JP2018523471A - システイン置換免疫グロブリン - Google Patents
システイン置換免疫グロブリン Download PDFInfo
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- JP2018523471A JP2018523471A JP2018502006A JP2018502006A JP2018523471A JP 2018523471 A JP2018523471 A JP 2018523471A JP 2018502006 A JP2018502006 A JP 2018502006A JP 2018502006 A JP2018502006 A JP 2018502006A JP 2018523471 A JP2018523471 A JP 2018523471A
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Abstract
Description
本特許出願は、あらゆる意味で参照により本明細書に組み入れられる米国特許仮出願第62/193,531号の優先権の恩典を主張する。
2016年7月15日に作製されたファイル1014170_ST25.txt(10,366バイト、機械フォーマットIBM-PC、MS-Windowsオペレーティングシステム)に書き込まれた配列リストがあらゆる意味で全体として参照により本明細書に組み入れられる。
モノクローナル抗体(mAb)は、標的抗原に対するその高い特異性および親和性が理由で、研究および治療における必須ツールである。1990代以来、治療用mAbは、炎症性障害およびがんをはじめとする広い範囲の疾患の医療的ケアに対して実質的な影響を及ぼしてきた。mAbの決定的な特徴は、高度に特異的なやり方で標的抗原に結合して、宿主免疫クリアランス法、たとえば補体依存性細胞傷害性(CDC)または抗体依存性細胞傷害性(ADCC)による除去のためにそれらをマーキングするその能力である。抗体はまた、トラスツズマブ(Herceptin(登録商標))、ベバシズマブ(Avastin(登録商標))およびセツキシマブ(Erbitux(登録商標))の場合のように、標的抗原に結合し、その機能を阻害することにより、治療有益性を付与することができる。
(a)可変軽鎖がCDR-L1、CDR-L2およびCDR-L3をさらに含み、さらに
a.CDR-L1が
であり、
b.CDR-L2がLAS(SEQ ID NO:2)であり、
c.CDR-L3が
であり、
(b)可変重鎖がCDR-H1、CDR-H2およびCDR-H3をさらに含み、さらに
a.CDR-H1が
であり、
b.CDR-H2が
であり、
c.CDR-H3が
である。
(c)可変軽鎖がCDR-L1、CDR-L2およびCDR-L3をさらに含み、さらに
a.CDR-L1が
であり、
b.CDR-L2が
であり、
c.CDR-L3が
であり、
(d)可変重鎖がCDR-H1、CDR-H2およびCDR-H3をさらに含み、さらに
a.CDR-H1が
であり、
b.CDR-H2が
であり、
CDR-H3が
である。
記載される特定の方法または特定の組成は変化し得るものであるため、本出願は、そのような特定の方法または特定の組成に限定されない。また、本出願の範囲は特許請求の範囲およびそれらの均等物によってのみ制限されるため、本明細書に使用される専門用語は、特定の態様を説明するためだけのものであり、限定的であることを意図したものではないことが理解されよう。
本明細書の中で使用される「免疫グロブリン」とは、免疫グロブリンポリペプチドまたは抗体をいう。
同じく提供されるものは、本明細書に記載されるシステイン置換免疫グロブリンまたはシステイン置換を有するその定常ドメインをコードするポリヌクレオチド(たとえばDNA)である。システイン置換免疫グロブリンをコードするポリヌクレオチドは、免疫グロブリンポリペプチドをコードするポリヌクレオチド上での部位特異的突然変異誘発によって調製することができる。部位特異的突然変異誘発を実施するためのキットは様々な販売元から市販されている。これらは、たとえば、Life Technologiesから市販されているPhusion、Agilent Technologiesから市販されているQuikChangeおよびNew England Biolabsから市販されているQ5を含む。概して、部位特異的突然変異誘発は、所望の部位にcysコドンを挿入する変異体を含むプライマーを使用する、標的免疫グロブリンをコードするポリヌクレオチドのプライマー伸長を含む。
