JP2014534233A - Trop−2に対して特異的な抗体およびこれらの使用 - Google Patents
Trop−2に対して特異的な抗体およびこれらの使用 Download PDFInfo
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Abstract
Description
本願は、2011年11月11日に出願された米国仮出願第61/559,015号、2012年4月30日に出願された米国仮出願第61/640,641号、および2012年10月23日に出願された米国仮出願第61/717,288号の利益を主張するものである。これらは、その全体が参照により本明細書に組み込まれている。
本発明の実施では、別段の指定のない限り、分子生物学(組換え技法を含む)、微生物学、細胞生物学、生化学、および免疫学の慣例的な技法を使用し、これらは、当技術分野の技術内である。このような技法は、文献、例えば、Molecular Cloning:A Laboratory Manual、2版(Sambrookら、1989)Cold Spring Harbor Press;Oligonucleotide Synthesis(M.J.Gait編、1984);Methods in Molecular Biology、Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis編、1998)Academic Press;Animal Cell Culture(R.I.Freshney編、1987);Introduction to Cell and Tissue Culture(J.P.MatherおよびP.E.Roberts、1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle、J.B.Griffiths、およびD.G.Newell編、1993〜1998)J.Wiley and Sons;Methods in Enzymology(Academic Press,Inc.);Handbook of Experimental Immunology(D.M. WeirおよびC.C.Blackwell編);Gene Transfer Vectors for Mammalian Cells(J.M.MillerおよびM.P.Calos編、1987);Current Protocols in Molecular Biology(F.M.Ausubelら編、1987);PCR:The Polymerase Chain Reaction、(Mullisら編、1994);Current Protocols in Immunology(J.E.Coliganら編、1991);Short Protocols in Molecular Biology(WileyおよびSons、1999);Immunobiology(C.A.JanewayおよびP.Travers、1997);Antibodies(P.Finch、1997);Antibodies:a practical approach(D.Catty編、IRL Press、1988〜1989);Monoclonal antibodies:a practical approach(P.ShepherdおよびC.Dean編、Oxford University Press、2000);Using antibodies:a laboratory manual(E.HarlowおよびD.Lane(Cold Spring Harbor Laboratory Press、1999);The Antibodies(M.ZanettiおよびJ.D.Capra編、Harwood Academic Publishers、1995)などで完全に説明されている。
「抗体」は、自己の可変領域に位置した少なくとも1つの抗原認識部位によって、標的、例えば、炭水化物、ポリヌクレオチド、脂質、ポリペプチドなどに特異的に結合することができる免疫グロブリン分子である。本明細書において、この用語は、インタクトなポリクローナルまた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’)2、Fvなど)、単鎖(ScFv)、ならびにドメイン抗体(例えば、サメおよびラクダ科の動物の抗体を含む)、ならびに抗体を含む融合タンパク質、ならびに抗原認識部位を含む免疫グロブリン分子の任意の他の修飾構成も包含する。抗体には、任意のクラスの抗体、例えば、IgG、IgA、もしくはIgM(またはこれらのサブクラス)などが含まれ、抗体は、任意の特定のクラスのものである必要はない。その重鎖の定常領域の抗体アミノ酸配列に応じて、免疫グロブリンは、異なるクラスに割り当てることができる。免疫グロブリンの5つの主要クラス、すなわち、IgA、IgD、IgE、IgG、およびIgMがあり、これらのうちのいくつかは、サブクラス(アイソタイプ)、例えば、IgG1、IgG2、IgG3、IgG4、IgA1、およびIgA2にさらに分類することができる。免疫グロブリンの異なるクラスに対応する重鎖定常領域は、それぞれ、α、δ、ε、γ、およびμと呼ばれる。免疫グロブリンの異なるクラスのサブユニット構造および3次元構成は、周知である。
本発明は、Trop−2に結合する抗体を提供する。一態様では、本発明は、表面プラズモン共鳴によって測定して6.5nM以下の一価抗体結合親和性(KD)でヒトTrop−2(例えば、配列番号27)のドメイン3(例えば、アミノ酸残基153〜206)およびドメイン4(例えば、アミノ酸残基209〜274)に特異的に結合する単離抗体またはその抗原結合断片を提供する。別の態様では、本発明は、表面プラズモン共鳴によって測定して約35nM以下の結合親和性(KD)でヒトTrop−2(例えば、配列番号27)のドメイン1(例えば、アミノ酸残基27〜71)に特異的に結合する単離抗体またはその抗原結合断片を提供する。
DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPYTFGGGTKLEIK(配列番号1)、
DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSYMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSRELPYTFGQGTKLEIK(配列番号3)、
DIVMTQSPDSLAVSLGERATINCRASKSVSTSLYSYMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSRELPYTFGQGTKLEI K(配列番号6)、DIVMTQSPDSLAVSLGERATINCRASKSVSTSNYSYMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSRELPYTFGQGTKLEIK(配列番号7)、
DILLTQSPAILSVSPGERVSFSCRASQTIGTSIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQSNSWPFTFGSGTKLEIK(配列番号8)、
GVHSEIVLTQSPATLSLSPGERATLSCRASQTIGTSIHWYQQKPGQAPRLLIYYASESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNSWPFTFGQGTKLEIK(配列番号10)、もしくは
EIVLTQSPATLSLSPGERATLSCRASQTIGTSIHWYQQKPGQAPRLLIYYASESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCSQSFSWPFTFGQGTKLEIK(配列番号12)
および/または(b)下記の部分重鎖配列を有する抗体
QVQLKESGPGLVAPSQSLSITCTVSGFSLTSYGVHWVRQPPGKGLEWLGVIWTGGSTDYNSALMSRLSINKDNSKSQVFLKMNSLQTDDTAMYYCARDGDYDRYTMDYWGQGTSVTVSS(配列番号2)、
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYGVHWIRQPPGKGLEWIGVIWTGGSTDYNSALMSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGDYDRYTMDYWGQGTLVTVSS(配列番号4)、
