JP6533534B2 - 膠芽腫の治療に使用するための組成物及びその使用 - Google Patents
膠芽腫の治療に使用するための組成物及びその使用 Download PDFInfo
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- JLYXXMFPNIAWKQ-UHFFFAOYSA-N γ Benzene hexachloride Chemical compound ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 description 1
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
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- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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Description
本出願は、連邦規則法典第37巻第1.821節以下による1つ又は複数の配列表を含み、これらの配列表は、書類及びコンピュータ可読媒体の両方において開示されており、上記書類及びコンピュータ可読型開示は、参照によりその全体が本出願に援用される。
腫瘍の成長及び転移は、これらが宿主の免疫監視機構を回避して宿主の防御を克服する能力に大きく左右される。ほとんどの腫瘍は、宿主の免疫系によって程度が可変であると認識できる抗原を発現するが、多くの場合、エフェクタT細胞の無効な活性化により、不十分な免疫応答が誘発される(非特許文献1)。
血管内皮成長因子(VEGF)は、血小板由来成長因子スーパー遺伝子ファミリーに属し、血管新生及びリンパ管新生の制御において中心的な役割を果たす。VEGFファミリーは、ホモ二量体構造を有する以下の5つのメンバーに分割される:VEGF‐A、VEGF‐B、VEGF‐C、VEGFD、胎盤成長因子(PlGF)(非特許文献34、35)。これらのペプチドは、別個の遺伝子によってコードされる。更に、VEGF‐Aは4つのアイソフォームで存在する。VEGF121、VEGF165、VEGF189、VEGF206は、選択的mRNAスプライシングによって生成される(非特許文献36、37)。VEGF‐Aは一般にVEGFと呼ばれる。というのは、VEGF‐Aは発生的血管形成、血管新生、及び前駆内皮細胞の分化の主要なレギュレータであるためである。VEGF‐Aアイソフォームのうち、量及び生物活性の観点から、VEGF165が支配的である。VEGF165は様々なヒト腫瘍において過剰発現し、この過剰発現は、腫瘍の進行、浸潤、転移に相関する(非特許文献38、39、40)。
抗体は、診断における公知の使用に加えて、治療剤として有用であることが分かっている。例えば免疫療法、即ち治療目的での抗体の使用は、近年癌治療のために使用されている。受動免疫療法は、癌治療におけるモノクローナル抗体の使用を伴う(例えば非特許文献43参照)。これらの抗体は、腫瘍細胞の成長又は生存の直接的な阻害、及び身体の免疫系の天然の細胞殺傷活性を回復させる能力の両方による、固有の治療的生物活性を有することができる。これらの作用剤は、単独で、又は放射若しくは化学療法剤と併用して投与できる。それぞれ非ホジキンリンパ腫及び乳癌の治療のために承認されているリツキシマブ及びトラスツズマブは、このような療法の例である。あるいは抗体を用いて、抗体が毒性剤に結合した抗体複合体を作製でき、腫瘍への特異的な結合によって腫瘍に上記作用剤を配向する。ゲムツズマブ・オゾガミシンは、白血病の治療のために使用される、承認されている抗体複合体の例である。
膠芽腫は、中枢神経系(CNS)の最も一般的な原発性腫瘍であり、ヒトの癌の中でも最も致命的なものである(非特許文献47、48)。悪性神経膠腫を有する患者の効果的な治療は未だ不明であり、手術、放射線及びテモゾロミドによる標準治療後の生存期間中央値は15ヶ月未満である(非特許文献49)。再発後の効果的な治療は存在しない(非特許文献50)。
(A)抗B7‐H3抗体;
(B)(A)のB7‐H3‐結合断片;又は
(C)B7‐H3に結合するダイアボディ
である。
(A)抗VEGF抗体若しくはVEGFアンタゴニスト;又は
(B)抗VEGFR抗体若しくはVEGFRアンタゴニスト
である。
A.B7‐H3結合に関して抗体BRCA84D、BRCA69D若しくはPRCA157と競合し;又は
B.抗体BRCA84D、抗体BRCA69D若しくは抗体PRCA157の3つの重鎖CDR及び3つの軽鎖CDRを有する。
A.VEGF結合に関してベバシズマブと競合し;又は
B.ベバシズマブの3つの重鎖CDR及び3つの軽鎖CDRを有する。
(A)BRCA84Dの軽鎖のCDR1、CDR2及びCDR3を備える軽鎖可変ドメイン;
(B)BRCA84Dの重鎖のCDR1、CDR2及びCDR3を備える重鎖可変ドメイン;並びに
(C)置換基:L235V、F243L、R292P、Y300L及びP396Lを備えるFc領域
を有する抗B7‐H3抗体である。
(A)hBRCA84D‐2VLのアミノ酸配列(配列番号69)を有する可変軽鎖;及び
(B)hBRCA84D‐2VHのアミノ酸配列(配列番号79)を有する可変重鎖
を備えるヒト化抗B7‐H3抗体であり、また腫瘍血管新生を促進する細胞表面因子又はその受容体に特異的な結合能を有する上記分子は、ベバシズマブである。
本発明の実施は、そうでないことが指示されていない限り、(組み換え技術を含む)分子生物学、微生物学、細胞生物学、生化学及び免疫学の従来の技術を採用することになり、これらは従来技術の範囲内である。このような技術については:Molecular Cloning: A Laboratory Manual, Third Edition (Sambrook et al. Eds., 2001) Cold Spring Harbor Press, Cold Spring Harbor, NY; Oligonucleotide Synthesis: Methods and Applications (Methods in Molecular Biology), Herdewijn, P., Ed., Humana Press, Totowa, NJ; Oligonucleotide Synthesis (Gait, M.J., Ed., 1984); Methods in Molecular Biology, Humana Press, Totowa, NJ; Cell Biology: A Laboratory Notebook (Cellis, J.E., Ed., 1998) Academic Press, New York, NY; Animal Cell Culture (Freshney, R.I., Ed., 1987); Introduction to Cell and Tissue Culture (Mather, J.P. and Roberts, P.E., Eds., 1998) Plenum Press, New York, NY; Cell and Tissue Culture: Laboratory Procedures (Doyle, A. et al., Eds., 1993‐8) John Wiley and Sons, Hoboken, NJ; Methods in Enzymology (Academic Press, Inc.) New York, NY; Weir’s Handbook of Experimental Immunology (Herzenberg, L.A. et al. Eds. 1997) Wiley‐Blackwell Publishers, New York, NY; Gene Transfer Vectors for Mammalian Cells (Miller, J.M. et al. Eds., 1987) Cold Spring Harbor Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (Ausubel, F.M. et al., Eds., 1987) Greene Pub. Associates, New York, NY; PCR: The Polymerase Chain Reaction, (Mullis, K. et al., Eds., 1994) Birkhauser, Boston MA; Current Protocols in Immunology (Coligan, J.E. et al., eds., 1991) John Wiley and Sons, Hoboken, NJ; Short Protocols in Molecular Biology (John Wiley and Sons, 1999) Hoboken, NJ; Immunobiology 7 (Janeway, C.A. et al. 2007) Garland Science, London, UK; Antibodies (P. Finch, 1997) Stride Publications, Devoran, UK; Antibodies: A Practical Approach (D. Catty., ed., 1989) Oxford University Press, USA, New York NY); Monoclonal Antibodies: A Practical Approach (Shepherd, P. et al. Eds., 2000) Oxford University Press, USA, New York NY; Using Antibodies: A Laboratory Manual (Harlow, E. et al. Eds., 1998) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; The Antibodies (Zanetti, M. et al. Eds. 1995) Harwood Academic Publishers, London, UK); and DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology, Eighth Edition, DeVita, V. et al. Eds. 2008, Lippincott Williams & Wilkins, Philadelphia, PA.等の文献に十分に説明されている。
本明細書において使用される場合、「抗体」は、免疫グロブリン分子であって、当該免疫グロブリン分子の可変領域に位置する少なくとも1つの抗原認識部位によって、炭水化物、ポリヌクレオチド、脂質、ポリペプチド等の標的に特異的に結合できる、免疫グロブリン分子である。本明細書において使用される場合、この用語は、完全なポリクローナル又はモノクローナル抗体だけでなく、これらの断片(Fab、Fab'、F(ab')2Fv等)、単鎖(ScFv)、その変異体、自然に発生する変異体、必要な特異性の抗原認識部位を有する抗体部分を備える融合タンパク質、ヒト化抗体、キメラ抗体、「BiTE」、「DART(商標)」分子、及び必要な特異性の抗原認識部位を備える免疫グロブリン分子の他のいずれの修飾構成を包含する。
本発明は、抗B7‐H3抗体、抗B7‐H3抗体由来のポリペプチド、抗B7‐H3抗体をコードする配列を含むポリヌクレオチド、及び本明細書に記載の他の作用剤からなる、医薬組成物を含む組成物を包含する。本明細書において使用される場合、組成物は更に、B7‐H3、B7‐H3アゴニスト、アンタゴニスト、モジュレータに結合する1つ若しくは複数の抗体、ポリペプチド及び/若しくはタンパク質、並びに/又はB7‐H3に結合する1つ若しくは複数の抗体、ポリペプチド及びタンパク質をコードする配列を含む1つ若しくは複数のポリヌクレオチドを含む。
(a)B7‐H3(及び特に腎臓、前立腺、若しくは肺癌細胞を含むがこれらに限定されない癌細胞の表面に発現するB7‐H3分子)に特異的に結合する能力;
(b)公知の抗B7‐H3抗体のB7‐H3への優先的結合を競合的に阻害する能力(オリジナルの抗体が優先的に結合するものと同一のB7‐H3エピトープに対して優先的に結合する能力を含む);
(c)インビトロ若しくはインビボで、生きた細胞の表面に露出したB7‐H3の一部分に結合する能力;
(d)B7‐H3を発現する生きた癌細胞の表面に露出したB7‐H3の一部分に結合する能力;
(e)表面にB7‐H3を発現する癌細胞(腎臓、前立腺若しくは肺癌細胞等)に化学療法剤を送達する能力;及び
(f)表面にB7‐H3を発現する癌細胞(限定するものではないが前立腺癌細胞等)に治療剤若しくは検出可能なマーカを送達する能力。