本明細書に記載される免疫グロブリン、たとえば組換え、モノクローナルまたはポリクローナル抗体の調製のために、当技術分野において公知の多くの技術を使用することができる(たとえば、Kohler & Milstein, Nature 256:495-497 (1975);Kozbor et al., Immunology Today 4: 72 (1983);Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985);Coligan, Current Protocols in Immunology (1991);Harlow & Lane, Antibodies, A laboratory Manual (1988);およびGoding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)を参照)。関心対象の抗体の重鎖および軽鎖をコードする遺伝子は、細胞からクローニングすることができる。たとえば、モノクローナル抗体をコードする遺伝子をハイブリドーマからクローニングし、組換えモノクローナル抗体を作製するために使用することができる。また、モノクローナル抗体の重鎖および軽鎖をコードする遺伝子ライブラリーをハイブリドーマまたは形質細胞から作製することもできる。重鎖および軽鎖遺伝子産物のランダムな組み合わせが、異なる抗原特異性を有する抗体の大きなプールを生成する(たとえばKuby, Immunology (3rd ed. 1997)を参照)。一本鎖抗体または組換え抗体の作製技術(米国特許第4,946,778号、米国特許第4,816,567号)を、本開示のポリペプチドに対する抗体を作製するために適合させることができる。また、トランスジェニックマウスまたは他の生物、たとえば他の哺乳動物を使用して、ヒト化またはヒト抗体を発現させることもできる(たとえば、米国特許第5,545,807号;第5,545,806号;第5,569,825号;第5,625,126号;第5,633,425号;第5,661,016号、Marks et al., Bio/Technology 10:779-783 (1992);Lonberg et al., Nature 368:856-859 (1994);Morrison, Nature 368:812-13 (1994);Fishwild et al., Nature Biotechnology 14:845-51 (1996);Neuberger, Nature Biotechnology 14:826 (1996);およびLonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)を参照)。または、ファージディスプレイ技術を使用して、選択された抗原に特異的に結合する抗体およびヘテロマーFabフラグメントを同定することもできる(たとえば、McCafferty et al., Nature 348:552-554 (1990);Marks et al., Biotechnology 10:779-783 (1992)を参照)。抗体はまた、二重特異性に、すなわち、2つの異なる抗原を認識することができるように作製することもできる(たとえば、WO 93/08829、Traunecker et al., EMBO J. 10:3655-3659 (1991);およびSuresh et al., Methods in Enzymology 121:210 (1986)を参照)。抗体はまた、ヘテロコンジュゲート、たとえば2つの共有結合した抗体または免疫毒素であることもできる(たとえば、米国特許第4,676,980号、WO 91/00360;WO 92/200373;およびEP 03089を参照)。
本開示のシステイン置換免疫グロブリン(CYSMAB)から調製される抗体−薬物コンジュゲートは、当業者に公知の有機化学反応、条件および試薬を使用して、いくつかの経路、たとえば(1)システイン改変抗体のシステイン基をリンカー試薬と反応させて、共有結合によって抗体−リンカー中間体Ab-Lを形成したのち、活性化された薬物部分Dと反応させる経路;および(2)薬物部分の求核性基をリンカー試薬と反応させて、共有結合によって薬物−リンカー中間体D-Lを形成したのち、システイン改変抗体(CYSMAB)のシステイン基と反応させる経路によって調製することができる。コンジュゲーション法(1)および(2)は、多様なシステイン改変抗体(CYSMAB)、薬物部分およびリンカーとともに用いられて、抗体−薬物コンジュゲート(ADC)を調製し得る。
「リンカー」、「リンカー単位」または「リンク」とは、抗体を薬物部分に共有結合させる共有結合または原子鎖を含む化学的部分を意味する。様々な態様において、リンカーはLと指定される。「リンカー」(L)は、抗体−薬物コンジュゲート(ADC)を形成するために1つまたは複数の薬物部分(D)と抗体単位(Ab)とを連結するために使用することができる二官能性または多官能性部分である。抗体−薬物コンジュゲート(ADC)は、薬物および抗体に結合するための反応性官能価を有するリンカーを使用して簡便に調製することができる。システイン改変抗体(CYSMAB)のシステインチオールは、リンカー試薬、薬物部分または薬物−リンカー中間体の求電子性官能基とで結合を形成することができる。