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYGVHWIRQPPGKGLEWIGVIWTSGVTDYNSALMGRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGDYDRYTMDYWGQGTLVTVSS(配列番号5)、
QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGHGLEWIGNIYPSDSYSNYNQKFKDKATLTVDKSSSTAYMQVSSPTSEDSAVYYCTYGSSFDYWGQGTTVTVSS(配列番号9)、
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIYPSDSYSNYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGSSFDYWGQGTLVTVSS(配列番号11)、もしくは
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIFPSDSYSNYNKKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGSGFDYWGQGTLVTVSS(配列番号13)。
(1)非極性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)電荷を有さない極性:Cys、Ser、Thr、Asn、Gln;
(3)酸性(負に荷電した):Asp、Glu;
(4)塩基性(正に荷電した):Lys、Arg;
(5)鎖配向に影響を与える残基:Gly、Pro、および
(6)芳香族:Trp、Tyr、Phe、His。
m7E6重鎖可変領域
CAGGTCCAACTGCAGGAATCAGGTCCAGGCCTGGTGAAACCGTCTGAAACCCTGAGCCTGACATGCACCGTGAGCGGTGGTAGTATTAGCTCTTACGGCGTCCATTGGATCCGTCAACCGCCTGGTAAAGGTCTGGAATGGATTGGCGTGATCTGGACCGGTGGTAGCACCGACTATAACAGCGCACTGATGAGCCGCGTGACCATCTCGGTAGACACGTCGAAAAACCAGTTCAGCCTGAAACTGAGCAGCGTGACCGCCGCGGATACCGCTGTTTATTACTGCGCACGCGACGGGGATTATGATCGCTACACCATGGATTATTGGGGCCAGGGTACCCTGGTCACCGTCTCCTCA(配列番号15)
m7E6軽鎖可変領域
GACATTGTGCTGACACAGTCTCCTGCTTCCTTAGCTGTATCTCTGGGGCAGAGGGCCACCATCTCATGCAGGGCCAGCAAAAGTGTCAGTACATCTGGCTATAGTTATATGCACTGGTACCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCTTGCATCCAACCTAGAATCTGGGGTCCCTGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATTACTGTCAGCACAGTAGGGAGCTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAGATCAAA(配列番号14)
に示したポリヌクレオチドのいずれか、または両方を含む。
h7E6重鎖可変領域
CAGGTCCAACTGCAGGAATCAGGTCCAGGCCTGGTGAAACCGTCTGAAACCCTGAGCCTGACATGCACCGTGAGCGGTGGTAGTATTAGCTCTTACGGCGTCCATTGGATCCGTCAACCGCCTGGTAAAGGTCTGGAATGGATTGGCGTGATCTGGACCGGTGGTAGCACCGACTATAACAGCGCACTGATGAGCCGCGTGACCATCTCGGTAGACACGTCGAAAAACCAGTTCAGCCTGAAACTGAGCAGCGTGACCGCCGCGGATACCGCTGTTTATTACTGCGCACGCGACGGGGATTATGATCGCTACACCATGGATTATTGGGGCCAGGGTACCCTGGTCACCGTCTCCTCA(配列番号17)
h7E6軽鎖可変領域
GATATCGTAATGACCCAATCTCCGGATTCGCTGGCGGTATCACTGGGCGAACGTGCCACGATTAACTGCCGTGCAAGCAAATCAGTGTCGACCTCCGGCTACAGCTATATGCACTGGTATCAACAGAAACCGGGCCAGCCGCCGAAACTGCTGATCTATCTGGCTAGCAACCTGGAGAGCGGTGTGCCTGATCGCTTTAGTGGCTCCGGTAGCGGTACCGATTTCACGCTGACCATCAGCTCCCTGCAGGCAGAAGACGTGGCCGTGTATTATTGTCAGCACAGCCGTGAGCTGCCGTATACTTTTGGCCAGGGGACAAAACTGGAAATCAAA(配列番号16)
に示したポリヌクレオチドのいずれか、または両方を含む。
h7E6_SVG重鎖可変領域
CAGGTCCAACTGCAGGAATCAGGTCCAGGCCTGGTGAAACCGTCTGAAACCCTGAGCCTGACATGCACCGTGAGCGGTGGTAGTATTAGCTCTTACGCGTCCATTGGATCCGTCAACCGCCTGGTAAAGGTCTGGAATGGATTGGCGTGATCTGGACCAGTGGTGTGACCGACTATAACAGCGCACTGATGGGCCGCGTGACCATCTCGGTAGACACGTCGAAAAACCAGTTCAGCCTGAAACTGAGCAGCGTGACCGCCGCGGATACCGCTGTTTATTACTGCGCACGCGACGGGGATTATGATCGCTACACCATGGATTATTGGGGCCAGGGTACCCTGGTCACCGTCTCCTCA(配列番号18)
h7E6_SVG軽鎖可変領域
GATATCGTAATGACCCAATCTCCGGATTCGCTGGCGGTATCACTGGGCGAACGTGCCACGATTAACTGCCGTGCAAGCAAATCAGTGTCGACCTCCGGCTACAGCTATATGCACTGGTATCAACAGAAACCGGGCCAGCCGCCGAAACTGCTGATCTATCTGGCTAGCAACCTGGAGAGCGGTGTGCCTGATCGCTTTAGTGGCTCCGGTAGCGGTACCGATTTCACGCTGACCATCAGCTCCCTGCAGGCAGAAGACGTGGCCGTGTATTATTGTCAGCACAGCCGTGAGCTGCCGTATACTTTTGGCCAGGGGACAAAACTGGAAATCAAA(配列番号16)
に示したポリヌクレオチドのいずれか、または両方を含む。
h7E6_SVGL重鎖可変領域
CAGGTCCAACTGCAGGAATCAGGTCCAGGCCTGGTGAAACCGTCTGAAACCCTGAGCCTGACATGCACCGTGAGCGGTGGTAGTATTAGCTCTTACGCGTCCATTGGATCCGTCAACCGCCTGGTAAAGGTCTGGAATGGATTGGCGTGATCTGGACCAGTGGTGTGACCGACTATAACAGCGCACTGATGGGCCGCGTGACCATCTCGGTAGACACGTCGAAAAACCAGTTCAGCCTGAAACTGAGCAGCGTGACCGCCGCGGATACCGCTGTTTATTACTGCGCACGCGACGGGGATTATGATCGCTACACCATGGATTATTGGGGCCAGGGTACCCTGGTCACCGTCTCCTCA(配列番号18)
h7E6_SVGL軽鎖可変領域
GATATCGTAATGACCCAATCTCCGGATTCGCTGGCGGTATCACTGGGCGAACGTGCCACGATTAACTGCCGTGCAAGCAAATCAGTGTCGACCTCCTTGTACAGCTATATGCACTGGTATCAACAGAAACCGGGCCAGCCGCCGAAACTGCTGATCTATCTGGCTAGCAACCTGGAGAGCGGTGTGCCTGATCGCTTTAGTGGCTCCGGTAGCGGTACCGATTTCACGCTGACCATCAGCTCCCTGCAGGCAGAAGACGTGGCCGTGTATTATTGTCAGCACAGCCGTGAGCTGCCGTATACTTTTGGCCAGGGGACAAAACTGGAAATCAAA(配列番号19)。