本明細書において使用される場合、用語「B7‐H3」は、CD276としても知られるIg様ドメインを有するタイプI膜タンパク質であるタンパク質のヒトB7ファミリーのメンバーを指す。用語「2Ig‐B7‐H3」は、Ig様ドメインを2つのみ含むB7‐H3の形態を指し、用語「4Ig‐B7‐H3」は、Ig様ドメインを4つ含むB7‐H3の形態を指す(Sun, M. et al. (2002) “Characterization of Mouse and Human B7-H3 Genes,” J. Immunol. 168:6294-6297; Steinberger et al. (2004), “Molecular Characterization Of Human 4Ig-B7-H3, A Member Of The B7 Family With Four Ig-Like Domains,” J. Immunol. 2004, 172(4):2352-2359 and Castriconi et al. (2004) “Identification Of 4Ig-B7-H3 As A Neuroblastoma-Associated Molecule That Exerts A Protective Role From An NK Cell-Mediated Lysis,” Proc. Natl. Acad. Sci. (U.S.A.) 101(34):12640-12645参照)。抗原「TES7」(国際公開第2008/066691号)は、4Ig‐B7‐H3の特性を共有する抗原である。従って、TES7に特異的に結合する抗体は4Ig‐B7‐H3に結合する。TES7抗原は、2つ以上の異なるエピトープを有してよく、エピトープは非直鎖であってよい。いくつかの抗B7‐H3抗体は、4Ig‐B7‐H3アイソフォーム上にのみ存在するものを含む非直鎖エピトープに結合することが知られている。現在、TES7は特定の癌細胞において、その正常な組織相対物に比べて過剰発現し得ると考えられている。
MLRRRGSPGM GVHVGAALGA LWFCLTGALE VQVPEDPVVA LVGTDATLCC
SFSPEPGFSL AQLNLIWQLT DTKQLVHSFA EGQDQGSAYA NRTALFPDLL
AQGNASLRLQ RVRVADEGSF TCFVSIRDFG SAAVSLQVAA PYSKPSMTLE
PNKDLRPGDT VTITCSSYRG YPEAEVFWQD GQGVPLTGNV TTSQMANEQG
LFDVHSVLRV VLGANGTYSC LVRNPVLQQD AHGSVTITGQ PMTFPPEALW
VTVGLSVCLI ALLVALAFVC WRKIKQSCEE ENAGAEDQDG EGEGSKTALQ
PLKHSDSKED DGQEIA
atgctgcgtc ggcggggcag ccctggcatg ggtgtgcatg tgggtgcagc
cctgggagca ctgtggttct gcctcacagg agccctggag gtccaggtcc
ctgaagaccc agtggtggca ctggtgggca ccgatgccac cctgtgctgc
tccttctccc ctgagcctgg cttcagcctg gcacagctca acctcatctg
gcagctgaca gataccaaac agctggtgca cagctttgct gagggccagg
accagggcag cgcctatgcc aaccgcacgg ccctcttccc ggacctgctg
gcacagggca acgcatccct gaggctgcag cgcgtgcgtg tggcggacga
gggcagcttc acctgcttcg tgagcatccg ggatttcggc agcgctgccg
tcagcctgca ggtggccgct ccctactcga agcccagcat gaccctggag
cccaacaagg acctgcggcc aggggacacg gtgaccatca cgtgctccag
ctaccggggc taccctgagg ctgaggtgtt ctggcaggat gggcagggtg
tgcccctgac tggcaacgtg accacgtcgc agatggccaa cgagcagggc
ttgtttgatg tgcacagcgt cctgcgggtg gtgctgggtg cgaatggcac
ctacagctgc ctggtgcgca accccgtgct gcagcaggat gcgcacggct
ctgtcaccat cacagggcag cctatgacat tccccccaga ggccctgtgg
gtgaccgtgg ggctgtctgt ctgtctcatt gcactgctgg tggccctggc
tttcgtgtgc tggagaaaga tcaaacagag ctgtgaggag gagaatgcag
gagctgagga ccaggatggg gagggagaag gctccaagac agccctgcag
cctctgaaac actctgacag caaagaagat gatggacaag aaatagcc
MLRRRGSPGM GVHVGAALGA LWFCLTGALE VQVPEDPVVA LVGTDATLCC
SFSPEPGFSL AQLNLIWQLT DTKQLVHSFA EGQDQGSAYA NRTALFPDLL
AQGNASLRLQ RVRVADEGSF TCFVSIRDFG SAAVSLQVAA PYSKPSMTLE
PNKDLRPGDT VTITCSSYQG YPEAEVFWQD GQGVPLTGNV TTSQMANEQG
LFDVHSILRV VLGANGTYSC LVRNPVLQQD AHSSVTITPQ RSPTGAVEVQ
VPEDPVVALV GTDATLRCSF SPEPGFSLAQ LNLIWQLTDT KQLVHSFTEG
RDQGSAYANR TALFPDLLAQ GNASLRLQRV RVADEGSFTC FVSIRDFGSA
AVSLQVAAPY SKPSMTLEPN KDLRPGDTVT ITCSSYRGYP EAEVFWQDGQ
GVPLTGNVTT SQMANEQGLF DVHSVLRVVL GANGTYSCLV RNPVLQQDAH
GSVTITGQPM TFPPEALWVT VGLSVCLIAL LVALAFVCWR KIKQSCEEEN
AGAEDQDGEG EGSKTALQPL KHSDSKEDDG QEIA
atgctgcgtc ggcggggcag ccctggcatg ggtgtgcatg tgggtgcagc
cctgggagca ctgtggttct gcctcacagg agccctggag gtccaggtcc
ctgaagaccc agtggtggca ctggtgggca ccgatgccac cctgtgctgc
tccttctccc ctgagcctgg cttcagcctg gcacagctca acctcatctg
gcagctgaca gataccaaac agctggtgca cagctttgct gagggccagg
accagggcag cgcctatgcc aaccgcacgg ccctcttccc ggacctgctg
gcacagggca acgcatccct gaggctgcag cgcgtgcgtg tggcggacga
gggcagcttc acctgcttcg tgagcatccg ggatttcggc agcgctgccg
tcagcctgca ggtggccgct ccctactcga agcccagcat gaccctggag
cccaacaagg acctgcggcc aggggacacg gtgaccatca cgtgctccag
ctaccagggc taccctgagg ctgaggtgtt ctggcaggat gggcagggtg
tgcccctgac tggcaacgtg accacgtcgc agatggccaa cgagcagggc
ttgtttgatg tgcacagcat cctgcgggtg gtgctgggtg caaatggcac
ctacagctgc ctggtgcgca accccgtgct gcagcaggat gcgcacagct
ctgtcaccat cacaccccag agaagcccca caggagccgt ggaggtccag
gtccctgagg acccggtggt ggccctagtg ggcaccgatg ccaccctgcg
ctgctccttc tcccccgagc ctggcttcag cctggcacag ctcaacctca
tctggcagct gacagacacc aaacagctgg tgcacagttt caccgaaggc
cgggaccagg gcagcgccta tgccaaccgc acggccctct tcccggacct
gctggcacaa ggcaatgcat ccctgaggct gcagcgcgtg cgtgtggcgg
acgagggcag cttcacctgc ttcgtgagca tccgggattt cggcagcgct
gccgtcagcc tgcaggtggc cgctccctac tcgaagccca gcatgaccct
ggagcccaac aaggacctgc ggccagggga cacggtgacc atcacgtgct
ccagctaccg gggctaccct gaggctgagg tgttctggca ggatgggcag
ggtgtgcccc tgactggcaa cgtgaccacg tcgcagatgg ccaacgagca
gggcttgttt gatgtgcaca gcgtcctgcg ggtggtgctg ggtgcgaatg
gcacctacag ctgcctggtg cgcaaccccg tgctgcagca ggatgcgcac
ggctctgtca ccatcacagg gcagcctatg acattccccc cagaggccct
gtgggtgacc gtggggctgt ctgtctgtct cattgcactg ctggtggccc
tggctttcgt gtgctggaga aagatcaaac agagctgtga ggaggagaat
gcaggagctg aggaccagga tggggaggga gaaggctcca agacagccct
gcagcctctg aaacactctg acagcaaaga agatgatgga caagaaatag
cc
複数の方法を用いて、B7‐H3に結合するポリペプチド及びモノクローナル抗体をスクリーニングしてよい。「結合」は、生物的又は免疫学的に妥当な特異的結合を指し、例えば免疫グロブリンが非特異的標的に対して極めて高い濃度で使用される場合に発生し得る非特異的結合を指すものではないことが理解される。一実施形態では、モノクローナル抗体は、標準的なスクリーニング技術を用いて、B7‐H3への結合に関してスクリーニングされる。このようにして、抗B7‐H3モノクローナル抗体が得られた。このような抗体を得るための方法は、米国特許公開第2013/0149236号及び国際公開第2011/109400号に記載されている。
(a)BRCA69D軽鎖配列
BRCA69D可変軽鎖のアミノ酸配列(配列番号5):
DIQMTQTTSS LSASLGDRVT ISCRASQDIS NYLNWYQQKP DGTVKLLIYY
TSRLHSGVPS RFSGSGSGTD YSLTIDNLEQ EDIATYFCQQ GNTLPPTFGG
GTKLEIK
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga
cagagtcacc atcagttgca gggcaagtca ggacattagt aattatttaa
actggtatca gcagaaacca gatggaactg ttaaactcct gatctactac
acatcacgat tacactcagg agtcccatca aggttcagtg gcagtgggtc
tggaacagat tattctctca ccattgacaa cctggagcaa gaagatattg
ccacttactt ttgccaacag ggtaatacgc ttcctccgac gttcggtgga
ggcaccaaac tggaaatcaa a
agggcaagtc aggacattag taattattta aac
BRCA69D可変重鎖のアミノ酸配列(配列番号13):
QVQLQQSGAE LARPGASVKL SCKASGYTFT SYWMQWVKQR PGQGLEWIGT
IYPGDGDTRY TQKFKGKATL TADKSSSTAY MQLSSLASED SAVYYCARRG
IPRLWYFDVW GAGTTVTVSS
caggttcagc tccagcagtc tggggctgag ctggcaagac ctggggcttc
agtgaagttg tcctgcaagg cttctggcta cacctttact agctactgga
tgcagtgggt aaaacagagg cctggacagg gtctggaatg gattgggact
atttatcctg gagatggtga tactaggtac actcagaagt tcaagggcaa
ggccacattg actgcagata aatcctccag cacagcctac atgcaactca
gcagcttggc atctgaggac tctgcggtct attactgtgc aagaagaggg
attccacggc tttggtactt cgatgtctgg ggcgcaggga ccacggtcac
cgtctcctca
(a)PRCA157軽鎖配列
PRCA157可変軽鎖のアミノ酸配列(配列番号21):
DIQMTQSPAS LSVSVGETVT ITCRASESIY SYLAWYQQKQ GKSPQLLVYN
TKTLPEGVPS RFSGSGSGTQ FSLKINSLQP EDFGRYYCQH HYGTPPWTFG
