプチド(より濃いバンド)。試料が最も濃縮されているレーン5において、第3の固有バンドが約35kDに見られることは注目すべきである。
本実施例において、MUC1癌細胞での細胞増殖を引き起こすMUC1癌細胞により産生されたリガンドがマルチマーであることを証明した。
MUC1IBRの放出が癌の進行に関連し得る。以下は、これらの受容体の開裂状態に影響する薬剤候補物を同定する細胞分析の全体の記載である。スクリーニングはまた、酵素開裂、受容体産生、発現、安定性、輸送もしくは分泌を含むが、これらに限定されない、結果として細胞から分断され、かつ放出される受容体の自己凝集部分の減少をもたらす全工程を直接もしくは間接に調節する薬剤候補物を同定する。
細胞培養:
全ての細胞株はATCC(American Type Culture Collection)から入手し、細胞株に添付のATCC推奨法に従って培養した。用いた細胞は以下のものを含む[出願人による名称(ATCC番号)]:T−47D(HTB−133),1500(CRL−1500),1504(CRL−1504),HeLa(CCL−2),HEK−293(CRL−1705),BT−474(HTB−20),MDA−MB−453(HTB−131)。
細胞可溶化液の調製において健康な細胞を100mm培養処理皿上に播種し、細胞が約80〜90%コンフルエントになるまでインキュベートした。その後、培地を除去し、単層を5mLの冷PBSで2回洗浄した。全ての残っているPBSを完全に除去した。冷たい高塩RIPA可溶化緩衝液1ml[400mM NaCl、50mM Tris pH8.0,1%NP−40、0.1%SDS,0.5%デオキシコール酸ナトリウム、1×プロテアーゼ阻害剤カクテル(Roche Applied Sciences; Indianapolis, IN)]を単層へ添加し、時折、攪拌しながら、5分間氷上でインキュベートすることにより細胞を可溶化した。細胞をこすり落として、1.5mLエッペンドルフチューブに可溶化液を回収した。可溶化液を10,000rpmで遠心分離し、透明の上清を除去し、新しいチューブ中に入れ、使用するまで−20℃で貯蔵した。
タンパク濃縮物は、Pierce BCA Protein Assay(Rockford, L)を用いて得た。製造者のプロトコールに従った。吸光度をHitachi(Randolph, MA)のU−2010 UV/Vis−吸光度計を用いて読んだ。データをプロットし、Microsoft Excelにより曲線を適合した。
試料をSigma(St. Louis, MO)のEnzymatic Protein Deglycosylation Kitを用いて脱グリコシル化した。キットには、反応緩衝液と変性緩衝液と共に、O−グリコシダーゼ、PNGase−Fおよびα−ノイラミニダーゼ酵素が含まれている。各脱グリコシル化は、可溶化液から総タンパク100μgを用いて行い、酵素と緩衝液をキットに添付の製造者のプロトコール通りに添加した。
可溶化液タンパクを分離するために、SDS−PAGE電気泳動を用いた。細胞可溶化液を融解し、50μgの総タンパク量で適切なSDS負荷緩衝液に希釈して、最終容量60μlに調製して試料とした。15%ポリアクリルアミドゲルを開裂MUC1部分の低分子量バンドを分離するために用いた。ゲルをBioRad Mini−Protean3(Hercules, CA)で電気泳動した。
電気泳動が終了した後、ゲルをMillipore(Bedford, MA)のImmobilon−P PVDF膜に、BioRad(Hercules, CA)のTrans−Blot SD Semi−Dry Transfer Cellを用いて半乾燥転写のために調製した。ゲル、PVDF膜、ブロッティング紙(BioRad;Hercules, CA)を、Tris/グリシン転写緩衝液(25mM Tris,192mMグリシン,20%メタノール)中で、15分間平衡化させた。サンドイッチを製造者の記載どおりに装置上に調製した。電気泳動転写を15Vで45分間行った。