に示したポリヌクレオチドのいずれか、または両方を含む。
h7E6_SVGN重鎖可変領域
CAGGTCCAACTGCAGGAATCAGGTCCAGGCCTGGTGAAACCGTCTGAAACCCTGAGCCTGACATGCACCGTGAGCGGTGGTAGTATTAGCTCTTACGCGTCCATTGGATCCGTCAACCGCCTGGTAAAGGTCTGGAATGGATTGGCGTGATCTGGACCAGTGGTGTGACCGACTATAACAGCGCACTGATGGGCCGCGTGACCATCTCGGTAGACACGTCGAAAAACCAGTTCAGCCTGAAACTGAGCAGCGTGACCGCCGCGGATACCGCTGTTTATTACTGCGCACGCGACGGGGATTATGATCGCTACACCATGGATTATTGGGGCCAGGGTACCCTGGTCACCGTCTCCTCA(配列番号18)
h7E6_SVGN軽鎖可変領域
GATATCGTAATGACCCAATCTCCGGATTCGCTGGCGGTATCACTGGGCGAACGTGCCACGATTAACTGCCGTGCAAGCAAATCAGTGTCGACCTCCAATTACAGCTATATGCACTGGTATCAACAGAAACCGGGCCAGCCGCCGAAACTGCTGATCTATCTGGCTAGCAACCTGGAGAGCGGTGTGCCTGATCGCTTTAGTGGCTCCGGTAGCGGTACCGATTTCACGCTGACCATCAGCTCCCTGCAGGCAGAAGACGTGGCCGTGTATTATTGTCAGCACAGCCGTGAGCTGCCGTATACTTTTGGCCAGGGGACAAAACTGGAAATCAAA(配列番号20)
に示したポリヌクレオチドのいずれか、または両方を含む。
h6G11_FKG_SF重鎖可変領域
CAGGTGCAGTTGGTTCAGAGCGGCGCGGAAGTCAAGAAACCCGGCGCCTCCGTGAAAGTGAGCTGCAAAGCGAGCGGCTACACCTTCACCAGTTATTGGATTAACTGGGTGCGCCAGGCCCCAGGCCAGGGGCTGGAGTGGATGGGAAACATCTTCCCATCTGACTCTTACAGCAACTATAATAAGAAATTTAAGGATCGCGTAACAATGACCCGTGACACCAGCACCAGCACTGTTTACATGGAGCTGAGTTCTCTGCGTTCTGAAGATACCGCCGTGTACTACTGCGCACGCGGTTCCGGGTTCGATTACTGGGGCCAGGGGACCCTGGTCACCGTCTCCTCA(配列番号25)
h6G11_FKG_SF軽鎖可変領域
GAGATCGTGCTGACCCAAAGTCCAGCCACCCTTTCCCTGTCTCCAGGCGAACGCGCAACCCTGAGCTGCCGCGCTTCTCAGACCATTGGTACCTCCATTCATTGGTATCAGCAGAAGCCCGGCCAAGCCCCGCGTCTGCTGATCTATTACGCCTCAGAAAGTATTTCAGGCATCCCCGCTCGCTTCTCCGGCTCCGGCAGCGGAACCGACTTCACACTTACAATCTCTAGTTTGGAGCCAGAAGACTTCGCCGTTTACTACTGTTCGCAGTCTTTTAGCTGGCCATTTACCTTTGGCCAGGGCACGAAGCTGGAAATCAAG(配列番号26)
に示したポリヌクレオチドのいずれか、または両方を含む。
m6G11重鎖可変領域
CAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTGAGGCCTGGGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTACTGGATAAACTGGGTGAAGCAGAGGCCTGGACATGGCCTTGAGTGGATCGGAAATATTTATCCTTCTGATAGTTATTCTAACTACAATCAAAAGTTCAAGGACAAGGCCACATTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAGGTCAGCAGCCCGACATCTGAGGACTCTGCGGTCTATTACTGTACGTACGGTAGTAGCTTTGACTACTGGGGCCAAGGCACCACGGTCACCGTCTCCTCA(配列番号22)
m6G11軽鎖可変領域
GACATCTTGCTGACTCAGTCTCCAGCCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCTCCTGCAGGGCCAGTCAGACCATTGGCACAAGCATACACTGGTATCAGCAAAGAACAAATGGTTCTCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATCCCTTCCAGGTTTAGTGGCAGTGGATCAGGGACAGATTTTACTCTTAGCATCAACAGTGTGGAGTCTGAAGATATTGCAGATTATTACTGTCAACAAAGTAATAGCTGGCCATTCACGTTCGGCTCGGGGACCAAGCTGGAAATAAAA(配列番号21)
に示したポリヌクレオチドのいずれか、または両方を含む。
h6G11重鎖可変領域
CAGGTGCAGTTGGTTCAGAGCGGCGCGGAAGTCAAGAAACCCGGCGCCTCCGTGAAAGTGAGCTGCAAAGCGAGCGGCTACACCTTCACCAGTTATTGGATTAACTGGGTGCGCCAGGCCCCAGGCCAGGGGCTGGAGTGGATGGGAAACATCTACCCATCTGACTCTTACAGCAACTATAATCAGAAATTTAAGGATCGCGTAACAATGACCCGTGACACCAGCACCAGCACTGTTTACATGGAGCTGAGTTCTCTGCGTTCTGAAGATACCGCCGTGTACTACTGCGCACGCGGTTCCAGTTTCGATTACTGGGGCCAGGGGACCCTGGTCACCGTCTCCTCA(配列番号24)
h6G11軽鎖可変領域
GAGATCGTGCTGACCCAAAGTCCAGCCACCCTTTCCCTGTCTCCAGGCGAACGCGCAACCCTGAGCTGCCGCGCTTCTCAGACCATTGGTACCTCCATTCATTGGTATCAGCAGAAGCCCGGCCAAGCCCCGCGTCTGCTGATCTATTACGCCTCAGAAAGTATTTCAGGCATCCCCGCTCGCTTCTCCGGCTCCGGCAGCGGAACCGACTTCACACTTACAATCTCTAGTTTGGAGCCAGAAGACTTCGCCGTTTACTACTGTCAGCAGTCTAACAGCTGGCCATTTACCTTTGGCCAGGGCACGAAGCTGGAAATCAAG(配列番号23)
に示したポリヌクレオチドのいずれか、または両方を含む。
本発明は、本明細書に記載のTrop−2抗体またはその抗原結合断片のコンジュゲート(または免疫複合体)であって、抗体または抗原結合断片は、直接に、またはリンカーを介して間接的に、標的免疫療法用作用物質(例えば、細胞毒性剤)にコンジュゲートしている(例えば、抗体−薬剤コンジュゲート)、コンジュゲートも提供する。例えば、腫瘍(例えば、Trop−2発現腫瘍)への細胞毒性剤部分の標的化局所送達のために、本明細書に記載のTrop−2抗体またはその抗原結合断片に細胞毒性剤を連結またはコンジュゲートすることができる。
本発明の抗体および抗体コンジュゲートは、それだけに限らないが、治療的処置方法および診断的処置方法を含めた、様々な用途で有用である。
本発明の方法で使用される組成物は、有効量の本明細書に記載のTrop−2抗体またはTrop−2抗体コンジュゲートを含む。このような組成物の例および製剤方法も、先のセクションおよび以下に記載されている。いくつかの実施形態では、組成物は、1種または複数のTrop−2抗体またはTrop−2抗体コンジュゲートを含む。例えば、Trop−2抗体は、ヒトTrop−2を認識する。いくつかの実施形態では、Trop−2抗体は、ヒト抗体、ヒト化抗体、またはキメラ抗体である。いくつかの実施形態では、Trop−2抗体は、所望の免疫応答、例えば、抗体媒介溶解またはADCCなどを誘発することができる定常領域を含む。他の実施形態では、Trop−2抗体は、望まれない、または望ましくない免疫応答、例えば、抗体媒介溶解またはADCCなどを誘発しない定常領域を含む。他の実施形態では、Trop−2抗体は、抗体の1つまたは複数のCDR(1つ,2つ、3つ、4つ、5つ、またはいくつかの実施形態では、6つすべてなどのCDR)を含む。