抗体とアウリスタチンとのコンジュゲートは、多様な二官能性リンカー試薬、たとえばN-スクシンイミジル-3-(2-ピリジルジチオ)プロピオネート(SPDP)、スクシンイミジル-4-(N-マレイミドメチル)シクロヘキサン-1-カルボキシレート(SMCC)、イミノチオラン(IT)、イミドエステル類の二官能性誘導体(たとえばジメチルアジピミデートHCl)、活性エステル類(たとえばジスクシンイミジルスベレート)、アルデヒド類(たとえばグルタルアルデヒド)、ビス−アジド化合物(たとえばビス(p-アジドベンゾイル)ヘキサンジアミン)、ビス−ジアゾニウム誘導体(たとえばビス−(p-ジアゾニウムベンゾイル)-エチレンジアミン)、ジイソシアネート類(たとえばトルエン2,6-ジイソシアネート)およびビス活性フッ素化合物(たとえば1,5-ジフルオロ-2,4-ジニトロベンゼン)を使用して作製し得る。
本開示のシステイン置換免疫グロブリンは、とりわけ、検出可能な部分または薬物、たとえば細胞傷害性薬剤にコンジュゲートされた分子を含むシステイン置換免疫グロブリンコンジュゲートの調製において有用である。
システイン置換免疫グロブリン薬物コンジュゲート(たとえばCYSMAB ADC)は、そのようなコンジュゲートが結合する細胞を標的とすることによって処置可能な任意の疾患の処置に有用である。これは、任意の形態のがんを含む。
本開示のシステイン置換免疫グロブリン薬物コンジュゲート(たとえばCYSMAB ADC)の有効性は、補体依存性細胞傷害性(CDC)、標的抗原、たとえばCLL-1を発現する細胞の抗体依存性細胞媒介性細胞傷害性(ADCC)アッセイによって評価することができる。CLL-1を発現する例示的な細胞は、異種の組換えCLL-1(たとえばヒトCLL-1)を発現する細胞株;ヒトAML細胞株、たとえばHL60、THP1、TF1-α、U937およびOCI AML-5(最初4つはATCCから入手可能である);1人または複数のAML患者からの初代細胞(たとえばPBMCまたは移植された腫瘍細胞);ヒトCML細胞株、たとえばK562およびKU812(ATCCから入手可能);ならびに1つまたは複数のCMLまたはMDS患者からの初代細胞を含む。
たとえば、システイン置換免疫グロブリンコンジュゲートは、がん細胞を検出するためのインビトロおよびインビボ診断アッセイに使用することができる。これは、CLL-1発現細胞(たとえばAML細胞およびAML CSC)の検出のための、CLL-1発現細胞に特異的に結合する、本明細書に記載されるCLL-1に特異的な抗体(このセクションでのみ「CLL-1抗体」)を含む。たとえば、試料(たとえば血液試料または組織生検材料)を患者から取得し、CLL-1抗体と接触させることができ、抗体結合を検出することによって患者試料中のCLL-1発現細胞の存在を決定することができる。抗体結合は、直接的に検出することもできるし(たとえば、抗体そのものが標識されている場合)、または第二の検出剤、たとえば二次抗体を使用することによって検出することもできる。検出可能な標識は、直接的、あるいはたとえばキレート剤もしくはリンカーを介して間接的に、本開示の抗体と会合することができる。
関心対象の標的に結合することができる抗体を含む診断剤は、たとえば以下の参考文献に提供されているような、当技術分野において公知の任意の診断剤を含むことができる:Armstrong et al., Diagnostic Imaging, 5th Ed., Blackwell Publishing (2004);Torchilin, V. P., Ed., Targeted Delivery of Imaging Agents, CRC Press (1995);Vallabhajosula, S., Molecular Imaging: Radiopharmaceuticals for PET and SPECT, Springer (2009)。診断剤は、検出可能なシグナルを提供および/または増強する薬剤を含む多様な方法によって検出することができる。検出可能なシグナルは、ガンマ線放出性、放射性、エコー源性、光学、蛍光、吸収性、磁気またはトモグラフィシグナルを含むが、これらに限定されない。診断剤を画像診断するための技術は、単一光子放出コンピュータ断層撮影法(SPECT)、磁気共鳴画像診断法(MRI)、光学画像診断法、陽電子放射断層撮影法(PET)、コンピュータ断層撮影法(CT)、X線画像診断法、ガンマ線画像診断法などを含むが、これらに限定されない。用語「検出可能な薬剤」、「検出可能な部分」、「標識」、「画像診断剤」および類似の用語は本明細書の中で同義に使用される。