膜を除去し、25mlブロット(PBS,0.05%Tween−20,5%ミルク)中に即座に置き、2時間緩やかに攪拌しながらインキュベートした。ブロットを除去し、25mlの一次抗体溶液[ブロット中、本発明のα−PSMGFR抗体の1:1000希釈液もしくはVU−4H5抗体(Santa Cruz Biotechnologies; Santa Cruz, CA)の1:200の希釈液]に置き換え、4℃で一晩インキュベートした。その後、溶液を廃棄し、膜を各10分間5回、PBS−T(PBS,0.05%Tween−20)で洗浄した。次いで、膜を二次抗体溶液[ブロット中、HRP(西洋ワサビパーオキシダーゼ)−結合ヤギ−α−ウサギIgG抗体もしくはHRP−結合ウサギ−α−マウスIgG抗体(Jackson Immunoresearch; West Grove, PA)の1:20000希釈液]で、1時間室温でインキュベートした。溶液を廃棄し、膜を5回、各10分間、PBS−T中で洗浄した。その後、膜をBioRad Laboratories(Hercules, CA)のImmun−Star HRP Luminol/Enhancerおよびパーオキシダーゼ緩衝液の1:1混合液中に5分間おいた。基質を除去し、膜をサランラップ上に置き、フィルムに露出し、Kodak X−OMATで現像した。
完全長MUC1受容体をコードするpMucl−Full
pMucl−Full構築物はMUC1の完全DNAを含み、完全長Muc1タンパク(図22および配列番号10)をコードする。pMucl−Fullプラスミドは、MUC1のcDNAの異なる部分を含む2つの別個のプラスミドから結合された。MUC1のアミノ−末端を韓国生命科学および生物科学研究機関(太田、韓国)のGenome Research Center and the Center for Functional Analysis of Human Genome(GRC/CFAHG)、から入手したEST0039670より得た。EST0039670はMUC1オープンリーディングフレームのアミノ−末端からMUC1のタンデム繰り返しセグメント中に約800塩基対までのcDNAを含んでいた。MUC1のcDNAのカルボキシ−末端は、American Type Culture Collection (ATCC)から得たIntegrated Molecular Analysis of Genomes and their Expression(IMAGE)のクローン番号2428103から得た。このプラスミドは、MUC1のカルボキシ−末端を通ってタンデム繰り返しの残りの1300塩基対を含む。SalIによりIMAGE2428103を含むプラスミドを制限酵素分解して、XhoI分解したEST0039670にサブクローニングすることにより、完全長Muc1構築物(Mucl−Full)を生成した。生じたサブクローン、pESTMucIを制限酵素分解とアガロースゲル電気泳動により確認し、正しく構築されたプラスミドについて予測される大きさのバンドを有することが見られた。pESTMuclプラスミドを哺乳動物発現ベクターpIRES2−GFPにサブクローニングするために用いた。
pMucl−Rep(配列番号46)構築物はアミノ末端が欠失したMuclタンパクをコードする(図1;配列番号41)。Repアイソフォームは、アミノ末端を失っており、そしてMUC1の末端繰り返しの約半分しか含まない。ESTプラスミド(IMAGE2428103)にMUC1のPCR増幅シグナルペプチドをサブクローニングすることにより、最初のpSP−Repを生成した。MUC1のシグナルペプチドをアミノ末端でサブクローニングし、原形質膜中のタンパクの発現を確実にした。IMAGEクローン番号4695020から得た正常なMUC1シグナルペプチドのPCR増幅を表6のプライマーを用いて行った。PCR産物をEcoRIとXhoIで分解して、EcoRIおよびSalI分解ESTプラスミド(IMAGE2428103)にサブクローニングした。生じたサブクローンの適切な構築物、pSP−Repを分解とアガロースゲル電気泳動により確認した。次いで、pSP−RepプラスミドとpIRES2−GFPをEcoRIとBamHIにより分解し、ともに連結した。pMucl−Repの適切な構築物を、制限酵素分解および引き続いてゲル電気泳動により確認した。配列決定もまた、pMucl−Repプラスミドが正しく作られたことを示した。