本発明は、本方法で使用するためのキットも提供する。本発明のキットは、本明細書に記載のTrop−2抗体またはTrop−2抗体コンジュゲート、および本明細書に記載の本発明の方法のいずれかによって使用するための指示書を含む、1つまたは複数の容器を含む。一般に、これらの指示書は、上述した治療的処置のためにTrop−2抗体またはTrop−2抗体コンジュゲートを投与する説明を含む。
本発明のTrop−2抗体を発現させるために、VHおよびVL領域をコードするDNA断片を、上述した方法のいずれかを使用して最初に得ることができる。様々な修飾、例えば、突然変異、置換、欠失、および/または付加も、当業者に公知の標準方法を使用して、DNA配列中に導入することができる。例えば、突然変異誘発は、PCR媒介突然変異誘発などの標準方法を使用して実施することができ、PCR媒介突然変異誘発では、突然変異したヌクレオチドがPCRプライマー中に組み込まれ、その結果、PCR産物が所望の突然変異または部位特異的突然変異誘発を含有する。
組換え抗Trop−2マウス抗体の抗体結合親和性決定
ハイブリドーマから生成される抗Trop−2マウス抗体の親和性を、研究グレードCM5センサーチップ(Biacore(商標)AB、Uppsala、スウェーデン−現在、GEHealthcare)を備えた表面プラズモン共鳴Biacore(商標)2000または3000バイオセンサーで測定した。抗マウスIgGをCM5センサー表面に最初にアミンカップリングさせた。次いで、様々な抗Trop−2マウスIgGを抗マウスIgGによって捕捉させた。Trop−2−Fc融合タンパク質のパパイン消化から調製した単量体Trop−2細胞外ドメインを、3倍希釈系列で分析物として注入した。抗Trop−2マウス抗体の親和性は、7.5〜31.8nMの範囲である。表4。
組換え抗Trop−2マウス抗体のドメインマッピング
ドメインマッピングを、Trop−2細胞外ドメインをTrop−1(EpCAM)またはマウスTrop−2等価領域と交換することによって行った。図4〜5を参照。抗Trop−2抗体3E9、6G11、7E6、および18B1(組換えマウスIgG2aとして発現された)は、ヒトTrop−1にもマウスTrop−2にも結合せず、一方、15E2は、マウスTrop−2に結合するがヒトTrop−1に結合しない。これらのハイブリッドタンパク質を、293F細胞内でヒトFc融合タンパク質として発現させた。抗Trop−2抗体のこれらのドメインハイブリッドへの結合を、Biacoreによって決定した。抗Trop−2抗体によるある特定のヒトTrop−2ドメインの認識は、ドメイン交換により結合が喪失または低減するとき、定義した。抗Trop−2抗体クローン3E9、7E6、および15E2は、ドメイン3および4に結合し、一方、クローン6G11および18B1は、ドメイン1に結合する。表5。Trop−2の異なるドメインの定義は、例えば、Chongら、J.Biol.Chem.、276(8):5804〜13、2001に見つけることができる。
Colo205異種移植片モデルを用いたIn Vivo効力試験
抗Trop−2マウスIgGのin vivo効力試験を、標的発現colo205異種移植片モデルを用いて実施した。100万のcolo205大腸がん細胞を、生後5〜8週のnu/nuマウスの皮下に移植した(0日目)。翌日(1日目)に体重によって動物をランダム化して、異なる処置コホート(対照IgG、7E6、15E2、または18B1群;n=10/群)にした。異なる処置コホートおよび対照mIgGからの20mg/kgの抗Trop−2抗体を、ボーラス尾静脈注射によって週3回、合計12回にわたって投与した。すべての実験動物を体重変化について毎日監視した。腫瘍体積をキャリパーデバイスで週2回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。TGI(%腫瘍増殖阻害)を[1−腫瘍サイズ(処置群)/腫瘍サイズ(対照群)]×100として求めた。表6および図1は、抗Trop−2抗体7E6、15E2、および18B1が、Colo205異種移植片腫瘍増殖をin vivoで阻害することを示す。
A431異種移植片モデルを用いたIn Vivo効力試験
a)抗Trop−2抗体7E6、15E2、および18B1によるA431異種移植片腫瘍増殖の阻害
抗Trop−2マウスIgGのin vivo効力試験を、標的発現A431異種移植片モデルを用いて実施した。200万のA431類表皮がん細胞を、生後5〜8週のnu/nuマウスの皮下に、腫瘍サイズが約100mm3に到達するまで移植した。動物を腫瘍サイズによってランダム化し、投薬をボーラス尾静脈注射によって行った。抗Trop−2抗体は、293Fの一過性発現から組換えマウスIgG2a抗体として発現させた。20mg/kgの抗Trop−2抗体(18B1、15E2、および7E6組換えmIgG2a)、または対照IgGを、ボーラス尾静脈注射によって週2回、合計6回にわたって投与した。腫瘍体積をキャリパーデバイスで週2回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。TGI(%腫瘍増殖阻害)を[1−腫瘍サイズ(処置群)/腫瘍サイズ(対照群)]×100として求めた。表7Aおよび図2Aは、抗Trop2抗体7E6、15E2、および18B1が、A431異種移植片腫瘍増殖をin vivoで阻害することを示す。
上記実施例4aに記載の同じ異種移植片モデルを使用して、様々な用量の抗Trop−2 7E6抗体(5、10、および20mg/kg)、または20mg/kgの対照IgGを、ボーラス尾静脈注射によって週2回、合計6回にわたって投与した。表7Bおよび図2Bは、様々な用量の7E6によるin vivoでのA431異種移植片腫瘍増殖の阻害を示す。
同様に、実施例4a)に記載したA431異種移植片モデルにおいて、すべてmIgG2として組換えで発現させた20mg/kgの抗Trop−2抗体(6G11、7E6、および18B1、ならびに対照IgG)を、ボーラス尾静脈注射によって週1回、合計3回にわたって投与した。表7Cおよび図2Cは、抗Trop2抗体6G11、7E6、および18B1が、A431異種移植片腫瘍増殖をin vivoで阻害することを示す。
ヒト化抗Trop−2抗体−7E6の抗体結合親和性決定
キメラおよびヒト化抗Trop−2 7E6抗体の親和性を、研究グレードCM4センサーチップ(Biacore(商標)AB、Uppsala、スウェーデン−現在、GEHealthcare)を備えた表面プラズモン共鳴Biacore(商標)T200バイオセンサーで測定した。ヒトTrop−2−hFcまたはカニクイザルTrop−2−hFcタンパク質を、抗ヒトFcとカップリングしたCM5 EDAチップ37センサー表面上で捕捉した。キメラおよびヒト化7E6組換えFab断片を、3倍希釈系列として注射した。表8Aおよび表8Bは、ヒト化抗Trop−2 7E6抗体の、それぞれヒトTrop−2タンパク質およびカニクイザルTrop−2タンパク質への親和性測定値を示す。
ヒト化抗Trop−2抗体−6G11の抗体結合親和性決定
ヒト化6G11抗体の親和性を、研究グレードCM5センサーチップ(Biacore(商標)AB、Uppsala、スウェーデン−現在、GEHealthcare)を備えた表面プラズモン共鳴Biacore(商標)2000バイオセンサーで測定した。ヒトTrop−2−mFcタンパク質を、抗マウスFcとカップリングしたCM5チップ上で捕捉した。ヒト6G11_WTまたはヒト6G11_FKG_SFキメラFab断片を、3倍希釈系列として注射した。表9は、ヒト化抗Trop−2 6G11抗体のヒトTrop−2タンパク質への親和性測定値を示す。
Trop−2陽性および陰性腫瘍細胞に対するマウスおよびヒト化抗Trop−2抗体のフローサイトメトリー
a)7E6
マウスキメラおよびヒト化抗Trop−2 7E6抗体(ヒトIgG1サブタイプ内で発現させた)の結合を、Trop−2発現(A431およびColo205)ならびに非発現(SW620)細胞について、フローサイトメトリーによって評価した。A431細胞染色に関して、200,000細胞を、結合緩衝液(PBS(リン酸緩衝溶液)+0.5%のBSA(ウシ血清アルブミン))100μL中で、抗体0.5μgとともにインキュベートし、その後Jackson immunoresearch Laboratories(West Grove、PA)製Dylight488コンジュゲートヤギ抗ヒト(Fab’)2−特異的二次抗体とともにインキュベートした。Colo205およびSW620細胞に関して、300,000細胞を、一次抗体1μgとともに、その後Jackson immunoresearch Laboratories(West Grove、PA)製AlexaFluor 647抗ヒト(Fab’)2−特異的二次抗体とともに使用した。表10は、マウス7E6およびヒト化7E6抗体によるTrop−2陽性腫瘍細胞に対する少なくとも約93%の結合を示す。