GGTNLEIK
gacatccaga tgactcagtc tccagcctcc ctatctgtat ctgtgggaga
aactgtcacc attacatgtc gagcaagtga gagtatttac agttatttag
catggtatca gcagaaacag ggaaaatctc ctcagctcct ggtctataat
acaaaaacct taccagaggg tgtgccatca aggttcagtg gcagtggatc
aggcacacag ttttctctga agatcaacag cctgcagcct gaagattttg
ggagatatta ctgtcaacat cattatggta ctcctccgtg gacgttcggt
ggaggcacca acctggaaat caaa
PRCA157可変重鎖のアミノ酸配列(配列番号29):
EVQQVESGGD LVKPGGSLKL SCAASGFTFS SYGMSWVRQT PDKRLEWVAT
INSGGSNTYY PDSLKGRFTI SRDNAKNTLY LQMRSLKSED TAMYYCARHD
GGAMDYWGQG TSVTVSS
gaggtgcagc aggtggagtc ggggggagac ttagtgaagc ctggagggtc
cctgaaactc tcctgtgcag cctctggatt cactttcagt tcctatggca
tgtcttgggt tcgccagact ccagacaaga ggctggagtg ggtcgcaacc
attaatagtg gtggaagtaa cacctactat ccagacagtt tgaaggggcg
attcaccatc tccagagaca atgccaagaa caccctttac ctgcaaatgc
gcagtctgaa gtctgaggac acagccatgt attactgtgc aagacatgac
gggggagcta tggactactg gggtcaagga acctcagtca ccgtctcctc
a
(a)BRCA84D軽鎖配列
BRCA84D可変軽鎖のアミノ酸配列(配列番号37):
DIAMTQSQKF MSTSVGDRVS VTCKASQNVD TNVAWYQQKP GQSPKALIYS
ASYRYSGVPD RFTGSGSGTD FTLTINNVQS EDLAEYFCQQ YNNYPFTFGS
GTKLEIK
gacattgcga tgacccagtc tcaaaaattc atgtccacat cagtaggaga
cagggtcagc gtcacctgca aggccagtca gaatgtggat actaatgtag
cctggtatca acagaaacca gggcaatctc ctaaagcact gatttactcg
gcatcctacc ggtacagtgg agtccctgat cgcttcacag gcagtggatc
tgggacagat ttcactctca ccatcaacaa tgtgcagtct gaagacttgg
cagagtattt ctgtcagcaa tataacaact atccattcac gttcggctcg
gggacaaagt tggaaataaa a
BRCA84D可変重鎖のアミノ酸配列(配列番号45):
DVQLVESGGG LVQPGGSRKL SCAASGFTFS SFGMHWVRQA PEKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNPKNTLF LQMTSLRSED TAMYYCGRGR
ENIYYGSRLD YWGQGTTLTV SS
gatgtgcagc tggtggagtc tgggggaggc ttagtgcagc ctggagggtc
ccggaaactc tcctgtgcag cctctggatt cactttcagt agctttggaa
tgcactgggt tcgtcaggct ccagagaagg ggctggagtg ggtcgcatac
attagtagtg acagtagtgc catctactat gcagacacag tgaagggccg
attcaccatc tccagagaca atcccaagaa caccctgttc ctgcaaatga
ccagtctaag gtctgaggac acggccatgt attactgtgg aagagggagg
gaaaacattt actacggtag taggcttgac tactggggcc aaggcaccac
tctcacagtc tcctca
DIQLTQSPSF LSASVGDRVT ITCKASQNVD TNVAWYQQKP GKAPKLLIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNNYPFTFGQ
GTKLEIK
gacatccagc tgacccagtc cccctccttc ctgtctgcct ccgtgggcga
cagagtgacc atcacatgca aggcctccca gaacgtggac accaacgtgg
cctggtatca gcagaagcct ggcaaggccc ctaagctgct gatctactcc
gcctcctacc ggtactccgg cgtgccttcc aggttctccg gctccggctc
tggcaccgac ttcaccctga ccatctccag cctgcagcct gaggacttcg
ccacctacta ctgccagcag tacaacaact accctttcac cttcggccag
ggcaccaagc tggaaatcaa g
EVQLVESGGG LVQPGGSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNAKNSLY LQMNSLRDED TAVYYCARGR
ENIYYGSRLD YWGQGTTVTV SS
gaggtgcagc tggtcgagtc tggcggagga ctggtgcagc ctggcggctc
cctgagactg tcttgcgccg cctccggctt caccttctcc agcttcggca
tgcactgggt ccgccaggct ccaggcaagg gactggaatg ggtggcctac
atctcctccg actcctccgc catctactac gccgacaccg tgaagggcag
gttcaccatc tcccgggaca acgccaagaa ctccctgtac ctgcagatga
actccctgcg ggacgaggac accgccgtgt actactgcgc cagaggccgg
gagaatatct actacggctc ccggctggat tattggggcc agggcaccac
cgtgaccgtg tcctct
DIQLTQSPSF LSASVGDRVT ITCKASQNVD TNVAWYQQKP GKAPKALIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNNYPFTFGQ
GTKLEIK
gacatccagc tgacccagtc cccctccttc ctgtctgcct ccgtgggcga
cagagtgacc atcacatgca aggcctccca gaacgtggac accaacgtgg
cctggtatca gcagaagcct ggcaaggccc ctaaggcgct gatctactcc
gcctcctacc ggtactccgg cgtgccttcc aggttctccg gctccggctc
tggcaccgac ttcaccctga ccatctccag cctgcagcct gaggacttcg
ccacctacta ctgccagcag tacaacaact accctttcac cttcggccag
ggcaccaagc tggaaatcaa g
DIQLTQSPSF LSASVGDRVS VTCKASQNVD TNVAWYQQKP GKAPKLLIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNNYPFTFGQ
GTKLEIK
gacatccagc tgacccagtc cccctccttc ctgtctgcct ccgtgggcga
cagagtgtcc gtcacatgca aggcctccca gaacgtggac accaacgtgg
cctggtatca gcagaagcct ggcaaggccc ctaagctgct gatctactcc
gcctcctacc ggtactccgg cgtgccttcc aggttctccg gctccggctc
tggcaccgac ttcaccctga ccatctccag cctgcagcct gaggacttcg
ccacctacta ctgccagcag tacaacaact accctttcac cttcggccag
ggcaccaagc tggaaatcaa g
DIQLTQSPSF LSASVGDRVT ITCKASQNVD TNVAWYQQKP GQAPKLLIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNNYPFTFGQ
GTKLEIK
gacatccagc tgacccagtc cccctccttc ctgtctgcct ccgtgggcga
cagagtgacc atcacatgca aggcctccca gaacgtggac accaacgtgg
cctggtatca gcagaagcct ggccaggccc ctaagctgct gatctactcc
gcctcctacc ggtactccgg cgtgccttcc aggttctccg gctccggctc
tggcaccgac ttcaccctga ccatctccag cctgcagcct gaggacttcg
ccacctacta ctgccagcag tacaacaact accctttcac cttcggccag
ggcaccaagc tggaaatcaa g
DIQLTQSPSF LSASVGDRVT ITCKASQNVD TNVAWYQQKP GQAPKALIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNNYPFTFGQ
GTKLEIK
gacatccagc tgacccagtc cccctccttc ctgtctgcct ccgtgggcga
cagagtgacc atcacatgca aggcctccca gaacgtggac accaacgtgg
cctggtatca gcagaagcct ggccaggccc ctaaggcgct gatctactcc
gcctcctacc ggtactccgg cgtgccttcc aggttctccg gctccggctc
tggcaccgac ttcaccctga ccatctccag cctgcagcct gaggacttcg
ccacctacta ctgccagcag tacaacaact accctttcac cttcggccag
ggcaccaagc tggaaatcaa g
DIQLTQSPSF LSASVGDRVT ITCKASQNVD TNVAWYQQKP GKAPKLLIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFAEYYCQQ YNNYPFTFGQ
GTKLEIK
gacatccagc tgacccagtc cccctccttc ctgtctgcct ccgtgggcga
cagagtgacc atcacatgca aggcctccca gaacgtggac accaacgtgg
cctggtatca gcagaagcct ggcaaggccc ctaagctgct gatctactcc
gcctcctacc ggtactccgg cgtgccttcc aggttctccg gctccggctc
tggcaccgac ttcaccctga ccatctccag cctgcagcct gaggacttcg
ccgagtacta ctgccagcag tacaacaact accctttcac cttcggccag
ggcaccaagc tggaaatcaa g
EVQLVESGGG LVQPGGSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNAKNSLY LQMNSLRDED TAVYYCGRGR
ENIYYGSRLD YWGQGTTVTV SS
gaggtgcagc tggtcgagtc tggcggagga ctggtgcagc ctggcggctc
cctgagactg tcttgcgccg cctccggctt caccttctcc agcttcggca
tgcactgggt ccgccaggct ccaggcaagg gactggaatg ggtggcctac
atctcctccg actcctccgc catctactac gccgacaccg tgaagggcag
gttcaccatc tcccgggaca acgccaagaa ctccctgtac ctgcagatga
actccctgcg ggacgaggac accgccgtgt actactgcgg cagaggccgg
