JP2019014752A - 抗ntb−a抗体ならびに関連する組成物および方法 - Google Patents
抗ntb−a抗体ならびに関連する組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、非仮出願であり、2012年12月21日に出願された米国特許第61/745,239号の利益を主張し、その内容は本明細書においてその全体が全ての目的のために参考として援用される。
2013年12月18日に作成されたNTBA−00111PC−ST25.txtという名前の8キロバイトの配列表が、参考として援用される。
SLAMF6とも呼ばれる、1型1回通過膜糖タンパク質であるNTB−Aは、CD2/SLAMサブファミリーに属する免疫グロブリンスーパーファミリー(Ig−SF)のメンバーである。例えば、Bottino et al.,J. Exp. Med. 194:235−246,2001を参照。NTB−Aは、その細胞外部分に、N末端V型ドメインおよびそれに続くC2型ドメインを特徴として有し、他方で、細胞質内部分は3つのチロシンベースのモチーフを含む:2つの免疫レセプターチロシンベーススイッチモチーフ(ITSM;TxYxxV/I)および古典的免疫レセプターチロシンベース阻害モチーフ(ITIM;I/V/L/SxYxxL)。同上を参照。そのITSMモチーフを通じて、NTB−Aは、SLAM−関連タンパク質SH2D1Aおよび関連するユーイング肉腫活性化転写物(EAT)2のSH2ドメインと関係する。Bottino et al.,上記;Falco et al.,Eur. J. Immunol. 34:1663−1672,2004;Flaig et al.,J. Immunol. 172:6524−6527,2004を参照。
1つの局面では、本発明は、ヒトNTB−Aに対する特異的結合について、配列番号1の残基20〜135および配列番号2の残基21〜140にそれぞれ示されるアミノ酸配列を有するVHドメインおよびVLドメインを含むモノクローナル抗体(mAb)と競合する、単離された抗体を提供する。
例えば、本発明は以下の項目を提供する。
(項目1)
ヒトNTB−Aに対する特異的結合について、配列番号1の残基20〜135および配列番号2の残基21〜140にそれぞれ示されるアミノ酸配列を有するVHドメインおよびVLドメインを含むモノクローナル抗体と競合する、単離された抗体。
(項目2)
前記抗体は、
配列番号5に示されるCDR−H1のアミノ酸配列;
配列番号6に示されるCDR−H2のアミノ酸配列;
配列番号7に示されるCDR−H3のアミノ酸配列;
配列番号8に示されるCDR−L1のアミノ酸配列;
配列番号9に示されるCDR−L2のアミノ酸配列;および
配列番号10に示されるCDR−L3のアミノ酸配列を含む、項目1に記載の抗体。
(項目3)
前記抗体は、
配列番号1の残基20〜135に示されるアミノ酸配列を有するVHドメインに由来するヒト化VHドメイン、および
配列番号2の残基21〜140に示されるアミノ酸配列を有するVLドメインに由来するヒト化VLドメイン、を含むヒト化抗体である、項目1に記載の抗体。
(項目4)
前記抗体は、
配列番号5に示されるCDR−H1のアミノ酸配列;
配列番号6に示されるCDR−H2のアミノ酸配列;
配列番号7に示されるCDR−H3のアミノ酸配列;
配列番号8に示されるCDR−L1のアミノ酸配列;
配列番号9に示されるCDR−L2のアミノ酸配列;および
配列番号10に示されるCDR−L3のアミノ酸配列を含む、項目3に記載の抗体。
(項目5)
前記抗体は、
配列番号11に示されるCDR−H1のアミノ酸配列;
配列番号12に示されるCDR−H2のアミノ酸配列;
配列番号13に示されるCDR−H3のアミノ酸配列;
配列番号14に示されるCDR−L1のアミノ酸配列;