実施例7a)と同様に、キメラマウスおよびヒト化抗Trop−2 6G11抗体(ヒトIgG1サブタイプ内で発現させた)の結合を、Trop−2発現(A431およびColo205)ならびに非発現(SW620)細胞について、フローサイトメトリーによって評価した。300,000細胞を、一次抗体1μg、その後AlexaFluor 647抗ヒト(Fab’)2−特異的二次抗体とともに使用した。表11は、マウス6G11およびヒト化6G11抗体によるTrop−2陽性腫瘍細胞に対する少なくとも約99%の結合を示す。
A431細胞に対するキメラおよびヒト化抗Trop−2 7E6 hIgG1抗体のADCC活性
キメラマウス(h7E6−WT)ならびにヒト化抗Trop−2 7E6ヒトIgG1抗体(h7E6_SVG(VH領域)、h7E6_L(VL領域)、ならびにh7E6−SVGL(VHおよびVL領域の両方))のADCC(抗体依存性細胞傷害)活性を、cytoTox96非放射性細胞傷害性アッセイキット(Promega、Madison WI)を用いて求めた。標的発現A431細胞を、アッセイの前日に10,000細胞/ウェルで播種した。ドナーPBMC(凍結保存した末梢血単核細胞)を、フィコール勾配によって単離し、X−VIVO培地(Lonza、Wakersville、MO)中で、37℃で一晩培養した。翌日、抗体を図3に示した濃度でウェルに添加し、その後RPMI+5%のFBS(ウシ胎児血清)中の500,000PBMC細胞(E:T=50:1)を添加した。抗EGFR(上皮成長因子受容体)抗体(ERBITUX(登録商標)、Imclone、Bridgewater、NJ)をアッセイの陽性対照として使用した。次いでプレートを37℃で4時間インキュベートした。3時間半の時点で、溶解液20μLを、標的細胞単独のウェルに添加した。プレートを8000rpmで3分間回転させた後、上清50μLを別のプレートに移した。次いで基質50μlを各ウェルに添加し、プレートを、暗所で、室温で30分間インキュベートした。Promega(Madison、WI)製停止液50μLを各ウェル添加することによって、反応を停止した。次いで、分光光度計(Molecular Devices、Sunnyvale、CA)を用いて490nmでプレートを読み取った。特異的溶解のパーセンテージ(%)を以下の式で計算した:
%特異的溶解=(処置LDH(乳酸脱水素酵素)放出−標的細胞自発的LDH放出−効果細胞自発的LDH放出)/(標的細胞最大LDH放出−標的細胞自発的LDH放出)×100
Trop−2陽性細胞内の抗Trop−2ADCの細胞傷害性
表12に示したように、キメラマウス(6G11および7E6)ならびにヒト化抗Trop−2(h7E6−SVG、h7E6−SVGL、およびh7E6−SVGN)抗体を、グルタミン含有トランスグルタミナーゼ(「Q」)タグ(例えば、TG1、LCQ03、およびTG6は、それぞれ、配列番号75,(LLQGG)、78(GGLLQGA)、および79(LLQGA)に対応する)で遺伝子工学的に改変され、AcLys−vcMMAD(アセチル−リシン−バリン−シトルリン−MMAD)、アミノカプロイル−vc−PABC−MMAD(アミノカプロイル−バリン−シトルリン−p−アミノベンジルオキシカルボニル−MMAD)、またはAcLys−vc−PABC−MMAD(アセチル−リシン−バリン−シトルリン−p−アミノベンジルオキシカルボニル−MMAD)とコンジュゲートしたヒトIgG1サブタイプとして発現させた。一例では、トランスグルタミナーゼタグは、抗体の軽鎖または重鎖C末端で遺伝子工学的に改変することができ、他の例では、トランスグルタミナーゼタグ(例えば、Q)は、ヒトIgGの297位(Kabat番号付けスキーム)などの抗体の別の部位で遺伝子工学的に改変される。例えば、野生型アミノ酸アスパラギン(N)は、Trop−2抗体の297位でグルタミンと置換される(N297Q)。次いで、MMADへの抗Trop−2抗体コンジュゲーションを、特定の部位(例えば、抗体の重鎖もしくは軽鎖のカルボキシル末端もしくはアミノ末端、297位、または別の部位)でグルタミン含有タグを担持する抗Trop−2抗体と、ペイロード(例えば、MMAD)のアミン含有誘導体との間の微生物トランスグルタミナーゼ触媒アミド基転移反応を介して実現した。場合によっては、カルボキシル末端(Kabat番号付けスキームによる447位)の野生型アミノ酸リシンを欠失させ、Q−タグと置き換えた。他の例では、222位、340位、または370位(Kabat番号付けスキームによる)の野生型アミノ酸リシンを、アミノ酸アルギニンと置き換えた(「K222R」、「K340R」、または「K370R」)。例えば、K222R置換は、より均質な抗体とペイロードのコンジュゲート、抗体とペイロードとのより良好な分子間架橋、および/または抗体軽鎖のC末端上のグルタミンタグとの鎖間架橋の著しい減少をもたらすという意外な効果を有することが判明した。アミド基転移反応では、抗体上のグルタミンは、アシルドナーとして作用し、アミン含有化合物は、アシルアクセプター(アミンドナー)として作用した。1.67〜4.04μMの濃度の精製抗Trop−2抗体を、6.2〜8.8のpH範囲の、150〜900mMのNaCl、および25mMのMES、HEPES[4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸]、またはTris HCl緩衝液中で、0.225〜0.545%(w/v)のストレプトベルチシリウム・モバラエンス(Streptoverticillium mobaraense)トランスグルタミナーゼ(ACTIVA(商標)、Ajinomoto、日本)の存在下で、167〜404μMの間の範囲で、20〜100M過剰のアシルアクセプターとともにインキュベートした。反応条件を個々のアシルアクセプター誘導体について調整し、最適な効率および特異性は一般に、150mMのNaCl、25mMのTris HCl、pH8.8中の2.87μMの抗体、287μMの誘導体、および0.378%(w/v)のトランスグルタミナーゼで観察された。室温で2.5時間インキュベートした後、GE Healthcareから市販されている親和性クロマトグラフィーなどの当業者に公知の標準的な親和性クロマトグラフィー法を使用して、MabSelect樹脂(GE Healthcare、Waukesha、WI)上で抗体を精製した。
抗Trop−2 7E6オーリスタチンコンジュゲートは、BxPC3異種移植片モデルにおいて長期間の腫瘍退縮を誘導した
対照抗体hIgG1−TG1−vcMMAD(「NNCTG1−vcMMAD」)、およびトランスグルタミナーゼを介して1)LCQ03−AcLys−vc−PABC−MMAD K222Rバリアントまたは2)TG6−AcLys−vc−PABC−MMADとコンジュゲートされたキメラ抗Trop−2抗体7E6のin vivo効力試験を、標的発現BxPC3異種移植片モデルを用いて実施した。h7E6−K222R−LCQ03−AcLys−vc−PABC−MMADバリアントコンジュゲートに関して、抗Trop−2抗体中の野生型アミノ酸リシンが、Kabat番号付けスキームによる222位でアミノ酸アルギニンと置換されている(すなわちK222R)。LCQ03は、配列番号78(GGLLQGG)に対応し、TG6は、配列番号79(LLQGA)に対応する。トランスグルタミナーゼタグLCQ03およびTG6を使用してTrop−2抗体をコンジュゲートする一般的な方法は、実施例9に記載されている。200万のBxPC3がん細胞を、生後5〜8週のCB17 SCIDマウスの皮下に、腫瘍サイズが約250mm3に到達するまで移植した。動物を腫瘍サイズによってランダム化し、投薬をボーラス尾静脈注射によって行った。3mg/kgの対照hIgG1、キメラh7E6−K222R−LCQ03−AcLys−vc−PABC−MMADバリアント、またはキメラ7E6−TG6−AcLys−vc−PABC−MMADを、ボーラス尾静脈注射によって1回、合計1回にわたって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。単回投与のAcLys−vc−PABC−MMADとコンジュゲートしたキメラ抗Trop−2抗体7E6は、長期間の腫瘍退縮をもたらした。図8を参照。