gagaatatct actacggctc ccggctggat tattggggcc agggcaccac
cgtgaccgtg tcctct
EVQLVESGGG LVQPGGSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNAKNSLY LQMNSLRDED TAMYYCGRGR
ENIYYGSRLD YWGQGTTVTV SS
gaggtgcagc tggtcgagtc tggcggagga ctggtgcagc ctggcggctc
cctgagactg tcttgcgccg cctccggctt caccttctcc agcttcggca
tgcactgggt ccgccaggct ccaggcaagg gactggaatg ggtggcctac
atctcctccg actcctccgc catctactac gccgacaccg tgaagggcag
gttcaccatc tcccgggaca acgccaagaa ctccctgtac ctgcagatga
actccctgcg ggacgaggac accgccatgt actactgcgg cagaggccgg
gagaatatct actacggctc ccggctggat tattggggcc agggcaccac
cgtgaccgtg tcctct
EVQLVESGGG LVQPGGSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNAKNSLY LQMNSLRSED TAVYYCARGR
ENIYYGSRLD YWGQGTTVTV SS
gaggtgcagc tggtcgagtc tggcggagga ctggtgcagc ctggcggctc
cctgagactg tcttgcgccg cctccggctt caccttctcc agcttcggca
tgcactgggt ccgccaggct ccaggcaagg gactggaatg ggtggcctac
atctcctccg actcctccgc catctactac gccgacaccg tgaagggcag
gttcaccatc tcccgggaca acgccaagaa ctccctgtac ctgcagatga
actccctgcg gagcgaggac accgccgtgt actactgcgc cagaggccgg
gagaatatct actacggctc ccggctggat tattggggcc agggcaccac
cgtgaccgtg tcctct
DIAMTQSQKF MSTSVGDRVS VTCKASQNVD TNVAWYQQKP GQSPKALIYS
ASYRYSGVPD RFTGSGSGTD FTLTINNVQS EDLAEYFCQQ YNNYPFTFGS
GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
gacattgcga tgacccagtc tcaaaaattc atgtccacat cagtaggaga
cagggtcagc gtcacctgca aggccagtca gaatgtggat actaatgtag
cctggtatca acagaaacca gggcaatctc ctaaagcact gatttactcg
gcatcctacc ggtacagtgg agtccctgat cgcttcacag gcagtggatc
tgggacagat ttcactctca ccatcaacaa tgtgcagtct gaagacttgg
cagagtattt ctgtcagcaa tataacaact atccattcac gttcggctcg
gggacaaagt tggaaataaa acgtacggtg gctgcaccat ctgtcttcat
cttcccgcca tctgatgagc agttgaaatc tggaactgcc tctgttgtgt
gcctgctgaa taacttctat cccagagagg ccaaagtaca gtggaaggtg
gataacgccc tccaatcggg taactcccag gagagtgtca cagagcagga
cagcaaggac agcacctaca gcctcagcag caccctgacg ctgagcaaag
cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag
DVQLVESGGG LVQPGGSRKL SCAASGFTFS SFGMHWVRQA PEKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNPKNTLF LQMTSLRSED TAMYYCGRGR
ENIYYGSRLD YWGQGTTLTV SSASTKGPSV FPLAPSSKST SGGTAALGCL
VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT
QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP
KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE
PQVYTLPPSR DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP
PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP
GK
gatgtgcagc tggtggagtc tgggggaggc ttagtgcagc ctggagggtc
ccggaaactc tcctgtgcag cctctggatt cactttcagt agctttggaa
tgcactgggt tcgtcaggct ccagagaagg ggctggagtg ggtcgcatac
attagtagtg acagtagtgc catctactat gcagacacag tgaagggccg
attcaccatc tccagagaca atcccaagaa caccctgttc ctgcaaatga
ccagtctaag gtctgaggac acggccatgt attactgtgg aagagggagg
gaaaacattt actacggtag taggcttgac tactggggcc aaggcaccac
tctcacagtc tcctcagcct ccaccaaggg cccatcggtc ttccccctgg
caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg
gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc
cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac
tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacc
cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga
caagagagtt gagcccaaat cttgtgacaa aactcacaca tgcccaccgt
gcccagcacc tgaactcctg gggggaccgt cagtcttcct cttcccccca
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt
ggtggtggac gtgagccacg aagaccctga ggtcaagttc aactggtacg
tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga
ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc
cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa
ccacaggtgt acaccctgcc cccatcccgg gatgagctga ccaagaacca
ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc gacatcgccg
tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt
ggacaagagc aggtggcagc aggggaacgt cttctcatgc tccgtgatgc
atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg
ggtaaatga
A.VEGF及びVEGFR
本明細書において使用される場合、用語「VEGF」は、血管内皮増殖因子Aを指す(Leung, D.W. et al. (1989) “Vascular Endothelial Growth Factor Is A Secreted Angiogenic Mitogen,” Science 246(4935):1306-1309)。VEGFは、代替的プロモータの使用、代替的スプライシング及び代替的開始を反映して、複数のアイソフォームで存在する。最初に発見された形態は、ここではアイソフォーム162(配列番号89):
MNFLLSWVHW SLALLLYLHH AKWSQAAPMA EGGGQNHHEV VKFMDVYQRS
YCHPIETLVD IFQEYPDEIE YIFKPSCVPL MRCGGCCNDE GLECVPTEES
NITMQIMRIK PHQGQHIGEM SFLQHNKCEC RPKKDRARQE NPCGPCSERR
KHLFVQDPQT CKCSCKNTDS RCKARQLELN ERTCRCDKPR R
と呼ばれ、cDNA配列(配列番号90):
cagtgtgctg gcggcccggc gcgagccggc ccggccccgg tcgggcctcc
gaaaccatga actttctgct gtcttgggtg cattggagcc tcgccttgct
gctctacctc caccatgcca agtggtccca ggctgcaccc atggcagaag
gaggagggca gaatcatcac gaagtggtga agttcatgga tgtctatcag
cgcagctact gccatccaat cgagaccctg gtggacatct tccaggagta
ccctgatgag atcgagtaca tcttcaagcc atcctgtgtg cccctgatgc
gatgcggggg ctgctgcaat gacgagggcc tggagtgtgt gcccactgag
gagtccaaca tcaccatgca gattatgcgg atcaaacctc accaaggcca
gcacatagga gagatgagct tcctacagca caacaaatgt gaatgcagac
caaagaaaga tagagcaaga caagaaaatc cctgtgggcc ttgctcagag
cggagaaagc atttgtttgt acaagatccg cagacgtgta aatgttcctg
caaaaacaca gactcgcgtt gcaaggcgag gcagcttgag ttaaacgaac
gtacttgcag atgtgacaag ccgaggcggt gagccgggca ggaggaagga
gcctccctca gggtttcggg aaccagatct ctcaccagga aagactgata
cagaacgatc gatacagaaa ccacgctgcc gccaccacac catcaccatc
gacagaacag tccttaatcc agaaacctga aatgaaggaa gaggagactc
tgcgcagagc actttgggtc cggagggcga gactccggcg gaagcattcc
cgggcgggtg acccagcacg gtccctcttg gaattggatt cgccatttta
tttttcttgc tgctaaatca ccgagcccgg aagattagag agttttattt
ctgggattcc tgtagacaca ccgcggccgc cagcacactg
によってコードされる
MNFLLSWVHW SLALLLYLHH AKWSQAAPMA EGGGQNHHEV VKFMDVYQRS
YCHPIETLVD IFQEYPDEIE YIFKPSCVPL MRCGGCCNDE GLECVPTEES
NITMQIMRIK PHQGQHIGEM SFLQHNKCEC RPKKDRARQE KKSVRGKGKG
QKRKRKKSRY KSWSVYVGAR CCLMPWSLPG PHPCGPCSER RKHLFVQDPQ
TCKCSCKNTD SRCKARQLEL NERTCRCDKP RR
MVSYWDTGVL LCALLSCLLL TGSSSGSKLK DPELSLKGTQ HIMQAGQTLH
LQCRGEAAHK WSLPEMVSKE SERLSITKSA CGRNGKQFCS TLTLNTAQAN
HTGFYSCKYL AVPTSKKKET ESAIYIFISD TGRPFVEMYS EIPEIIHMTE
GRELVIPCRV TSPNITVTLK KFPLDTLIPD GKRIIWDSRK GFIISNATYK