検出可能な治療薬剤を抗体にコンジュゲートするための技術は周知である(たとえば、Amon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985);Hellstrom et al., "Antibodies For Drug Delivery" in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987);Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985);およびThorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982)を参照)。
CLL-1発現細胞、たとえばAML細胞は、本明細書に記載されるシステイン置換CLL-1 ADC抗体(このセクションでのみ「CLL-1抗体」)を使用して標的とすることができる。CLL-1発現は、AML細胞およびCSC(たとえばAML CSC)で増加する。CLL-1は、正常なCD34+造血幹細胞(HSC)上では有意に発現せず、したがって、本CLL-1抗体を使用してCSCをHSCから区別することができる。AMLは非常に高い再発率を有するため、AML細胞に一般的なCLL-1エピトープを認識し、したがってAML細胞に普遍的に結合することができる高親和性CLL-1抗体が特に貴重である。上記のように、CLL-1抗体を含む治療組成物はさらに、たとえば、CLL-1発現細胞の検出および限局化ならびに治療効果のモニタリングのために、セラノーシス組成物を形成するための検出可能な標識をさらに含むことができる。CLL-1に結合する抗体の配列は、全体として参照により組み入れられる、2015年11月24日出願のUSSN 62/259,100(Jiang et al., "Humanized Anti-")および2013年11月7日に公開されたUS 2013/0295118(Jiang et al., "Antibodies Specific For CLL-1)に記載されている。
QuickChange II部位特異的突然変異誘発キット(Agilent)を使用して、CLL-1抗体(HuM31)重鎖の選択された位置(EUナンバリング)でシステイン残基を改変して、対応するCYSMAB変異体を作製した。システイン置換の確実性をDNA配列決定によって確認した。CYSMAB軽鎖および重鎖構築物をHEK-293細胞中に一過的にトランスフェクトした。発現したCYSMAB変異体を、MabSelectsuReビーズを使用して精製し、様々なCLL-1機能アッセイによってさらに特性決定した。
重鎖定常領域の選択された残基でのコンジュゲーションを実証するために、抗体−蛍光体コンジュゲートを創製した。以下の手順を使用した:精製したHuM31またはCYSMAB変異体(それぞれ1.5mg)をPBSに対して4℃で一晩透析した。抗体をMabSelectsuReビーズ200μLとともに室温で1時間インキュベートした。各回2mL PBSでビーズを3回洗浄したのち、2mM DTT中の抗体を、150mM NaCl-50mM Tris(pH8.0)緩衝剤中、室温で一晩還元した。ビーズを3回洗浄したのち、抗体を、1mMデヒドロアスコルビン酸(DHAA)中、室温で3時間再酸化させた。抗体を3回洗浄し、10モル過剰のAlexa488-C5-マレイミドと室温で2時間コンジュゲートさせた。ビーズを3回洗浄し、Alexa488コンジュゲート抗体を0.1Mグリシン(pH2.7)500μLで溶出した。NanoDrop 2000を使用することにより、抗体濃度およびAlexa488コンジュゲーション効率(抗体1つあたりAlexa488の数)を測定した。
図1:HuM31にコンジュゲートされたAlexa488(A488)(HuM31-A488 AFC)を特異的に検出するためのELISAアッセイを開発した。ヒト血漿中のHuM31にコンジュゲートされたA488を検出するために、3つの異なるフォーマットのELISAを設計した。非コンジュゲートHuM31、HuM31-A488およびIgG-A488をこれらの3つのELISA法で試験した。結果は、ELISAフォーマット#1が最良のSN比(信号対雑音比)を有することを示した。そして、フォーマット#2および#3は、より高いバックグラウンド結合を示した。フォーマット#1 ELISAをさらに使用してHuM31-A488を検出した。
本開示のAFCのヒト血漿中の安定性をヒト血漿中でのインキュベーションによって試験した。AFC(50μg/mL)を、プールされたヒト血漿またはPBS中0.5%BSAに添加した。次いで、各試料を5%CO2とともに37℃でインキュベートしたのち、0、24、48、72および96時間の時点で-80℃に移した。試料を試料希釈剤(0.5%BSA、0.05%Tween 20、5mM EDTA、0.35M NaCl、0.25%CHAPSおよび0.2%BGGを含有するPBS緩衝剤)中、1:5000に希釈した。次いで、様々な時点で試料をELISAによってアッセイした。