Trop−2陽性細胞内の抗Trop−2−ADCの細胞傷害性
陰性対照(NNC)およびヒト化抗Trop−2(h7E6SVG)抗体を、指定されたように、重鎖(TG6(配列番号79))、軽鎖(LCQ03(配列番号78)およびLCQ04(配列番号79))のC末端で、グルタミン含有トランスグルタミナーゼタグで、または重鎖のCH2/ヒンジドメイン内のN297Q/K222R突然変異で遺伝子工学的に改変され、AcLys−vc−PABC−0101(「vc0101」またはアセチル−リシン−バリン−シトルリン−p−アミノベンジルオキシカルボニル−(2−メチルアラニル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1S)−2−フェニル−1−(1,3−チアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド))またはアミノカプロイル−PEG6(プロピレングリコール)6−プロピオニル)−MMADとコンジュゲートしたヒトIgG1サブタイプとして発現させた。2−メチルアラニル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1S)−2−フェニル−1−(1,3−チアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミドは、米国出願第61/561,255号および同第61/676,423号に記載された新規オーリスタチンである。トランスグルタミナーゼタグを使用してTrop−2抗体をコンジュゲートする方法は、実施例9に記載されている。標的発現または非発現(SW620)細胞を、処置の24時間前に、1ウェル当たり2000(A431、BxPC3、NCI−H292、NCI−H1650、MDA−MB−468、およびSW620)、2500(Calu−3)、または3000(OVCAR3およびSKBR3)細胞で白色壁透明底プレート上に播種した。4倍連続希釈した抗体−薬剤コンジュゲートを用いて三つ組で細胞を処置した。処置して96時間後に、CellTiter−Glo(登録商標)Luminescent Cell Viability Assay 96(Promega、Madison WI)によって細胞生存能を求めた。相対的な細胞生存能を、未処置対照のパーセンテージとして求めた。IC50をGraphPad Prism5ソフトウェアによって計算し、総Abの濃度(nM)として表現した。表13は、トランスグルタミナーゼタグによってvc0101またはPEG6−MMADにコンジュゲートしたヒト化抗Trop−2 7E6抗体が、Trop−2発現細胞内で強力な細胞殺傷活性を発揮することを示す。
抗Trop−2 7E6オーリスタチンコンジュゲートは、膵臓腫瘍BxPC3異種移植片モデルにおいて腫瘍退縮を誘導した
Trop−2 ADCのin vivo効力試験を、標的発現BxPC3異種移植片モデルを用いて実施した。200万のBxPC3膵がん細胞を、生後5〜8週のCB17/SCIDマウスの皮下に、腫瘍サイズが300〜400mm3に到達するまで移植した。動物を腫瘍サイズによってランダム化し、単回投与の1)TG6−AcLys−vc−PABC−0101(図9Aに表したTG6−AcLys−vc−0101に等しい)、2)N297Q/K222R−PEG6−MMAD((プロピレングリコール)6−プロピオニル−MMAD)、および3)LCQ04−K222R−vc−PABC0101(図9Cに表したLCQ04/K222R−vc0101に等しい)、LCQ04は、配列番号79(LLQGA)に対応する)とコンジュゲートしたヒト化抗Trop−2抗体、ならびに対照コンジュゲートを、ボーラス尾静脈注射によって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。図9A〜9Cは、単回投与の1)TG6−AcLys−vc−PABC−0101、2)N297Q/K222R−PEG6−MMAD、および3)LCQ04−K222R−vc−PABC0101とコンジュゲートしたヒト化抗Trop−2抗体が、膵臓腫瘍BxPC3異種移植片モデルにおいて腫瘍退縮をもたらすことを示す。
抗Trop−2 7E6オーリスタチンコンジュゲートは、大腸腫瘍Colo205異種移植片モデルにおいて腫瘍退縮を誘導した
Trop−2 ADCのin vivo効力試験を、標的発現colo205異種移植片モデルを用いて実施した。300万のcolo205大腸がん細胞を、生後5〜8週のnu/nuマウスの皮下に、腫瘍サイズが約300mm3に到達するまで移植した。動物を腫瘍サイズによってランダム化し、単回投与の6mg/kgの1)TG6−AcLys−vc−PABC−0101(図10に表したTG6−vc−0101に等しい)、および2)重鎖のヒンジ/CH2ドメイン内にK222R置換を有するLCQ03−vc−PABC−0101(図10に表したLCQ03/K222R−vc0101に等しく、LCQ03は、配列番号78(GGLLQGG)に対応する)とコンジュゲートしたヒト化抗Trop−2抗体、ならびに対照コンジュゲート(IgG−vc−PABC−0101)を、ボーラス尾静脈注射によって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。図10は、単回投与の1)TG6−AcLys−vc−PABC−0101、および2)重鎖のヒンジ/CH2ドメイン内にK222R置換を有するLCQ03−vc−PABC−0101とコンジュゲートしたヒト化抗Trop−2抗体が、大腸腫瘍Colo205異種移植片モデルにおいて腫瘍退縮をもたらしたことを示す。
抗Trop−2 7E6オーリスタチンコンジュゲートは、卵巣PDX Ova196756異種移植片モデルにおいて腫瘍退縮を誘導した
TG6−vc−0101とコンジュゲートしたヒト化抗Trop2抗体(h7E6SVG)を使用するTrop−2 ADCのin vivo効力試験を、標的発現卵巣がん患者由来異種移植片モデル(PDX Ova196756)を用いて実施した。この腫瘍試料を外科標本から得、NSGマウス(Jackson Laboratories、Bar Harbor、Maine)内で増殖させた。効力試験のために、およそ1〜2mm3の腫瘍断片を、CB17/SCIDマウスの外側側腹部の皮下に移植した。腫瘍サイズが約400mm3に到達した際、動物を腫瘍サイズによってランダム化し、単回投与のh7E6SVG−TG6−AcLys−vc−PABC−0101(0.75mg/kgおよび1.5mg/kg;図11に表したTG6−vc0101に等しい)、ならびに対照コンジュゲート(1.5mg/kg;図11に表したIgG−vc−PABC−0101またはIgG−vc0101)を、ボーラス尾静脈注射によって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。図11は、単回投与のTG6−AcLys−vc−PABC−0101とコンジュゲートしたヒト化抗Trop−2抗体が、卵巣PDX Ova196756異種移植片モデルにおいて腫瘍退縮をもたらしたことを示す。
抗Trop−2 7E6オーリスタチンコンジュゲートは、Pan0146膵臓PDXモデルにおいて腫瘍退縮を誘導するのにゲムシタビンより優れた効力を示す
TG6−vc0101とコンジュゲートしたヒト化抗Trop−2抗体(h7E6SVG)を使用するTrop−2 ADCのin vivo効力試験を、Jackson Laboratories(Bar Harbor、Maine)製の標的発現膵がん患者由来異種移植片モデル(PDX Pan0146)を用いて実施した。効力試験のために、1〜2mm3の腫瘍断片を、動物の外側側腹部の皮下に移植した。腫瘍サイズが約300mm3に到達した際、動物を腫瘍サイズによってランダム化し、h7E6SVG−TG6−AcLys−vc−PABC−0101および対照コンジュゲートを、ボーラス尾静脈注射によって投与した。図12A:単回投与のh7E6SVG−TG6−AcLys−vc−PABC−0101(図でh7E6SVG−TG6−vc0101と示されている)および対照コンジュゲートを指定した用量で投与した。ゲムシタビンは、毎週2回、合計6回にわたって75mg/kgで投与した。図12B:h7E6SVG−TG6−AcLys−vc−PABC−0101を、0.75mg/kgを毎週1回で4回にわたって、1.5mg/kgを隔週で2回にわたって、または3.0mg/kgの単回投与で投与した。ゲムシタビンは、毎週1回、75mg/kgで4回にわたって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。データは、TG6−AcLys−vc−PABC−0101とコンジュゲートしたヒト化抗Trop2抗体が、Pan0146膵臓PDXモデルにおいて腫瘍退縮を誘導するのに、ゲムシタビンより優れた効力を有し、h7E6SVG−TG6−AcLys−vc−PABC−0101を連続的に投薬すると、膵臓PDX Pan0146異種移植片モデルにおいて腫瘍退縮が持続したことを示す。