EIGLLTCEAT VNGHLYKTNY LTHRQTNTII DVQISTPRPV KLLRGHTLVL
NCTATTPLNT RVQMTWSYPD EKNKRASVRR RIDQSNSHAN IFYSVLTIDK
MQNKDKGLYT CRVRSGPSFK SVNTSVHIYD KAFITVKHRK QQVLETVAGK
RSYRLSMKVK AFPSPEVVWL KDGLPATEKS ARYLTRGYSL IIKDVTEEDA
GNYTILLSIK QSNVFKNLTA TLIVNVKPQI YEKAVSSFPD PALYPLGSRQ
ILTCTAYGIP QPTIKWFWHP CNHNHSEARC DFCSNNEESF ILDADSNMGN
RIESITQRMA IIEGKNKMAS TLVVADSRIS GIYICIASNK VGTVGRNISF
YITDVPNGFH VNLEKMPTEG EDLKLSCTVN KFLYRDVTWI LLRTVNNRTM
HYSISKQKMA ITKEHSITLN LTIMNVSLQD SGTYACRARN VYTGEEILQK
KEITIRDQEA PYLLRNLSDH TVAISSSTTL DCHANGVPEP QITWFKNNHK
IQQEPGIILG PGSSTLFIER VTEEDEGVYH CKATNQKGSV ESSAYLTVQG
TSDKSNLELI TLTCTCVAAT LFWLLLTLFI RKMKRSSSEI KTDYLSIIMD
PDEVPLDEQC ERLPYDASKW EFARERLKLG KSLGRGAFGK VVQASAFGIK
KSPTCRTVAV KMLKEGATAS EYKALMTELK ILTHIGHHLN VVNLLGACTK
QGGPLMVIVE YCKYGNLSNY LKSKRDLFFL NKDAALHMEP KKEKMEPGLE
QGKKPRLDSV TSSESFASSG FQEDKSLSDV EEEEDSDGFY KEPITMEDLI
SYSFQVARGM EFLSSRKCIH RDLAARNILL SENNVVKICD FGLARDIYKN
PDYVRKGDTR LPLKWMAPES IFDKIYSTKS DVWSYGVLLW EIFSLGGSPY
PGVQMDEDFC SRLREGMRMR APEYSTPEIY QIMLDCWHRD PKERPRFAEL
VEKLGDLLQA NVQQDGKDYI PINAILTGNS GFTYSTPAFS EDFFKESISA
PKFNSGSSDD VRYVNAFKFM SLERIKTFEE LLPNATSMFD DYQGDSSTLL
ASPMLKRFTW TDSKPKASLK IDLRVTSKSK ESGLSDVSRP SFCHSSCGHV
SEGKRRFTYD HAELERKIAC CSPPPDYNSV VLYSTPPI
MQSKVLLAVA LWLCVETRAA SVGLPSVSLD LPRLSIQKDI LTIKANTTLQ
ITCRGQRDLD WLWPNNQSGS EQRVEVTECS DGLFCKTLTI PKVIGNDTGA
YKCFYRETDL ASVIYVYVQD YRSPFIASVS DQHGVVYITE NKNKTVVIPC
LGSISNLNVS LCARYPEKRF VPDGNRISWD SKKGFTIPSY MISYAGMVFC
EAKINDESYQ SIMYIVVVVG YRIYDVVLSP SHGIELSVGE KLVLNCTART
ELNVGIDFNW EYPSSKHQHK KLVNRDLKTQ SGSEMKKFLS TLTIDGVTRS
DQGLYTCAAS SGLMTKKNST FVRVHEKPFV AFGSGMESLV EATVGERVRI
PAKYLGYPPP EIKWYKNGIP LESNHTIKAG HVLTIMEVSE RDTGNYTVIL
TNPISKEKQS HVVSLVVYVP PQIGEKSLIS PVDSYQYGTT QTLTCTVYAI
PPPHHIHWYW QLEEECANEP SQAVSVTNPY PCEEWRSVED FQGGNKIEVN
KNQFALIEGK NKTVSTLVIQ AANVSALYKC EAVNKVGRGE RVISFHVTRG
PEITLQPDMQ PTEQESVSLW CTADRSTFEN LTWYKLGPQP LPIHVGELPT
PVCKNLDTLW KLNATMFSNS TNDILIMELK NASLQDQGDY VCLAQDRKTK
KRHCVVRQLT VLERVAPTIT GNLENQTTSI GESIEVSCTA SGNPPPQIMW
FKDNETLVED SGIVLKDGNR NLTIRRVRKE DEGLYTCQAC SVLGCAKVEA
FFIIEGAQEK TNLEIIILVG TAVIAMFFWL LLVIILRTVK RANGGELKTG
YLSIVMDPDE LPLDEHCERL PYDASKWEFP RDRLKLGKPL GRGAFGQVIE
ADAFGIDKTA TCRTVAVKML KEGATHSEHR ALMSELKILI HIGHHLNVVN
LLGACTKPGG PLMVIVEFCK FGNLSTYLRS KRNEFVPYKT KGARFRQGKD
YVGAIPVDLK RRLDSITSSQ SSASSGFVEE KSLSDVEEEE APEDLYKDFL
TLEHLICYSF QVAKGMEFLA SRKCIHRDLA ARNILLSEKN VVKICDFGLA
RDIYKDPDYV RKGDARLPLK WMAPETIFDR VYTIQSDVWS FGVLLWEIFS
LGASPYPGVK IDEEFCRRLK EGTRMRAPDY TTPEMYQTML DCWHGEPSQR
PTFSELVEHL GNLLQANAQQ DGKDYIVLPI SETLSMEEDS GLSLPTSPVS
CMEEEEVCDP KFHYDNTAGI SQYLQNSKRK SRPVSVKTFE DIPLEEPEVK
VIPDDNQTDS GMVLASEELK TLEDRTKLSP SFGGMVPSKS RESVASEGSN
QTSGYQSGYH SDDTDTTVYS SEEAELLKLI EIGVQTGSTA QILQPDSGTT
LSSPPV
既に示したように、膠芽腫の治療において、抗VEGF抗体が考察されている。更に、乳癌、膠芽腫、子宮頸癌、転移性結腸直腸癌、胃癌、肝細胞癌、白血病、肺癌、転移性黒色腫、血管新生性膵臓癌及び転移前立腺癌等の、多数の他のタイプの血管新生性癌に関して、VEGR及びその受容体が考察されている(Roberts, E. et al. (2013) “The Role of Vascular Endothelial Growth Factor in Metastatic Prostate Cancer to the Skeleton,” Prostate Cancer 2013:418340; Vici, P. et al. (2014) “Emerging Biological Treatments for Uterine Cervical Carcinoma,” J. Cancer 5(2):86-97; Dietvorst, M.H. et al. (2013) “Current and Novel Treatment Options for Metastatic Colorectal Cancer: Emphasis on Aflibercept,” Biol. Ther. 3:25-33; Moeini, A. et al. (2012) “Emerging Signaling Pathways in Hepatocellular Carcinoma,” Liver Cancer 1(2):83-93; Cesca, M. et al. (2013) “Tumor Delivery of Chemotherapy Combined with Inhibitors of Angiogenesis and Vascular Targeting Agents,” Front Oncol. 3:259:1-7; Pavlidis, E.T. et al. (2013) “Role Of Bevacizumab In Colorectal Cancer Growth And Its Adverse Effects: A Review,” World J. Gastroenterol. 19(31):5051-5060; Welti, J. et al. (2013) “Recent Molecular Discoveries In Angiogenesis And Antiangiogenic Therapies In Cancer,” J. Clin. Invest. 123(8):3190-3200; Eveno, C. et al. (2012) “VEGF Levels And The Angiogenic Potential Of The Microenvironment Can Affect Surgical Strategy For Colorectal Liver Metastasis,” Cell. Adh. Migr. 6(6):569-573; Miyake, T.M. et al. (2013) “Contemporary Use Of Bevacizumab In Ovarian Cancer,” Expert Opin. Biol. Ther. 13(2):283-294; Plate, K.H. et al. (2012) “Tumor Angiogenesis And Anti-Angiogenic Therapy In Malignant Gliomas Revisited,” Acta Neuropathol. 124(6):763-775; Liu, L. et al. (2012) “Prognostic Value Of Vascular Endothelial Growth Factor Expression In Resected Gastric Cancer,” Asian Pac. J. Cancer Prev. 13(7):3089-3097; Kim, K.B. (2013) “Is There A Role For Targeting Vascular Endothelial Growth Factor/Receptor Axis In The Treatment Of Patients With Metastatic Melanoma?,” Cancer 119(3):477-480; Kubota, Y. (2012) “Tumor Angiogenesis And Anti-Angiogenic Therapy,” Keio J. Med. 61(2):47-56; Wicki, A. et al. (2012) “Targeted Therapies In Breast Cancer,” Swiss Med. Wkly. 142:w13550:1-7; Parente Lamelas, I. et al. (2012) “Directed Therapies In Lung Cancer: New Hope?,” Arch. Bronconeumol. 48(10):367-371; Saintigny, P. et al. (2012) “Recent Advances In Non-Small Cell Lung Cancer Biology And Clinical Management,” Discov. Med. 13(71):287-297; Stevenson, C.E. et al. (2012) “Bevacizumab And Breast Cancer: What Does The Future Hold?,” Future Oncol. 8(4):403-414; Aggarwal, C. et al. (2012) “Antiangiogenic Agents In The Management Of Non-Small Cell Lung Cancer: Where Do We Stand Now And Where Are We Headed?,” Cancer Biol. Ther. 13(5):247-263)。
DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF
TSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ
GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEEDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGKGLEWVGW
INTYTGEPTY AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP
HYYGSSHWYF DVWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC
LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG
TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE
QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR
EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT
PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS
PGK
従来の免疫機能では、抗体‐抗原複合体と免疫系の細胞との相互作用は、抗体依存性細胞毒性、肥満細胞脱顆粒及び食作用等のエフェクタ機能から、リンパ球増殖及び抗体分泌を制御するもの等の免疫調節性信号にまで及ぶ、広範な応答をもたらす。これらの相互作用は全て、抗体又は免疫複合体のFcドメインの、造血細胞上の特殊化された細胞表面受容体への結合によって開始される。抗体及び免疫複合体によってトリガされる細胞応答の多様性は、3つのFc受容体:FcγRI(CD64)、FcγRII(CD32)及びFcγRIII(CD16)の構造不均質性によって得られる。FcγRI(CD64)、FcγRIIA(CD32A)及びFcγRIII(CD16)は活性化(即ち免疫系増強)受容体であり;FcγRIIB(CD32B)は阻害性(即ち免疫系減衰)受容体。IgG1Fc領域のアミノ酸配列を以下に示す。(Kabat et al., Sequence of Proteins of Immunological Interest, 5th Ed. Public Health Service, NIH, MD (1991)に従って、配列番号96として番号を付与した;上記文献は参照により本出願に明示的に援用され、これ以降「Kabat EU」と呼ぶ)(配列番号96):
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV
230 240 250 260 270
DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP
280 290 300 310 320
APIEKTISKA KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV
330 340 350 360 370
EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH
380 390 400 410 420
EALHNHYTQK SLSLSPGK
430 440
残基230‐341はFcCH2領域である。残基342‐447はFcCH3領域である。
(1)288位をアスパラギンで、330位をセリンで、及び396位をロイシンで;
(2)334位をグルタミン酸で、359位をアスパラギンで、及び366位をセリンで;
(3)316位をアスパラギン酸で、378位をバリンで、399位をグルタミン酸で;
(4)247位をロイシンで、及び421位をリジンで置換;
(5)392位をスレオニンで、及び396位をロイシンで;
(6)221位をグルタミン酸で、270位をグルタミン酸で、308位をアラニンで、311位をヒスチジンで、396位をロイシンで、及び402位をアスパラギン酸で;
(7)419位をヒスチジンで、及び396位をロイシンで置換;
(8)240位をアラニンで、及び396位をロイシンで;
(9)410位をヒスチジンで、及び396位をロイシンで;
(10)243位をロイシンで、305位をイソロイシンで、378位をアスパラギン酸で、404位をセリンで、及び396位をロイシンで;
(11)255位をイソロイシンで、及び396位をロイシンで;
(12)370位をグルタミン酸で、及び396位をロイシンで;
(13)270位をグルタミン酸で;又は
(14)上記(1)〜(12)の置換のいずれの組み合わせ。
(I)以下の位置のうちの1つ若しくは複数におけるアミノ酸修飾:235、240、241、243、244、247、262、263、269、298、328、若しくは330位、及びより好ましくは以下の修飾のうちの1つ若しくは複数:V240A、V240I、F241L、F243L、P244H、S298N、L328I、A330V;ここで上記抗体は、このような修飾を有しない野生型Fc領域を有する抗体に対して変化したエフェクタ機能を呈する;
(II)以下の位置のうちの1つ若しくは複数におけるアミノ酸修飾:268、269、270、272、276、278、283、285、286、289、292、293、301、303、305、307、309、331、333、334、335、337、338、340、360、373、376、416、419、430、434、435、437、438若しくは439位、及びより好ましくは以下の修飾のうちの1つ若しくは複数:D280H、D280Q、D280Y、K290G、K290S、K290T、K290Y、E294N、Q295K、Y296P、S298D、S298N、S298P、S298V、Y300I、Y300L;ここで上記抗体は、このような修飾を有しない野生型Fc領域を有する抗体に対して変化したエフェクタ機能を呈する;
(III)以下の位置のうちの1つ若しくは複数におけるアミノ酸修飾:255、256、258、267、268、269、270、272、276、278、280、283、285、286、289、290、292、293、294、295、296、298、300、301、303、305、307、309、312、320、322、326、329、330、332、331、333、334、335、337、338、339、340、359、360、373、376、416、419、430、434、435、437、438、439位、及びより好ましくは以下の修飾のうちの1つ若しくは複数:T256A、H268N、E272Q、N286D、N286Q、N286S、K290A、K290S、S298A、R301M、D312A、K320E、K320M、K320Q、K320R、K322E、K326A、K326D、K326E、K326N、K326S、A330K、A339T、E333A、K334A、K334E、K334H、K334L、K334M、K334Q、K334V、T335K、T335Q、T359A、K360A、E430A;ここで上記抗体は、このような修飾を有しない野生型Fc領域を有する抗体に対して変化したエフェクタ機能を呈する;
(IV)以下の位置のうちの1つ若しくは複数におけるアミノ酸修飾:252、254、265、268、269、270、278、289、292、293、294、295、296、298、300、301、303、322、324、327、329、333、335、338、340、373、376、382、388、389、414、416、419、434、435、437、438、若しくは439位;ここで上記抗体は、このような修飾を有しない野生型Fc領域を有する抗体に比べて低下したエフェクタ機能を呈する;
(V)以下の位置のうちの1つ若しくは複数におけるアミノ酸修飾:280、283、285、286、290、294、295、298、300、301、305、307、309、312、315、331、333、334、337、340、360、378、398、若しくは430位;ここで上記抗体は、このような修飾を有しない野生型Fc領域を有する抗体に比べて増強されたエフェクタ機能を呈する;又は
(VI)以下の位置のうちの1つ若しくは複数におけるアミノ酸修飾:R255A、T256A、E258A、S267A、H268A、H268N、E272A、E272Q、N276A、D280A、E283A、H285A、N286A、N286D、N286Q、N286S、K290A、K290S、R301M、K320E、K320M、K320Q、K320R、K322E、K326A、K326D、K326E、K326S、A330K、P331A、T335Q、S337A、E430A;ここで上記抗体は、このような修飾を有しない野生型Fc領域を有する抗体に比べて増強されたエフェクタ機能を呈する。
(1)ロイシンを247位に、リジンを421位に、及びグルタミン酸を270位に;
(2)スレオニンを392位に、ロイシンを396位に、グルタミン酸を270位に、及びロイシンを243位に;
(3)ヒスチジンを419位に、ロイシンを396位に、に、及びグルタミン酸を270位に;
(4)ヒスチジンを419位に、ロイシンを396位に、グルタミン酸を270位に、及びロイシンを243位に;
(5)アラニンを240位に、ロイシンを396位に、及びグルタミン酸を270位に;
(6)リジンを255位に、及びロイシンを396位に;
(7)リジンを255位に、ロイシンを396位に、及びグルタミン酸を270位に;
(8)リジンを255位に、ロイシンを396位に、グルタミン酸を270位に、及びリジンを300位に;
(9)リジンを255位に、ロイシンを396位に、グルタミン酸を270位に、及びグリシンを292位に;
(10)リジンを255位に、ロイシンを396位に、グルタミン酸を270位に、及びロイシンを243位に;
(11)グルタミン酸を370位に、ロイシンを396位に、及びグルタミン酸を270位に;
(12)グルタミン酸を270位に、アスパラギン酸を316位に、及びグリシンを416位に;
(13)ロイシンを243位に、プロリンを292位に、イソロイシンを305位に、及びロイシンを396位に;
(14)ロイシンを243位に、グルタミン酸を270位に、アスパラギンを392位に、及びロイシンを396位に;
(15)ロイシンを243位に、ロイシンを255位に、グルタミン酸を270位に、及びロイシンを396位に;
(16)グルタミンを297位に;又は
(17)上記(1)〜(16)の置換のいずれの組み合わせ
を有する。
上述のように、本発明は更に、少なくとも2つのエピトープ結合部位を形成する少なくとも2つの共有結合したポリペプチド鎖を含む、ダイアボディ(特に「DART(商標)」(二重親和性再標的化試薬))分子を包含し、上記エピトープ結合部位のうちの1つは、B7‐H3に特異的に結合し、上記エピトープ結合部位のうちの第2のものは、腫瘍血管新生の促進に関わる細胞表面因子(又はその受容体)に結合する。最も好ましくは、このようなダイアボディは、B7‐H3及びVEGFに、又はB7‐H3及びVEGFRに結合することになる。
(i)B7‐H3のエピトープに対して特異的な、第1の免疫グロブリンの軽鎖可変ドメイン(VL1)の結合領域を含むドメイン(A);
(ii)VEGF又はVEGFRのエピトープに対して特異的な、第2の免疫グロブリンの重鎖可変ドメイン(VH2)の結合領域を含むドメイン(B);及び
(iii)任意に、ドメイン(C)
を含む。このようなダイアボディの第2のポリペプチド鎖は:
(i)上述のようなVEGF又はVEGFRのエピトープに対して特異的な、第2の免疫グロブリンの軽鎖可変ドメイン(VL2)の結合領域を含むドメイン(D);
(ii)上述のようなB7‐H3のエピトープに対して特異的な、第1の免疫グロブリンの重鎖可変ドメイン(VH1)の結合領域を含むドメイン(E);及び
(iii)任意に、ドメイン(F)
を含む。
(i)上述のようなVEGF又はVEGFRのエピトープに対して特異的な、第2の免疫グロブリンの軽鎖可変ドメイン(VL2)の結合領域を含むドメイン(A);
(ii)上述のようなB7‐H3のエピトープに対して特異的な、第1の免疫グロブリンの重鎖可変ドメイン(VH1)の結合領域を含むドメイン(B);及び
(iii)任意に、ドメイン(C);
を含み、またこのようなダイアボディの第2のポリペプチド鎖は:
(i)B7‐H3のエピトープに対して特異的な、第1の免疫グロブリンの軽鎖可変ドメイン(VL1)の結合領域を含むドメイン(D);
(ii)VEGF又はVEGFRのエピトープに対して特異的な、第2の免疫グロブリンの重鎖可変ドメイン(VH2)の結合領域を含むドメイン(E);及び
(iii)任意に、ドメイン(F)。
を含む。
B7‐H3又は腫瘍血管新生の促進に関わる細胞表面因子(若しくはその受容体)(特にVEGF若しくはその受容体、VEGFR)に特異的に結合する抗体(又はダイアボディ)を、癌又は他の疾患を有する個体の治療目的で使用してよい。一実施形態では、このような結合活性を提供する1つ又は複数の分子は、共に投与される。本明細書において使用される場合、このような「共に(concurrent)」投与は、以下を意味することが意図されている:
A.B7‐H3に特異的な結合能を有する分子と、腫瘍血管新生の促進に関わる細胞表面因子(又はその受容体)(特にVEGF又はその受容体、VEGFR)に特異的な結合能を有する分子との両方を含有する、単一の医薬組成物の投与。これらの分子は同一の分子であってよく(例えばダイアボディ)、又は別個であってよい(例えば抗B7‐H3抗体、若しくはその抗原結合性断片、及び抗VEGF抗体若しくはその抗原結合性断片);あるいは
B.2つ以上の医薬組成物の個別投与、そのうちの1つの組成物は、B7‐H3に特異的な結合能を有する分子を含有し、別の組成物は、腫瘍血管新生の促進に関わる細胞表面因子(又はその受容体)(特にVEGF又はその受容体、VEGFR)に特異的な結合能を有する分子を含有し、ここで2番目に投与される組成物は、1番目に投与される分子の投与後、1生物的半減期以内、又は1番目に投与される分子の投与後、2、3、4、5、6、7、8、9若しくは10半減期以内に投与される。ベバシズマブは、推定半減期が約20日である。ヒト化抗B7‐H3の推定半減期は2〜3週である。