CYSMABをHPDP-ビオチンおよびBMCC-ビオチンとコンジュゲートさせることによってHuM31-ビオチンコンジュゲートを作製した。
図11は、試料V266、V303、T307、G316、Y436、L441、H285、R301、Q295が、5日間のインキュベーション後、>80%の安定性を有することを示す。
システイン置換CLL-1 CYSMABに対する結合親和性は、それらの裸の非コンジュゲート相対物に対する比較結合親和性に関して試験することができる。簡潔にいうと、ビオチン化CLL-1(25μg/mL)をストレプトアビジンセンサーチップ上に22℃で2時間ロードする。グローバル1:1カーブフィッティングを使用するFortebioまたはBIAcore分析(10、30および90μg/mL)のいずれかにより、抗体ごとに3つの異なる濃度でAb-Ag解離曲線を生成した。
システイン置換CYSMABは、ヒトCLL-1を発現する組換え293細胞および2つのAML細胞株、HL60およびOCI AML-5への比較結合に関して試験することができる。抗体結合を有する生細胞の割合は、任意の適当な手段、たとえばFACSによって検出することができる。また、結合の一貫性、すなわち患者間の変動を評価することもできる。
抗体−薬物コンジュゲート(ADC)アッセイは、適当なAML細胞株(たとえばHL60およびOCI AML-5)およびCLL-1を発現する組換え293細胞に対して実施することができる。簡潔にいうと、細胞を様々な濃度のADCとともに37℃で72〜120時間インキュベートする。細胞生存率は、IC50値を決定するためのCellTiter-Glo(Promega)発光細胞生存率アッセイによって測定される。
CLL-1 CYSMAB ADCをインビボ効能に関して評価することができる。適当な研究は、(1)マウスにおけるCLL-1陽性HL60 AMLヒト細胞株を利用する皮下(SC)腫瘍移植および成長モデル、ならびに(2)CLL-1陽性HL60またはOCI AML-5ヒトAML細胞株を利用する同所(骨髄、血液、脾臓およびリンパ節)腫瘍移植および増殖モデルを含む。
本開示にしたがって調製されたCLL-1 CYSMAB ADCの特異性は、ADCアッセイにおける特異的死滅に関して試験することができる。初代患者AML細胞または正常なCD34陽性造血幹細胞をヒト対象の骨髄から単離し、軟寒天コロニー形成アッセイ用に播種する(細胞100,000個/プレート)。次いで、CLL-1 CYSMAB ADCの存在下、細胞を14日間インキュベートする。ADCは、AML幹細胞のクローン原性増殖の選択的な特異的阻害を生じさせることができるが、正常なHSCが影響を受けるべきではない。コンジュゲーションの効果を裸の親抗体とで比較することができる。負の対照は、処理されない、または無関係のIgG-ADCで処理される。
以下のような多様な抗体−薬物コンジュゲートを作製した。
すべてのコンジュゲートは、以下の可変領域:
を含む軽鎖可変領域配列、および以下:
を含む重鎖可変領域配列を有する抗CLL-1抗体とで作製した。以下のようなイソキノリジノベンゾジアゼピンダイマーへのシステイン反応性リンカーを介して、抗体を表記システイン置換にコンジュゲートさせた。
(「D202」と称す。)
Claims (70)
- EUナンバリングでV266C、G316C、H285C、R301C、V303C、T307C、Y436CおよびL441Cからなる群より選択される置換アミノ酸残基を含む、システイン置換免疫グロブリンポリペプチド。
- 免疫グロブリンポリペプチドがヒトIgG重鎖定常領域に由来する、請求項1記載のポリペプチド。
- IgGが、IgG1、IgG2、IgG3またはIgG4からなる群より選択されるアイソタイプである、請求項2記載のポリペプチド。
- アイソタイプがIgG1である、請求項3記載のポリペプチド。
- システイン置換をコードするヌクレオチド配列を含む、核酸分子。
- EUナンバリングでV266C、G316C、H285C、R301C、V303C、T307C、Y436CおよびL441Cからなる群より選択される置換アミノ酸残基を含む、免疫グロブリンポリペプチド。
- 前記ヌクレオチド配列と機能的に連結された発現制御配列をさらに含む、請求項5記載の核酸分子。
- 発現ベクターに含まれる、請求項6記載の核酸分子。
- EUナンバリングでV266C、G316C、H285C、R301C、V303C、T307C、Y436CおよびL441Cからなる群より選択される置換アミノ酸残基を含むシステイン置換免疫グロブリンポリペプチドをコードするヌクレオチド配列を含む核酸分子を含む、組換え細胞。