抗Trop−2 7E6オーリスタチンコンジュゲートは、膵臓Pan144607 PDXモデルにおいて腫瘍退縮を誘導する
vc0101またはPEG6MMADとコンジュゲートしたヒト化抗Trop−2抗体(h7E6SVG)を使用するTrop−2 ADCのin vivo効力試験を、標的発現膵がん患者由来異種移植片モデル(PDX Pan144607)を用いて実施した。この腫瘍試料を外科標本から得、NSGマウス(Jackson Laboratories、Bar Harbor、Maine)内で増殖させた。効力試験のために、およそ1〜2mm3の腫瘍断片を、CB17/SCIDマウスの外側側腹部の皮下に移植した。腫瘍サイズが約300mm3に到達した際、動物を腫瘍サイズによってランダム化し、1.5、3.0、および6.0mg/kgの単回投与のh7E6SVG−N297Q/K222R−PEG6MMAD、ならびに対照コンジュゲートを、ボーラス尾静脈注射によって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。図13は、単回投与のPEG6−MMADとコンジュゲートしたヒト化抗Trop2抗体が膵臓Pan144607 PDXモデルにおいて腫瘍退縮をもたらしたことを示す。
抗Trop−2 7E6オーリスタチンコンジュゲートは、膵臓Pan0135 PDXモデルにおいて腫瘍退縮を誘導する
PEG6MMADとコンジュゲートしたヒト化抗Trop−2抗体(h7E6SVG)を使用するTrop−2 ADCのin vivo効力試験を、Jackson Laboratories製の標的発現膵がん患者由来異種移植片モデル(PDX Pan0135)を用いて実施した。効力試験のために、およそ1〜2mm3の腫瘍断片を、動物の外側側腹部の皮下に移植した。腫瘍サイズが約300mm3に到達した際、動物を腫瘍サイズによってランダム化し、6mg/kgのh7E6SVG−N297Q/K222R−PEG6MMAD、および対照コンジュゲートを、単回投与でボーラス尾静脈注射によって投与した。腫瘍体積をキャリパーデバイスで週1回測定し、以下の式、すなわち、腫瘍体積=(長さ×幅2)/2で計算した。腫瘍体積が2000mm3に到達する前に試験を終わらせた。図14は、単回投与のPEG6−MMADとコンジュゲートしたヒト化抗−Trop2抗体が、膵臓Pan0135 PDXモデルにおいて腫瘍退縮をもたらしたことを示す。
ヒト化抗Trop−2抗体の抗体結合親和性決定
Fab/ヒトTrop2−ECD(細胞外ドメイン)相互作用の分析を、GLCセンサーチップを備えたBio−Rad Proteon XPR36表面プラズモン共鳴(SPR)バイオセンサー(Bio−Rad、Hercules、CA)を使用して実施した。アッセイ温度は25℃であり、アッセイ緩衝液は、10mMのリン酸ナトリウム、150mMのNaCl、0.05%のTween−20、pH7.4であった。アミンカップリングしたFabのアレイを、Abdicheら(Anal.Biochem.、411:139〜151(2011))に記載の方法を使用して調製した。各分析サイクルにおいて、一価ヒトTrop2−ECD抗原を、固定化されたFab上に30μL/分で3分間流し、その後15分間緩衝液で洗浄してFab/Trop2複合体の解離を監視した。Pierce IgG溶出緩衝液:4MのNaCl(Pierce、Rockford、IL)の2:1混合物(体積による)の18秒の注入を3回使用して、センサー表面を分析サイクル間で再生させた。結合および再生サイクルを、6、30、および150nMのヒトTrop2−ECD濃度で繰り返した。得られたデータを、Proteon評価ソフトウェアを使用して、1:1のラングミュア結合モデルにフィッティングした。結果を以下の表に表す。
Claims (41)
- 栄養膜細胞表面抗原−2(Trop−2)に特異的に結合する単離抗体またはその抗原結合断片であって、
(a)(i)配列SYGVH(配列番号30)、GGSISSY(配列番号36)、もしくはGGSISSYGVH(配列番号37)を含む重鎖可変(VH)領域相補性決定領域1(CDR1)、(ii)配列VIWTX1GX2TDYNSALMX3(式中、X1は、GもしくはSであり、X2は、SもしくはVであり、X3は、SもしくはGである)(配列番号49)、もしくはWTX1GX2(式中、X1は、GもしくはSであり、X2は、SもしくはVである)(配列番号50)を含むVH CDR2、およびiii)配列DYDRYTX1DY(式中、X1、はEもしくはMである)(配列番号82)を含むVH CDR3を含むVH領域相補性決定領域、ならびに/または
(b)(i)配列RASKSVSTSX1YSYMH(式中、X1は、G、L、もしくはNである)(配列番号63)を含む軽鎖可変領域(VL)CDR1、(ii)配列LASNLES(配列番号55)を含むVL CDR2、および(iii)配列QHSRELPYT(配列番号56)を含むVL CDR3を含むVL領域相補性決定領域
を含む、単離抗体またはその抗原結合断片。 - Trop−2に特異的に結合する単離抗体またはその抗原結合断片であって、
配列番号5もしくは85に示したVH配列のVH CDR1、VH CDR2、およびVH CDR3を含むVH領域、ならびに/または
配列番号3もしくは6に示したVL配列のVL CDR1、VL CDR2、およびVL CDR3を含むVL領域
を含む、単離抗体またはその抗原結合断片。 - VH領域が、(i)配列SYGVH(配列番号30)、GGSISSY(配列番号36)、またはGGSISSYGVH(配列番号37)を含むVH CDR1、(ii)配列VIWTSGVTDYNSALMG(配列番号38)またはWTSGV(配列番号39)を含むVH CDR2、および(iii)配列DGDYDRYTMDY(配列番号35)、DYDRYTMDY(配列番号99)、またはDYDRYTEDY(配列番号100)を含むVH CDR3を含む、請求項2に記載の抗体または抗原結合断片。
- VL領域が、(i)配列RASKSVSTSGYSYMH(配列番号54)またはRASKSVSTSLYSYMH(配列番号57)を含むVL CDR1、(ii)配列LASNLES(配列番号55)を含むVL CDR2、および(iii)配列QHSRELPYT(配列番号56)を含むVL CDR3を含む、請求項3に記載の抗体または抗原結合断片。
- VH領域が、配列番号5、85に示した配列、またはCDR内にない残基中に1つもしくはいくつかの保存的アミノ酸置換を有するバリアントを含み、かつ/またはVL領域が、配列番号3、6に示したアミノ酸配列、またはCDR内にないアミノ酸中に1つもしくはいくつかのアミノ酸置換を有するそのバリアントを含む、請求項4に記載の抗体または抗原結合断片。
- 配列番号66に示した配列を含む軽鎖、および配列番号65または102に示した配列を含む重鎖を含む、請求項5に記載の抗体または抗原結合断片。
- ATCC受託番号PTA−12872を有する発現ベクターによって生成されるVH領域を含む、請求項3に記載の抗体または抗原結合断片。
- ATCC受託番号PTA−12871を有する発現ベクターによって生成されるVL領域を含む、請求項4に記載の抗体または抗原結合断片。
- 表面プラズモン共鳴によって測定して約6.5nM以下の一価抗体結合親和性(KD)でヒトTrop−2(配列番号27)のドメイン3およびドメイン4に特異的に結合する単離抗体またはその抗原結合断片。
- Trop−2に特異的に結合する単離抗体またはその抗原結合断片であって、
(a)(i)配列SYWIN(配列番号40)、GYTFTSY(配列番号41)、もしくはGYTFTSYWIN(配列番号42)を含む重鎖可変(VH)相補性決定領域1(CDR1)、(ii)配列NIX1PSDSYSNYNX2KFKD(式中、X1は、YもしくはFであり、X2は、QもしくはKである)(配列番号51)、もしくはX1PSDSY(式中、X1は、YもしくはFである)(配列番号52)を含むVH CDR2、およびiii)配列GSX1FDY(式中、X1は、SもしくはGである)(配列番号53)を含むVH CDR3を含むVH領域相補性決定領域、ならびに/または