これらの3つ構築物はMUC1の種々のアミノ末端欠失アイソフォーム、タンデム繰り返し部までのカルボキシ末端をコードする(図1参照。pMucl−UR(配列番号44)は配列番号39をコードし;pMucl−CM(配列番号43)は配列番号38をコードし;そして、pMucl−PMMGFRTC(配列番号42)は配列番号37をコードする)。pMucl−URはMUC1のアミノ酸981から1255を含むアイソフォームをコードする。pMucl−CMはMUC1のアミノ酸1085から1255を含むアイソフォームをコードし、168個のアミノ酸のペプチドをコードする。pMucl−PSMGFRTCはMUC1のアミノ酸1110からアミノ酸1255のペプチドをコードし、長さが143個のアミノ酸になる。これらのプラスミドの3つ全ては以下の同じ手順により構築された。まず、IMAGEクローン番号4695020から、各々がEcoRIまたはEagIのいずれかの制限酵素部位を含むプライマーを用いて、MUC1のシグナルペプチドをPCRにより増幅した。その後、EagIまたはBamHI部位を含んだプライマーにより構築物のカルボキシ末端部分をPCRにより増幅した。PCRに用いたプライマーを表6に記載する。PCR産物をEagIで分解し、その後、連結した。連結は先に用いたEcoRIおよびBamHIを含むプライマーを用いてPCRにより再度、増幅した。これは、連結したPCR産物を増幅した。生じたDNA断片をEcoRIとBamHIで分解し、同様に分解したpIRES2−EGFPにサブクローニングした。所望のPCR産物とプラスミドの大きさをアガロースゲル電気泳動により確認した。配列決定により、正しいプラスミドが作られたことを確認した。
pMucl−YプラスミドはMUC1の選択的にスプライスされた型をコードする(図1参照。pMucl−UR(配列番号45)は配列番号40をコードする)。Mucl−YのcDNAはIMAGEクローン番号4695020から得た。このクローンを配列決定すると、余分な9個のアミノ酸を含むことがわかった。これらはPCRによって削除された。Mucl−YのcDNAの前部分は制限酵素部位EcoRIを含むプライマーおよびAlwNI制限酵素部位を含むプライマーにより増幅した。Mucl−Yの末端部分を、AlwNI制限酵素部位を含むプライマーおよび制限酵素部位BamHIを含むプライマーにより増幅した。両方のPCR産物をAlwNIで分解後、2つの断片を連結した。連結は先に用いたEcoRIおよびBamHIを含むプライマーを用いてPCRにより再度、増幅した。これは連結したPCR産物を増幅した。生じたDNA断片をEcoRIとBamHIで分解し、同様に分解したpIRES2−EGFPにサブクローニングした。所望のPCR産物とプラスミドの大きさをアガロースゲル電気泳動により確認した。配列決定により、9個のアミノ酸が欠失した正しいプラスミドが作られたことを確認した。
ポリメラーゼチェーンリアクション(PCR)をMJ Research(Watertown, MA)のMiniCylcerを用いて行った。PCRに以下の工程を用いた。第1工程:94℃、2分間、第2変性工程:94℃、30秒間、第3アニーリング工程:55℃、30秒間、第4伸長工程:68℃、1分間、第5工程:第2工程から第4工程を34回、第6工程:68℃、5分間、そして4℃で維持。Invitrogen(Carlsbad, CA)のPlatinum Pfx DNA Polymeraseを増幅に用いた。PCR反応は、全50μlの反応容量中、2ngプラスミドDNA、1×Pfx増幅緩衝液、1mM MgSO4、0.3μlの各プライマー、1.25単位のPfxポリメラーゼ、および0.3μMの各dNTPを含んでいた。PCR産物をQiagenのQiaquick PCR除去キットを用いて、プライマーと緩衝液を取り除いて精製した。PCR産物を制限酵素分解前にこの方法で処理した。
目的は、MUC1タンパクの種々のアイソフォームによるHEK293細胞の形質移入であり、細胞表面に発現したタンパクを有することである。HEK293細胞にMUC1アイソフォームを形質移入し、形質移入された細胞の表面上はMUC1アイソフォームの発現を示した。
ヒト胚性腎臓(HEK)293細胞を播種して、90%コンフルエンシーを生成した。Invitrogen (Carlsbad, CA)のリポフェクトアミン2000を用いて細胞に形質移入した。製造者のプロトコールに従った。DNAとリポフェクトアミンの両方を血清と抗生物質を含まない培地中に希釈した。5分後、DNAとリポフェクトアミンを混合し、室温で30分間インキュベートした。細胞を滅菌1×PBSで1回洗浄し、その後形質移入混合液を細胞に添加した。細胞をDNA:リポフェクトアミン複合体と共に、10%血清を含む培地に変更する前に、培地を4〜6時間インキュベートした。これらの細胞を24時間もしくは48時間後に、MUC1アイソフォームの発現について分析した。安定した細胞株を10日間、Invitrogenの600μg/mlのGenetimicin(G418)により、形質移入の48時間後に、選択した。