- システイン置換ポリペプチドを作製する方法であって、EUナンバリングでV266C、G316C、H285C、R301C、V303C、T307C、Y436CおよびL441Cからなる群より選択される置換アミノ酸残基を含むシステイン置換免疫グロブリンポリペプチドをコードするヌクレオチド配列を含む核酸分子を含む組換え細胞を培養する工程を含む、方法。
- 重鎖定常領域中、EUナンバリングでV266C、G316C、H285C、R301C、V303C、T307C、Y436CおよびL441Cからなる群より選択される置換アミノ酸残基を含むシステイン置換免疫グロブリンポリペプチドを含む、システイン置換抗体。
- 重鎖定常領域が、IgG1、IgG2、IgG3およびIgG4からなる群より選択されるヒトIgGアイソタイプに由来する、請求項10記載の抗体。
- κおよびλからなる群より選択される免疫グロブリン軽鎖を含む、請求項10記載の抗体。
- 軽鎖がκである、請求項12記載の抗体。
- CLL-1、GPR114、IL1RAP、TIM-3、CD19、CD20、CD22、ROR1、メソテリン、CD33、CD123/IL3Ra、c-Met、PSMA、前立腺酸性ホスファターゼ(PAP)、CEA、CA-125、Muc-1、AFP、糖脂質F77、EGFRvIII、GD-2、NY-ESO-1 TCR、チロシナーゼ、TRPI/gp75、gp100/pmel-17、Melan-A/MART-1、Her2/neu、WT1、EphA3、テロメラーゼ、HPV E6、HPV E7、EBNA1、BAGE、GAGEおよびMAGE A3 TCRSLITRK6、ENPP3、ネクチン-4、CD27、SLC44A4、CAIX、Cripto、CD30、MUC16、GPNMB、BCMA、Trop-2、組織因子(TF)、CanAg、EGFR、αv-インテグリン、CD37、葉酸受容体、CD138、CEACAM5、CD56、CD70、CD74、GCC、5T4、CD79b、Steap 1、Napi2b、Lewis Y抗原、LIV、c-RET、DLL3、EFNA4またはエンドシアリン/CD248に結合する、請求項10記載の抗体。
- 可変軽鎖および可変重鎖を含み、
(a)可変軽鎖がCDR-L1、CDR-L2およびCDR-L3を含み、さらに
CDR-L1が
であり、
CDR-L2がLAS(SEQ ID NO:2)であり、
CDR-L3が
であり、
(b)可変重鎖がCDR-H1、CDR-H2およびCDR-H3を含み、さらに
CDR-H1が
であり、
CDR-H2が
であり、
CDR-H3が
である、または
(c)可変軽鎖がCDR-L1、CDR-L2およびCDR-L3をさらに含み、さらに
CDR-L1が
であり、
CDR-L2が
であり、
CDR-L3が
であり、
(d)可変重鎖がCDR-H1、CDR-H2およびCDR-H3をさらに含み、さらに
CDR-H1が
であり、
CDR-H2が
であり、
CDR-H3が
である、請求項14記載の抗体。 - 請求項10〜17記載の抗体をコードするヌクレオチド配列を含む、核酸分子。
- 発現制御配列と機能的に連結されている、請求項17記載の核酸分子。
- 発現ベクターをさらに構成する、請求項18記載の核酸分子。
- 請求項19記載の核酸分子を含む、組換え細胞。
- 請求項1記載の組換え細胞を培養する工程を含む、抗体を作製する方法。
- 抗体を単離する工程をさらに含む、請求項1記載の方法。
- 抗体中の置換アミノ酸残基(システイン)からリンカーを介して、薬物、放射性核種、蛍光体、ビオチン、RNA、抗生物質、タンパク質および検出可能な部分からなる群より選択される部分にコンジュゲートされている請求項1〜4または10〜15のいずれか1項記載の抗体を含む、抗体コンジュゲート。
- 薬物にコンジュゲートされている、請求項1記載の抗体コンジュゲート。
- 薬物が、単量体または二量体のベンゾジアゼピン誘導体、メイタンシノイド、アウリスタチン、ドラスタチン、チューブリシン、クリプトフィシン、ピロロベンゾジアゼピン(PBD)ダイマー、インドリノベンゾジアゼピンダイマー、イソキノリジノベンゾジアゼピンダイマー、α-アマニチン、トリコテン、SN-38、デュオカルマイシン、CC1065、カリケアミシン、エンジイン系抗生物質、タキサン、ドキソルビシン誘導体、アントラサイクリン、アザノフィド(azanofide)、およびそれらの立体異性体、同配体、類似体または誘導体からなる群より選択される、請求項1記載の抗体コンジュゲート。
- 薬物がイソキノリジノベンゾジアゼピンダイマーである、請求項1記載の抗体コンジュゲート。
- リンカーが薬物と共有結合されている、請求項22〜25のいずれか1項記載の抗体コンジュゲート。