(b)(i)配列RASQTIGTSIH(配列番号59)を含む軽鎖可変領域(VL)CDR1、(ii)配列YASESIS(配列番号60)を含むVL CDR2、および(iii)配列X1QSX2SWPFT(X1は、QもしくはSであり、X2は、NもしくFである)(配列番号64)を含むVL CDR3を含むVL領域相補性決定領域
を含む、単離抗体またはその抗原結合断片。 - Trop−2に特異的に結合する単離抗体またはその抗原結合断片であって、
配列番号13に示したVH配列のVH CDR1、VH CDR2、およびVH CDR3を含むVH領域、ならびに/または
配列番号12に示したVL配列のVL CDR1、VL CDR2、およびVL CDR3を含むVL領域
を含む、単離抗体またはその抗原結合断片。 - VH領域が、(i)配列SYWIN(配列番号40)、GYTFTSY(配列番号41)、またはGYTFTSYWIN(配列番号42)を含むVH CDR1、(ii)配列NIFPSDSYSNYNKKFKD(配列番号46)またはFPSDSY(配列番号47)を含むVH CDR2、および(iii)配列GSGFDY(配列番号48)を含むVH CDR3を含む、請求項11に記載の抗体または抗原結合断片。
- VL領域が、(i)配列RASQTIGTSIH(配列番号59)を含むVL CDR1、(ii)配列YASESIS(配列番号60)を含むVL CDR2、および(iii)配列SQSFSWPFT(配列番号62)を含むVL CDR3を含む、請求項12に記載の抗体または抗原結合断片。
- VH領域が、配列番号13に示した配列、またはCDR内にない残基中に1つもしくはいくつかの保存的アミノ酸置換を有するバリアントを含み、かつ/またはVL領域が、配列番号12に示したアミノ酸配列、またはCDR内にないアミノ酸中に1つもしくはいくつかのアミノ酸置換を有するそのバリアントを含む、請求項13に記載の抗体または抗原結合断片。
- 配列番号68に示した配列を含む軽鎖、および配列番号67に示した配列を含む重鎖を含む、請求項14に記載の抗体または抗原結合断片。
- Trop−2に特異的に結合し、請求項2または4に記載の抗体と競合する単離抗体。
- 表面プラズモン共鳴によって測定して、約6.5nM以下の一価抗体結合親和性(KD)を有する、請求項16に記載の抗体。
- 特定の部位で遺伝子工学的に改変されたアシルドナーグルタミン含有タグを含む、請求項1から15のいずれか一項に記載の抗体。
- タグが、アミノ酸配列GGLLQGG(配列番号78)、LLQGA(配列番号79)、またはLLQを含む、請求項18に記載の抗体。
- 222位、340位、または370位でアミノ酸修飾をさらに含む、請求項19に記載の抗体。
- アミノ酸修飾が、リシンからアルギニンへの置換である、請求項20に記載の抗体。
- 請求項1から15および18から21のいずれか一項に記載の、抗体または抗原結合断片のコンジュゲートであって、抗体または抗原結合断片が、細胞毒性剤、免疫調節剤、造影剤、治療用タンパク質、バイオポリマー、およびオリゴヌクレオチドからなる群から選択される作用物質にコンジュゲートしている、コンジュゲート。
- 作用物質が細胞毒性剤である、請求項22に記載のコンジュゲート。
- 細胞毒性剤が、MMAD(モノメチルオーリスタチンD)、または0101(2−メチルアラニル−N−[(3R,4S,5S)−3−メトキシ−1−{(2S)−2−[(1R,2R)−1−メトキシ−2−メチル−3−オキソ−3−{[(1S)−2−フェニル−1−(1,3−チアゾール−2−イル)エチル]アミノ}プロピル]ピロリジン−1−イル}−5−メチル−1−オキソヘプタン−4−イル]−N−メチル−L−バリンアミド)である、請求項23に記載のコンジュゲート。
- 式:抗体−(アシルドナーグルタミン含有タグ)−(リンカー)−(細胞毒性剤)を有する、請求項24に記載のコンジュゲート。
- アシルドナーグルタミン含有タグが、アミノ酸配列GGLLQGG(配列番号78)、LLQGA(配列番号79)、LLQ、またはLLQX1X2X3X4X5(式中、X1は、GもしくはPであり、X2は、A、G、Pであるかもしくは存在せず、X3は、A、G、K、Pであるかもしくは存在せず、X4は、G、Kであるかもしくは存在せず、X5は、Kであるかもしくは存在しない)(配列番号88)を含み、リンカーが、アセチル−リシン−バリン−シトルリン−p−アミノベンジルオキシカルボニル、またはアミノ−PEG6−プロピオニルを含む、請求項25に記載のコンジュゲート。
- 1)抗体−LLQGA(配列番号79)−(アセチル−リシン−バリン−シトルリン−p−アミノベンジルオキシカルボニル(AcLys−VC−PABC))−0101、2)抗体−LLQGA(配列番号79)−(AcLys−VC−PABC)−MMAD、3)抗体−LLQX1X2X3X4X5(配列番号88)−(AcLys−VC−PABC)−0101、4)抗体−LLQX1X2X3X4X5(配列番号88)−(AcLys−VC−PABC)−MMAD、5)抗体−GGLLQGG(配列番号78)−(AcLys−VC−PABC)−0101、および6)抗体−GGLLQGG(配列番号78)−(AcLys−VC−PABC)−MMADからなる群から選択される、請求項26に記載のコンジュゲート。
- コンジュゲート1)抗体−GGLLQGG(配列番号78)−(AcLys−VC−PABC)−0101、2)抗体−GGLLQGG(配列番号78)−(AcLys−VC−PABC)−MMAD、3)抗体−LLQX1X2X3X4X5(配列番号88)−(AcLys−VC−PABC)−0101、4)抗体−LLQX1X2X3X4X5(配列番号88)−(AcLys−VC−PABC)−MMAD、5)抗体−LLQGA(配列番号79)−(AcLys−VC−PABC)−0101、または6)抗体−LLQGA(配列番号79)−AcLys−VC−PABC−MMADが、222位でリシンからアルギニンへのアミノ酸置換を含む、請求項27に記載のコンジュゲート。
- コンジュゲートが、1)抗体−LLQGA(配列番号79)−(AcLys−VC−PABC)−0101、2)抗体−LLQGA(配列番号79)−AcLys−VC−PABC−MMAD、3)抗体−LLQX1X2X3X4X5(配列番号88)−(AcLys−VC−PABC)−0101、または4)抗体−LLQX1X2X3X4X5(配列番号88)−(AcLys−VC−PABC)−MMADであって、かつ、抗体の重鎖のC末端におけるアミノ酸リシンが欠失している、請求項27に記載のコンジュゲート。
- N297Q位およびK222R位におけるアミノ酸置換、アミノ−PEG6−プロピオニルを含むリンカー、ならびにMMADを含む細胞毒性剤を含む、請求項24に記載のコンジュゲート。
- 治療有効量の請求項1から15のいずれか一項に記載の抗体または請求項22から30のいずれか一項に記載のコンジュゲート、および薬学的に許容できる担体を含む医薬組成物。
- 請求項1から15のいずれか一項に記載の抗体をコードするヌクレオチド配列を含む単離ポリヌクレオチド。
- 請求項32に記載のポリヌクレオチドを含むベクター。
- 請求項1から15のいずれか一項に記載の抗体を組換え産生する単離宿主細胞。
- 抗体を生成する方法であって、抗体の産生をもたらす条件下で請求項34に記載の宿主細胞を培養するステップと、宿主細胞または培養物から抗体を単離するステップとを含む、方法。
- 対象におけるTrop−2発現に関連する状態を治療する方法であって、それを必要とする対象に、有効量の請求項31に記載の医薬組成物を投与するステップを含む、方法。
- 状態ががんである、請求項36に記載の方法。
- がんが、膀胱、乳房、子宮頸部、絨毛癌、大腸、食道、胃、グリア芽細胞腫、頭頸部、腎臓、肺、口腔、卵巣、膵臓、前立腺、および皮膚のがんからなる群から選択される、請求項37に記載の方法。
- Trop−2発現腫瘍を有する対象における腫瘍増殖または進行を阻害する方法であって、それを必要とする対象に、有効量の請求項31に記載の医薬組成物を投与するステップを含む、方法。
- 対象におけるTrop−2発現がん細胞の転移を阻害する方法であって、それを必要とする対象に、有効量の請求項31に記載の医薬組成物を投与するステップを含む、方法。
- Trop−2発現腫瘍を有する対象における腫瘍退縮を誘導する方法であって、それを必要とする対象に、有効量の請求項31に記載の医薬組成物を投与するステップを含む、方法。
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