免疫化に用いたペプチド配列は、GTINVHDVETQFNQYKTEAASPYNLTISDVSVSDVPFPFSAQSGA(var−PSMGFR 配列番号7)であった。2匹のウサギをメーカー独自の市販技術であるPolyquickTM法を用いて免疫した。4週間後、血液をPSMGFR特異的抗体について評価した。ウサギは、抗体を回収する2週間前に、抗原の追加免疫を受けた。抗体をカラム支持体に結合したペプチドを用いて親和性精製した。
実施例8にて産生したポリクローナル抗体の抗体断片化を、Maine Biotechnology Servises Inc.(Portand, ME)によるパパイン分解を用いて行った。断片化した抗体を未開裂の抗体およびFc断片から精製した。開裂反応および精製はSDS PAGEで評価した。
MUC1アイソフォーム形質移入体が細胞の表面にタンパクを発現したことを立証するために、フローサイトメトリーを形質移入細胞に行った。細胞の間接染色プロトコールを以下のように簡単に続ける。1億個の細胞を1mgの一次抗−PSMGFR抗体により染色した。その後、細胞を1×PBSで洗浄した。その後、細胞をJackson Laboratoriesのフィコエリトリン(PE)−標識−Fab−断片、抗−ウサギ二次抗体で染色した。細胞を洗浄し、PIで染色した。フローサイトメトリーをBeckton Dickinson(Palo Alto, CA)のFACS Calibur設備で行った。前方散乱光および側方散乱光とプロピジウムイオジン(PI)ネガティブ染色により、細胞集団を生細胞について探索した。形質移入体を示すGFPのレベルおよびMUC1染色を示すPEについて細胞を評価した。形質移入体はベクターコントロールのレベルより高くPSMGFRを染色していた(データは示されず)。MUC1−PSMGFRTCとMUC1−Yの構築物が他の形質移入体に比べて高いレベルまで染色されていることが観察された。大部分の他の形質移入体はGFPが低く、これは低形質移入レベルを示す可能性がある。
試薬:
* 血清不含RPMI培地中で実施例8と9に記載の通り産生されたANTI−PSMGFR抗体の連続希釈液(1×、1×の1/10、1/50、1/250、1/1000)
* 所望の細胞の入った60〜70%コンフルエントフラスコ
* 10%および0.1%細胞特異的培地
* トリプシン
* 96ウェルプレート
1. 96ウェルプレートの周辺ウェルに100μlの培地を置く。1ウェルあたり6000個の細胞を内側のウェル中に置く(10%血清を含む成長培地100μl容量中)。
2. 翌日、培地を0.1%血清成長培地に変更し、2.5%血清を含む培地に変更したBT474細胞を除いて、一晩インキュベートする(12〜24時間)。
3. 翌日、所望のウェルに抗体(1ウェルあたり1μl)を添加し、緩やかに混合し、インキュベータにもどす。抗体を24時間ごとに添加する。腫瘍細胞株1500、1504、およびBT474については、抗体を5回添加し、最後の抗体の添加後、24時間後に細胞を計数した。腫瘍細胞株T47Dについて、抗体を2もしくは3回添加した。実施例7において上述の通り産生されたK293細胞安定形質移入体について、抗体を2回添加した。1価抗体断片と2価抗体の間での競合実験において、1価抗体断片を2価抗体の添加の前に10〜15分の間に添加した。
4. 所望の分析(BrdU,個々の細胞の計数)を行って、細胞を計数した。
5. 成長百分率を以下の式を用いて算出した:
成長%=100{最終細胞数−開始細胞数}/開始細胞数
6. 正常化成長を以下のように算出した:
正常化成長%=100{抗体の有無に係わらない最終細胞数}/抗体なしの最終細胞数
成長%=100×{最終細胞数−開始細胞数}/開始細胞数
正常化成長百分率を以下のように算出した:
正常化成長%=100×{抗体の有無に係わらない最終細胞数}/抗体なしの最終細胞数