- リンカーが、チオールと、マレイミド、ハライドおよびスルホニルから選択されるチオール反応性基との間の反応を介して抗体と結合されている、請求項22〜25のいずれか1項記載の抗体コンジュゲート。
- リンカーがジスルフィド結合を介して薬物と接続されている、請求項23〜25のいずれか1項記載の抗体コンジュゲート。
- ジスルフィド結合がピリジルジスルフィド部分である、請求項28記載の抗体コンジュゲート。
- リンカーが標的の微小環境中で切断可能である、請求項22〜25のいずれか1項記載の抗体コンジュゲート。
- 検出可能な部分にコンジュゲートされている、請求項22記載の抗体コンジュゲート。
- 検出可能な部分が、A488、BMCC-ビオチンおよびHPDP-ビオチンからなる群より選択される、請求項31記載の抗体コンジュゲート。
- 請求項10〜32のいずれか1項記載の抗体またはコンジュゲート抗体と、アジュバントとを含む、組成物。
- 薬学的に許容可能である、請求項1記載の組成物。
- 関心対象の細胞の存在を検出する方法であって、
(a)細胞と、該細胞に結合することができる有効量の、請求項1〜4または10〜15のいずれか1項記載の抗体とを、接触させる工程、および
(b)該細胞への該抗体の結合を検出する工程
を含み、該結合が該関心対象の細胞を示す、方法。 - 関心対象の細胞がCLL-1を発現する、請求項1記載の方法。
- 抗体が検出可能な部分にコンジュゲートされている、請求項1記載の方法。
- 疾患を診断する方法であって、
(a)個体からの生物学的試料を、病変細胞に結合することができる有効量の、請求項1〜4または10〜15のいずれか1項記載の抗体と接触させる工程;および
(b)病変細胞への該抗体の結合を検出する工程
を含み、結合が該疾患の存在を示す、方法。 - 抗体が検出可能な部分にコンジュゲートされている、請求項1記載の方法。
- 疾患ががんであり、抗体が腫瘍関連抗原またはがん幹細胞関連抗原に結合する、請求項1記載の方法。
- 腫瘍関連抗原またはがん幹細胞関連抗原がCLL-1である、請求項1記載の方法。
- 疾患が骨髄増殖性疾患である、請求項1記載の方法。
- 骨髄増殖性疾患が、AML、CML、CMML、多発性骨髄腫、形質細胞腫および骨髄線維症からなる群より選択される、請求項42記載の方法。
- 細胞分裂を阻害する方法であって、細胞と、該細胞にとって細胞傷害性である薬物にコンジュゲートされている、該細胞に結合することができる少なくとも有効量の、請求項22〜32のいずれか1項記載の抗体コンジュゲートとを、接触させる工程を含む、方法。
- 細胞分裂の阻害が細胞死を生じさせる、請求項1記載の方法。
- 細胞が腫瘍またはがん幹細胞であり、抗体が腫瘍関連抗原またはがん幹細胞抗原に結合する、請求項1記載の方法。
- 腫瘍またはがん幹細胞が骨髄増殖性疾患に由来する、請求項1記載の方法。
- 骨髄増殖性疾患が、AML、CML、CMML、多発性骨髄腫、形質細胞腫、骨髄線維症からなる群より選択される、請求項1記載の方法。
- 腫瘍関連抗原またはがん幹細胞抗原がCLL-1である、請求項1記載の方法。
- がんを処置する方法であって、治療有効量の、請求項22〜32のいずれか1項記載の抗体コンジュゲートを患者に投与する工程を含み、該抗体コンジュゲートが腫瘍関連抗原またはがん幹細胞抗原に結合することができる、方法。
- がんが骨髄増殖性疾患である、請求項1記載の方法。
- 骨髄増殖性疾患が、AML、CML、CMML、多発性骨髄腫、形質細胞腫および骨髄線維症からなる群より選択される、請求項1記載の方法。
- 腫瘍関連抗原またはがん幹細胞抗原がCLL-1である、請求項1記載の方法。
- 単量体または二量体のベンゾジアゼピン誘導体、メイタンシノイド、アウリスタチン、ドラスタチン、チューブリシン、クリプトフィシン、ピロロベンゾジアゼピン(PBD)ダイマー、インドリノベンゾジアゼピンダイマー、イソキノリジノベンゾジアゼピンダイマー、α-アマニチン、トリコテン、SN-38、デュオカルマイシン、CC1065、カリケアミシン、エンジイン系抗生物質、タキサン、ドキソルビシン誘導体、アントラサイクリン、アザノフィド、およびそれらの立体異性体、同配体、類似体または誘導体にシステインを介して連結された重鎖中のS156(Kabatナンバリング)に置換アミノ酸残基を含むシステイン置換免疫グロブリンポリペプチドを含む、抗体コンジュゲート。
- インドリノベンゾジアゼピンダイマーまたはイソキノリジノベンゾジアゼピンダイマーがリンカーを介して抗体に結合し、該リンカーがジスルフィド結合を介して薬物に接続されている、請求項54記載の抗体コンジュゲート。
- ジスルフィド結合がピリジルジスルフィド部分である、請求項54記載の抗体コンジュゲート。
- リンカーが標的の微小環境中で切断可能である、請求項54記載の抗体コンジュゲート。
- 請求項54〜57のいずれか1項記載の抗体またはコンジュゲート抗体と、アジュバントとを含む、組成物。