本発明の組成物は、有効量の本発明の医薬組成物を被験体に投与することによる、疾患、障害又は感染症に関連する1つ又は複数の症状の治療、予防及び改善のために提供できる。好ましい態様では、上記組成物は実質的に精製される(即ち上記組成物の効果を制限する、又は望ましくない副作用を生成する物質を実質的に含まない)。ある具体的実施形態では、被験体は動物、好ましくは非霊長類(例えばウシ属、ウマ科、ネコ科、イヌ科、齧歯類等)又は霊長類(例えばカニクイザル等のサル、ヒト等)といった哺乳類である。ある好ましい実施形態では、被験体はヒトである。
抗B7‐H3抗体及び抗VEGF抗体を用いた再発性多形性膠芽腫(GBM)の治療
B7‐H3に対して特異的な結合能及び腫瘍血管新生の促進に関わる細胞表面因子(又はその受容体)に対して特異的な第2の結合能をもたらす作用剤を使用併用療法の能力を実証するために、再発性多形性膠芽腫(GBM)に罹患した患者を、ヒト化抗B7‐H3抗体及びベバシズマブ(アバスチン(登録商標))を用いて治療した。
図1は、患者NFの臨床的進行を示す。この患者の脳のMRI走査により、3つの病変が明らかになった。ヒト化抗B7‐H3抗体の最初のサイクルを、ベースラインにおいて投与した。行Aは、ベースラインにおける患者の病変の状態を示す(病変3に関して、行A内の矢印は、病変が図の行Bにおいて確認される部位を指し、図の行Aにおいて病変3のエビデンスは見られないことに留意されたい。)。行Bは、抗B7‐H3抗体投与の計画された第2のサイクルの開始前の、患者の病変の状態を示す。行Bは、3つの病変のサイズが増大しているように見えることを明らかにしている(「擬進行」として知られる現象)。このような擬進行と共に、患者は脳内の浮腫の増大(第4列)、頭痛及び発作の増加を経験した。抗B7‐H3抗体治療を停止し、患者にベバシズマブの3回の投与及びCCNUの1回の投与を提供した(行C)。
図2A〜2Cは、患者MRの臨床的進行を示す。患者MRは、二次膠芽腫を呈しており、またIDH1変異体を特徴とする膠芽腫を有していた(Ichimura, K. et al. (2009) “IDH1 Mutations Are Present In The Majority Of Common Adult Gliomas But Rare In Primary Glioblastomas,” Neuro. Oncol. 11(4):341-347)。IDH1変異に関連する膠芽腫の特徴は、このような腫瘍がコントラスト非強調性であることである(Carillo, J.A. et al. (2012) “Relationship between Tumor Enhancement, Edema, IDH1 Mutational Status, MGMT Promoter Methylation, and Survival in Glioblastoma,” Amer. J. Neuroradiol. 10.3174/ajnr.A2950, pages 1-7)。
図3は、患者GCの臨床的進行を示す。この患者の脳のMRI走査により、3つの病変が明らかになった。ヒト化抗B7‐H3抗体の最初のサイクルを、ベースラインにおいて投与した。サイクル1の後、認知及び歩行の低下に対する著しく増大した強化が観察された。
図4は、患者DKの臨床的進行を示す。この患者の脳のMRI走査により、3つの病変が明らかになった。ヒト化抗B7‐H3抗体の最初のサイクルを、ベースラインにおいて投与した。サイクル2の1日目(C2D1)に、デキサメタゾンの投与(2mg bid)を含むように治療を修正した。行Aは、ベースラインにおける患者の病変の状態を示す。行B(サイクル2の途中に取得された画像)は、疾患の進行及び擬進行を示す。行C(ベバシズマブの2回の投与後に取得された画像)は穏やかな応答を示し、認知機能及び歩行が緩やかに改善されている。
図5は、患者JKの臨床的進行を示す。この患者の脳のMRI走査により、3つの病変が明らかになった。ヒト化抗B7‐H3抗体の最初のサイクルを、ベースラインにおいて投与した。サイクル1の後、デキサメタゾンの投与(2mg bid)を含むように治療を修正した。言語能力及び右腕の器用さの穏やかな低下が観察された。行Aは、ベースラインにおける患者の病変の状態を示す。行B(サイクル2の前に取得された画像)は、疾患の進行及び擬進行を示す。ベバシズマブ及びCCNU×1ヶ月の投与後、患者は安定した言語能力及び右腕の器用さを示す。更なるMRI走査は留保されている。
図6は、患者DWの臨床的進行を示す。この患者の脳のMRI走査により、3つの病変が明らかになった。ヒト化抗B7‐H3抗体の最初のサイクルを、ベースラインにおいて投与した。行Aは、ベースラインにおける患者の病変の状態を示す。サイクル1の後、重篤な言語機能並びに右腕及び右脚機能の低下により、疾患の進行が示された。患者はベバシズマブの1回の投与を受けたが、重篤な言語機能並びに右腕及び右脚機能の低下を経験し続けた。行B(サイクル2の前に取得された画像)は、疾患の進行を示す。患者は、抗B7‐H3抗体の最後の投与の5週間後に、病によって死亡した(全生存期間は診断から14ヶ月であった)。患者は、抗B7‐H3抗体治療後、ベバシズマブに対する臨床的応答を全く示さなかった。応答の欠如はおそらく、ベースラインにおける高いステロイド、又は特に難治性の疾患によるものである。
抗B7‐H3抗体を受容した患者の評価
癌の治療における抗B7‐H3抗体治療の効力を評価するための進行中の臨床試験の過程において、レシピエント患者における可溶性B7‐H3(「sB7‐H3」)のレベルを測定した。治療前のレシピエント患者におけるsB7‐H3のレベルはゼロであった。
配列番号1:ヒトB7‐H3の「2Ig」形態
配列番号2:ヒトB7‐H3の「2Ig」形態をコードするポリヌクレオチド配列
配列番号3:ヒトB7‐H3の「4Ig」形態
配列番号4:ヒトB7‐H3の「4Ig」形態をコードするポリヌクレオチド配列
配列番号5:BRCA69D可変軽鎖のアミノ酸配列
配列番号6:BRCA69D可変軽鎖をコードするポリヌクレオチド配列
配列番号7:BRCA69D可変軽鎖CDR1
配列番号8:BRCA69D可変軽鎖CDR1をコードするポリヌクレオチド配列
配列番号9:BRCA69D可変軽鎖CDR2
配列番号10:BRCA69D可変軽鎖CDR2をコードするポリヌクレオチド配列
配列番号11:BRCA69D可変軽鎖CDR3
配列番号12:BRCA69D可変軽鎖CDR3をコードするポリヌクレオチド配列
配列番号13:BRCA69D可変重鎖のアミノ酸配列
配列番号14:BRCA69D可変重鎖をコードするポリヌクレオチド配列
配列番号15:BRCA69D可変重鎖CDR1
配列番号16:BRCA69D可変重鎖CDR1をコードするポリヌクレオチド配列
配列番号17:BRCA69D可変重鎖CDR2
配列番号18:BRCA69D可変重鎖CDR2をコードするポリヌクレオチド配列
配列番号19:BRCA69D可変重鎖CDR3
配列番号20:BRCA69D可変重鎖CDR3をコードするポリヌクレオチド配列
配列番号21:PRCA157可変軽鎖のアミノ酸配列
配列番号22:PRCA157可変軽鎖をコードするポリヌクレオチド配列
配列番号23:PRCA157可変軽鎖CDR1
配列番号24:PRCA157可変軽鎖CDR1をコードするポリヌクレオチド配列
配列番号25:PRCA157可変軽鎖CDR2
配列番号26:PRCA157可変軽鎖CDR2をコードするポリヌクレオチド配列
配列番号27:PRCA157可変軽鎖CDR3
配列番号28:PRCA157可変軽鎖CDR3をコードするポリヌクレオチド配列
配列番号29:PRCA157可変重鎖のアミノ酸配列
配列番号30:PRCA157可変重鎖をコードするポリヌクレオチド配列
配列番号31:PRCA157可変重鎖CDR1
配列番号32:PRCA157可変重鎖CDR1をコードするポリヌクレオチド配列
配列番号33:PRCA157可変重鎖CDR2
配列番号34:PRCA157可変重鎖CDR2をコードするポリヌクレオチド配列
配列番号35:PRCA157可変重鎖CDR3
配列番号36:PRCA157可変重鎖CDR3をコードするポリヌクレオチド配列
配列番号37:BRCA84D可変軽鎖のアミノ酸配列
配列番号38:BRCA84D可変軽鎖をコードするポリヌクレオチド配列
配列番号39:BRCA84D可変軽鎖CDR1
配列番号40:BRCA84D可変軽鎖CDR1をコードするポリヌクレオチド配列
配列番号41:BRCA84D可変軽鎖CDR2
配列番号42:BRCA84D可変軽鎖CDR2をコードするポリヌクレオチド配列
配列番号43:BRCA84D可変軽鎖CDR3
配列番号44:BRCA84D可変軽鎖CDR3をコードするポリヌクレオチド配列
配列番号45:BRCA84D可変重鎖のアミノ酸配列
配列番号46:BRCA84D可変重鎖をコードするポリヌクレオチド配列
配列番号47:BRCA84D可変重鎖CDR1
配列番号48:BRCA84D可変重鎖CDR1をコードするポリヌクレオチド配列
配列番号49:BRCA84D可変重鎖CDR2
配列番号50:BRCA84D可変重鎖CDR2をコードするポリヌクレオチド配列
配列番号51:BRCA84D可変重鎖CDR3
配列番号52:BRCA84D可変重鎖CDR3をコードするポリヌクレオチド配列
配列番号53:ヒト化BRCA84D‐1可変軽鎖
配列番号54:ヒト化BRCA84D‐1可変軽鎖をコードするポリヌクレオチド配列
配列番号55:ヒト化BRCA84D‐1可変軽鎖CDR1
配列番号56:ヒト化BRCA84D‐1可変軽鎖CDR1をコードするポリヌクレオチド配列
配列番号57:ヒト化BRCA84D‐1可変軽鎖CDR2
配列番号58:ヒト化BRCA84D‐1可変軽鎖CDR2をコードするポリヌクレオチド配列
配列番号59:ヒト化BRCA84D‐1可変軽鎖CDR3
配列番号60:ヒト化BRCA84D‐1可変軽鎖CDR3をコードするポリヌクレオチド配列
配列番号61:ヒト化BRCA84D‐1可変重鎖のアミノ酸配列
配列番号62:ヒト化BRCA84D‐1可変重鎖をコードするポリヌクレオチド配列
配列番号63:ヒト化BRCA84D‐1可変重鎖CDR1
配列番号64:ヒト化BRCA84D‐1可変重鎖CDR1をコードするポリヌクレオチド配列
配列番号65:ヒト化BRCA84D‐1可変重鎖CDR2
配列番号66:ヒト化BRCA84D‐1可変重鎖CDR2をコードするポリヌクレオチド配列
配列番号67:ヒト化BRCA84D‐1可変重鎖CDR3
配列番号68:ヒト化BRCA84D‐1可変重鎖CDR3をコードするポリヌクレオチド配列
配列番号69:hBRCA84D‐2VLのアミノ酸配列
配列番号70:hBRCA84D‐2VLをコードするポリヌクレオチド
配列番号71:hBRCA84D‐3VLのアミノ酸配列
配列番号72:hBRCA84D‐3VLをコードするポリヌクレオチド
配列番号73:hBRCA84D‐4VLのアミノ酸配列
配列番号74:hBRCA84D‐4VLをコードするポリヌクレオチド
配列番号75:hBRCA84D‐5VLのアミノ酸配列
配列番号76:hBRCA84D‐5VLをコードするポリヌクレオチド
配列番号77:hBRCA84D‐6VLのアミノ酸配列
配列番号78:hBRCA84D‐6VLをコードするポリヌクレオチド
配列番号79:hBRCA84D‐2VHのアミノ酸配列
配列番号80:hBRCA84D‐2VHをコードするポリヌクレオチド
配列番号81:hBRCA84D‐3VHのアミノ酸配列
配列番号82:hBRCA84D‐3VHをコードするポリヌクレオチド
配列番号83:hBRCA84D‐4VHのアミノ酸配列
配列番号84:hBRCA84D‐4VHをコードするポリヌクレオチド
配列番号85:chBRCA84D軽鎖のアミノ酸配列
配列番号86:chBRCA84D軽鎖をコードするポリヌクレオチド
配列番号87:chBRCA84D重鎖のアミノ酸配列
配列番号88:chBRCA84D重鎖をコードするポリヌクレオチド
配列番号89:VEGFアイソフォーム162のアミノ酸配列
配列番号90:VEGFアイソフォーム162のアミノ酸配列をコードするポリヌクレオチド
配列番号91:VEGFアイソフォーム206のアミノ酸配列
配列番号92:VEGF受容体VEGFR‐1のアミノ酸配列
配列番号93:VEGF受容体VEGFR‐2のアミノ酸配列
配列番号94:ベバシズマブの軽鎖のアミノ酸配列
配列番号95:ベバシズマブの重鎖のアミノ酸配列
配列番号96:IgG1Fc領域のアミノ酸配列
配列番号97:VL及びVHダイアボディドメインの好ましいリンカー
配列番号98:VL及びVHダイアボディドメインの好ましいリンカーをコードするポリヌクレオチド
配列番号99:システイン含有リンカー
配列番号100:ヒンジドメインリンカーのアミノ酸配列
配列番号101:ヒンジドメインリンカーのアミノ酸配列
配列番号102:IgGヒンジドメインに由来するシステイン含有、ヘテロ二量体促進リンカー
配列番号103:IgGヒンジドメインに由来するシステイン含有、ヘテロ二量体促進リンカーをコードするポリヌクレオチド
配列番号104:ヒトカッパ軽鎖ドメインに由来するシステイン含有、ヘテロ二量体促進リンカー
配列番号105:ヒトカッパ軽鎖ドメインに由来するシステイン含有、ヘテロ二量体促進リンカーをコードするポリヌクレオチド
配列番号106:ヒトカッパ軽鎖ドメインに由来するシステイン含有、ヘテロ二量体促進リンカー
配列番号107:ヒトカッパ軽鎖ドメインに由来するシステイン含有、ヘテロ二量体促進リンカーをコードするポリヌクレオチド
配列番号108:Eコイルヘテロ二量体促進ドメインのアミノ酸配列
配列番号109:Kコイルヘテロ二量体促進ドメインのアミノ酸配列