ヒト乳房腺腫CRL−1500細胞をAmerican Type Culture Collection(ATCC)から取得した。細胞を10%ウシ胎児血清、Pen/Sterp、1mMピルビン酸ナトリウム、0.5%グルコースおよび0.15%重炭酸ナトリウムを含むRPMI1604を入れたT75通気式フラスコ中に播種した。さらに、細胞を実験前に10回継代した。準備ができたら、10%ウシ胎児血清、Pen/Sterp、1mMピルビン酸ナトリウム、0.5%グルコースおよび0.15%重炭酸ナトリウムおよびインシュリン(10μg/ml)を含むRPMI1640中に60mmプレートあたり、細胞1×106個を播種した。翌日、70%コンフルエントの細胞を乱さないように注意深く、(1回、)血清不含RPMI培地で洗浄し、一晩、5%CO2および37℃で、2ml血清不含RPMI培地中でインキュベートした。翌日、細胞を5μlの親和性精製2価抗−PSMGFRポリクローナル抗体、1価抗−PSMFGRのみ(10μl)のいずれか、もしくは両方一緒に刺激した。未処理細胞をコントロールとして用いた。活性化後、細胞を即座に2回、氷冷PBSで洗浄し、緩衝液(1%Triton X−100、10%グリセロール、20mM HEPES、pH7.2、100mM NaCl、1mMフェニルメチルスルホニルフルオライド、10μg/mlアプロチニン、10μg/mlロイペプチンおよび1mM Na3VO4)を用いて可溶化した。細胞可溶化液を15分間回転プレート上でインキュベートし、次いで10分間(10g)、遠心分離して、界面活性剤不溶物質を除去した。等量のタンパク(1レーンあたり100μg)をSDS−PAGE試料緩衝液と混合し、5分間煮沸し、10%SDS−ポリアクリルアミドゲルにて分離し、その後、ポリビニリデンジフルオライド膜に転写した。次いで、5%無脂肪乾燥乳を含むリン酸緩衝生理食塩水(PBS)中で、室温にて1時間、膜をブロッキングした。膜を一晩、4℃で抗−ERK2もしくは抗−ppERK1/2抗体(Cell Signaling Technology Inc., Beverly, MA, USA)(0.5%ミルクを含むPBS中で1:1000に希釈)でインキュベートした。イムノブロットを20分間1回、5分間2回、PBSで洗浄し、西洋ワサビパーオキシダーゼを結合した二次抗体で(1:20000に希釈)1時間、インキュベートし、20分間1回、5分間2回、PBSで洗浄し、増強した化学蛍光試薬(BioRad)を用いた化学発光により可視化した。
コロイドを25μM NTAチオールで上述の通りに調製した。次に、ヒスチジンタグPSMGFRペプチド(例えばHis−var−PSMGFR 配列番号2)もしくはコントロールRGDペプチドをコロイドに結合させた。
マイクロタイタープレートのウェルに55μlのリン酸緩衝液を添加し、続いて5μlの100μM BSA(ウシ胎児血清アルブミン)を添加した。
次いで、1種の抗体/複数種の抗体(未希釈の貯蔵液の最小10μl、概ね1μg/μl)をウェルに添加して、中身をピペッティングにより混合した。
30μlのコントロールRGDコロイドもしくはHis−PSMGFRコロイドのいずれかを添加し、次に続いて混合した。抗体−ペプチド相互作用を3〜4時間進行させた。
ウェルを650nmで吸光度を測定することによりスコア化した。
Claims (1)
- ユビキチン化タンパク質、あるいはバロシン含有タンパク質に結合するFas関連因子1(Fas associated Factor 1)のポリペプチドフラグメント。
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JP2016094423A (ja) * | 2003-08-26 | 2016-05-26 | ミネルバ バイオオテクノロジーズ コーポレーション | 癌(muc1)の診断および治療のための技術および組成物 |
Citations (5)
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WO2002022685A2 (en) * | 2000-09-11 | 2002-03-21 | Kufe Donald W | Muc1 extracellular domain and cancer treatment compositions and methods derived therefrom |
WO2002051871A2 (fr) * | 2000-12-26 | 2002-07-04 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Anticorps anti-cd28 |