- 薬学的に許容可能である、請求項58記載の組成物。
- 細胞分裂を阻害する方法であって、細胞と、少なくとも有効量の、請求項54〜57のいずれか1項記載の抗体コンジュゲートとを、接触させる工程を含む、方法。
- 細胞分裂の阻害が細胞死を生じさせる、請求項60記載の方法。
- 細胞が腫瘍またはがん幹細胞であり、抗体が腫瘍関連抗原またはがん幹細胞抗原に結合する、請求項60記載の方法。
- 腫瘍またはがん幹細胞が骨髄増殖性疾患に由来する、請求項62記載の方法。
- 骨髄増殖性疾患が、AML、CML、CMML、多発性骨髄腫、形質細胞腫、骨髄線維症からなる群より選択される、請求項63記載の方法。
- 腫瘍関連抗原またはがん幹細胞抗原がCLL-1である、請求項62記載の方法。
- がんを処置する方法であって、治療有効量の、請求項54〜57のいずれか1項記載の抗体コンジュゲートを患者に投与する工程を含み、該抗体コンジュゲートが腫瘍関連抗原またはがん幹細胞抗原に結合することができる、方法。
- がんが骨髄増殖性疾患である、請求項66記載の方法。
- 骨髄増殖性疾患が、AML、CML、CMML、多発性骨髄腫、形質細胞腫および骨髄線維症からなる群より選択される、請求項67記載の方法。
- 腫瘍関連抗原またはがん幹細胞抗原がCLL-1である、請求項66記載の方法。
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PCT/US2016/042645 WO2017011803A1 (en) | 2015-07-16 | 2016-07-15 | Cysteine-substituted immunoglobulins |
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US11793880B2 (en) | 2015-12-04 | 2023-10-24 | Seagen Inc. | Conjugates of quaternized tubulysin compounds |
SG11201804268RA (en) | 2015-12-04 | 2018-06-28 | Seattle Genetics Inc | Conjugates of quaternized tubulysin compounds |
JP7237344B2 (ja) | 2016-06-15 | 2023-03-13 | アイカーン スクール オブ メディシン アット マウント サイナイ | インフルエンザウイルス血球凝集素タンパク質及びその使用 |
WO2017219029A2 (en) | 2016-06-17 | 2017-12-21 | Magenta Therapeutics, Inc. | Compositions and methods for the depletion of cd117+cells |
BR112019014991A2 (pt) | 2017-01-20 | 2020-04-07 | Magenta Therapeutics Inc | composições e métodos para a supressão de células cd137+ |
KR20240023449A (ko) | 2017-02-08 | 2024-02-21 | 드래곤플라이 쎄라퓨틱스, 인크. | 천연 킬러 세포의 활성화를 위한 다중-특이적 결합 단백질 및 암 치료에서의 그의 치료적 용도 |
US11884732B2 (en) | 2017-02-20 | 2024-01-30 | Dragonfly Therapeutics, Inc. | Proteins binding HER2, NKG2D and CD16 |
WO2018187706A2 (en) | 2017-04-07 | 2018-10-11 | Icahn School Of Medicine At Mount Sinai | Anti-influenza b virus neuraminidase antibodies and uses thereof |
EP3638697A4 (en) | 2017-06-12 | 2021-07-07 | Bluefin Biomedicine, Inc. | ANTI-IL1RAP ANTIBODIES AND ANTIBODY INGREDIENT CONJUGATES |
WO2018233572A1 (zh) * | 2017-06-20 | 2018-12-27 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物(tdc)定点偶联位点筛选 |
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