配列番号110:リンカーのアミノ酸配列
Claims (16)
- a)B7‐H3に特異的な抗体、Fab、Fab'、F(ab') 2 若しくはFvから選択されたその抗体断片又はダイアボディ;及び
b)VEGF又はVEGFRに特異的な抗体又はFab、Fab'、F(ab') 2 若しくはFvから選択されたその抗体断片
を含む、膠芽腫の治療に使用するための組成物。 - 前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は:
(A)VEGFアンタゴニスト;又は
(B)VEGFRアンタゴニスト
である、請求項1に記載の組成物。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは、前記B7‐H3への結合に関して:
(1)配列番号7のアミノ酸配列を有するCDR1、配列番号9のアミノ酸配列を有するCDR2及び配列番号11のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号15のアミノ酸配列を有するCDR1、配列番号17のアミノ酸配列を有するCDR2及び配列番号19のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む抗体;
(2)配列番号23のアミノ酸配列を有するCDR1、配列番号25のアミノ酸配列を有するCDR2及び配列番号27のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号31のアミノ酸配列を有するCDR1、配列番号33のアミノ酸配列を有するCDR2及び配列番号35のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む抗体;又は
(3)配列番号39のアミノ酸配列を有するCDR1、配列番号41のアミノ酸配列を有するCDR2及び配列番号43のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号47のアミノ酸配列を有するCDR1、配列番号49のアミノ酸配列を有するCDR2及び配列番号51のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む抗体
と競合する、請求項1又は2に記載の組成物。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは:
(1)配列番号7のアミノ酸配列を有するCDR1、配列番号9のアミノ酸配列を有するCDR2及び配列番号11のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号15のアミノ酸配列を有するCDR1、配列番号17のアミノ酸配列を有するCDR2及び配列番号19のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含むか;
(2)配列番号23のアミノ酸配列を有するCDR1、配列番号25のアミノ酸配列を有するCDR2及び配列番号27のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号31のアミノ酸配列を有するCDR1、配列番号33のアミノ酸配列を有するCDR2及び配列番号35のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含むか;又は
(3)配列番号39のアミノ酸配列を有するCDR1、配列番号41のアミノ酸配列を有するCDR2及び配列番号43のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号47のアミノ酸配列を有するCDR1、配列番号49のアミノ酸配列を有するCDR2及び配列番号51のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む、
請求項1乃至3の何れか1項に記載の組成物。 - 前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は:
A.VEGF結合に関してベバシズマブと競合し;又は
B.ベバシズマブの3つの重鎖CDR及び3つの軽鎖CDRを含む、
請求項1乃至4の何れか1項に記載の組成物。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは:
(A)配列番号39のアミノ酸配列を有するCDR1、配列番号41のアミノ酸配列を有するCDR2及び配列番号43のアミノ酸配列を有するCDR3を備える軽鎖可変ドメイン;
(B)配列番号47のアミノ酸配列を有するCDR1、配列番号49のアミノ酸配列を有するCDR2及び配列番号51のアミノ酸配列を有するCDR3を備える重鎖可変ドメイン;並びに
(C)置換基:L235V、F243L、R292P、Y300L及びP396Lを備えるFc領域
を含む抗B7‐H3抗体である、請求項1乃至5の何れか1項に記載の組成物。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは:
(A)配列番号69のアミノ酸配列を有する可変軽鎖;及び
(B)配列番号79のアミノ酸配列を有する可変重鎖
を備えるヒト化抗B7‐H3抗体であり、
前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は、ベバシズマブである、請求項6に記載の組成物。 - VEGF又はVEGFRに特異的な抗体又はFab、Fab'、F(ab') 2 若しくはFvから選択されたその抗体断片を併用した、B7‐H3に特異的な抗体、Fab、Fab'、F(ab') 2 若しくはFvから選択されたその抗体断片又はダイアボディの、膠芽腫を治療するための薬剤の製造における使用。
- 前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は:
(A)VEGFアンタゴニスト;又は
(B)VEGFRアンタゴニスト
である、請求項8に記載の使用。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは、前記B7‐H3への結合に関して:
(1)配列番号7のアミノ酸配列を有するCDR1、配列番号9のアミノ酸配列を有するCDR2及び配列番号11のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号15のアミノ酸配列を有するCDR1、配列番号17のアミノ酸配列を有するCDR2及び配列番号19のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む抗体;
(2)配列番号23のアミノ酸配列を有するCDR1、配列番号25のアミノ酸配列を有するCDR2及び配列番号27のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号31のアミノ酸配列を有するCDR1、配列番号33のアミノ酸配列を有するCDR2及び配列番号35のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む抗体;又は
(3)配列番号39のアミノ酸配列を有するCDR1、配列番号41のアミノ酸配列を有するCDR2及び配列番号43のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号47のアミノ酸配列を有するCDR1、配列番号49のアミノ酸配列を有するCDR2及び配列番号51のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む抗体
と競合する、請求項8又は9に記載の使用。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは:
(1)配列番号7のアミノ酸配列を有するCDR1、配列番号9のアミノ酸配列を有するCDR2及び配列番号11のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号15のアミノ酸配列を有するCDR1、配列番号17のアミノ酸配列を有するCDR2及び配列番号19のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含むか;
(2)配列番号23のアミノ酸配列を有するCDR1、配列番号25のアミノ酸配列を有するCDR2及び配列番号27のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号31のアミノ酸配列を有するCDR1、配列番号33のアミノ酸配列を有するCDR2及び配列番号35のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含むか;又は
(3)配列番号39のアミノ酸配列を有するCDR1、配列番号41のアミノ酸配列を有するCDR2及び配列番号43のアミノ酸配列を有するCDR3を備える軽鎖可変ドメインと、配列番号47のアミノ酸配列を有するCDR1、配列番号49のアミノ酸配列を有するCDR2及び配列番号51のアミノ酸配列を有するCDR3を備える重鎖可変ドメインとを含む、
請求項8乃至10の何れか1項に記載の使用。 - 前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は:
A.VEGF結合に関してベバシズマブと競合し;又は
B.ベバシズマブの3つの重鎖CDR及び3つの軽鎖CDRを含む、
請求項8乃至11の何れか1項に記載の使用。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは:
(A)配列番号39のアミノ酸配列を有するCDR1、配列番号41のアミノ酸配列を有するCDR2及び配列番号43のアミノ酸配列を有するCDR3を備える軽鎖可変ドメイン;
(B)配列番号47のアミノ酸配列を有するCDR1、配列番号49のアミノ酸配列を有するCDR2及び配列番号51のアミノ酸配列を有するCDR3を備える重鎖可変ドメイン;並びに
(C)置換基:L235V、F243L、R292P、Y300L及びP396Lを備えるFc領域
を含む抗B7‐H3抗体である、請求項8乃至10又は12の何れか1項に記載の使用。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディは:
(A)配列番号69のアミノ酸配列を有する可変軽鎖;及び
(B)配列番号79のアミノ酸配列を有する可変重鎖
を備えるヒト化抗B7‐H3抗体であり、
前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は、ベバシズマブである、請求項13に記載の使用。 - 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディ及び前記VEGF又はVEGFRに特異的な抗体又はその抗体断片は同時に投与される、請求項8乃至14のいずれか1項に記載の使用。
- 前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディ、又は前記VEGF又はVEGFRに特異的な抗体又はその抗体断片のうちの第2のものは、前記B7‐H3に特異的な抗体、その抗体断片又はダイアボディ、又は前記VEGF又はVEGFRに特異的な抗体又はその抗体断片のうちの第1のものの投与後5半減期以内に患者に投与される、請求項8乃至14のいずれか1項に記載の使用。
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Also Published As
Publication number | Publication date |
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CN106604740A (zh) | 2017-04-26 |
RU2016136527A (ru) | 2018-03-19 |
SG11201606714TA (en) | 2016-09-29 |
CA2939556A1 (en) | 2015-08-20 |
RU2016136527A3 (ja) | 2018-10-04 |
BR112016018754A2 (pt) | 2017-10-10 |
EP3104880A1 (en) | 2016-12-21 |
IL247267A0 (en) | 2016-09-29 |
AU2015217278B2 (en) | 2020-03-19 |
AU2015217278A1 (en) | 2016-09-01 |
EP3104880A4 (en) | 2017-10-18 |
JP2017506669A (ja) | 2017-03-09 |
EP3104880B1 (en) | 2020-03-25 |
KR20160135190A (ko) | 2016-11-25 |
RU2692248C2 (ru) | 2019-06-24 |
WO2015123241A1 (en) | 2015-08-20 |
MX2016010505A (es) | 2017-04-13 |
US20170008961A1 (en) | 2017-01-12 |
US10100115B2 (en) | 2018-10-16 |
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