WO2002056022A2 (en) * | 2000-11-27 | 2002-07-18 | Minerva Biotechnologies Corp | Diagnostics, drug screening and treatment for cancer |
WO2002078598A2 (en) * | 2001-03-29 | 2002-10-10 | Ramot University Authority For Applied Research & Industrial Development Ltd. | Peptides and antibodies to muc 1 proteins |
WO2002079429A2 (en) * | 2001-03-30 | 2002-10-10 | The Regents Of The University Of California | Anti-muc-1 single chain antibodies for tumor targeting |
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DK2363410T3 (en) * | 2003-08-26 | 2018-01-15 | Minerva Biotechnologies Corp | ISOFORMER OF MUC1 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002022685A2 (en) * | 2000-09-11 | 2002-03-21 | Kufe Donald W | Muc1 extracellular domain and cancer treatment compositions and methods derived therefrom |
WO2002056022A2 (en) * | 2000-11-27 | 2002-07-18 | Minerva Biotechnologies Corp | Diagnostics, drug screening and treatment for cancer |
WO2002051871A2 (fr) * | 2000-12-26 | 2002-07-04 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Anticorps anti-cd28 |
WO2002078598A2 (en) * | 2001-03-29 | 2002-10-10 | Ramot University Authority For Applied Research & Industrial Development Ltd. | Peptides and antibodies to muc 1 proteins |
WO2002079429A2 (en) * | 2001-03-30 | 2002-10-10 | The Regents Of The University Of California | Anti-muc-1 single chain antibodies for tumor targeting |
Non-Patent Citations (1)
Title |
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JPN5006012573; MEERZAMAN DAOUD: AMERICAN JOURNAL OF PHYSIOLOGY V281 N1 PART 1, 200107, P. L86-L91 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2016094423A (ja) * | 2003-08-26 | 2016-05-26 | ミネルバ バイオオテクノロジーズ コーポレーション | 癌(muc1)の診断および治療のための技術および組成物 |
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JP2016094423A (ja) | 2016-05-26 |
JP6111018B2 (ja) | 2017-04-05 |
DK2363410T3 (en) | 2018-01-15 |
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