配列番号15に示されるCDR−L2のアミノ酸配列;および
配列番号16に示されるCDR−L3のアミノ酸配列を含む、項目1に記載の抗体。
(項目6)
前記抗体は、
配列番号3の残基20〜137に示されるアミノ酸配列を有するVHドメインに由来するヒト化VHドメイン、および
配列番号4の残基21〜128に示されるアミノ酸配列を有するVLドメインに由来するヒト化VLドメイン、を含むヒト化抗体である、項目1に記載の抗体。
(項目7)
前記抗体は、
配列番号11に示されるCDR−H1のアミノ酸配列;
配列番号12に示されるCDR−H2のアミノ酸配列;
配列番号13に示されるCDR−H3のアミノ酸配列;
配列番号14に示されるCDR−L1のアミノ酸配列;
配列番号15に示されるCDR−L2のアミノ酸配列;および
配列番号16に示されるCDR−L3のアミノ酸配列を含む、項目6に記載の抗体。
(項目8)
配列番号1の残基20〜135および配列番号2の残基21〜140にそれぞれ示されるアミノ酸配列を有するVHドメインおよびVLドメインを含む単離されたマウスモノクローナル抗体、またはそのキメラもしくはヒト化形態。
(項目9)
配列番号5(CDR1)、配列番号6(CDR2)、および配列番号7(CDR3)で示される相補性(complementary)決定領域(CDR)配列、ならびに配列番号8(CDR4)、配列番号9(CDR5)、および配列番号10(CDR6)で示される軽鎖CDR配列を含む単離されたヒト化モノクローナル抗体であって、それぞれのCDR中に0、1、2または3か所の保存的アミノ酸置換を有する、抗体。
(項目10)
さらに免疫グロブリン重鎖定常領域の少なくとも部分を含む、項目1から9のいずれか1つに記載の抗体。
(項目11)
前記抗体は、VHドメインを含む第一のポリペプチド鎖およびVLドメインを含む第二のポリペプチド鎖を含む、項目1から10のいずれか1つに記載の抗体。
(項目12)
前記第一のポリペプチド鎖は、VHドメインと融合された免疫グロブリン重鎖定常領域の少なくとも部分をさらに含み、そして、前記第二のポリペプチド鎖は、VLドメインと融合された免疫グロブリン軽鎖定常領域の少なくとも部分をさらに含む、項目11に記載の抗体。
(項目13)
前記重鎖定常領域は、天然のヒト定常領域に対してFcγレセプターへの結合が低減された、天然のヒト定常領域の変異形態である、項目10または12に記載の抗体。
(項目14)
前記重鎖定常領域は、ヒトアイソタイプIgG1、IgG2、IgG3、およびIgG4からなる群より選択されるアイソタイプのものである、項目10、12、または13のいずれか1つに記載の抗体。
(項目15)
前記抗体は、細胞傷害性作用物質または細胞増殖抑制作用物質と結合体化される、項目1から14のいずれか1つに記載の抗体。
(項目16)
項目1から15のいずれか1つによって定義されるVHドメインおよび/またはVLドメインをコードする単離された核酸。
(項目17)
医薬組成物であって、以下:
項目1から15のいずれか1つに記載の抗体;および
薬学的に適合性の成分、を含む、医薬組成物。
(項目18)
NTB−A発現を特徴とするがんを有する患者を処置する方法であって:
項目1から15のいずれか1つに記載の抗体の効果的なレジメンを患者に投与する工程、を含む方法。
(項目19)
前記がんは、多発性骨髄腫、急性骨髄性白血病(AML)、およびT細胞リンパ腫もしくはB細胞リンパ腫からなる群より選択される、項目18に記載の方法。
(項目20)
前記B細胞リンパ腫は、非ホジキンリンパ腫(NHL)である、項目19に記載の方法。
異なって定義されない限り、本明細書で用いられる全ての技術的および科学的用語は、説明される方法および組成物の属する分野の当業者に通常理解されるのと同じ意味を有する。本明細書で用いられる場合、以下の用語および句は、異なって特定されない限りそれらに与えられた意味を有する。
I.総論
本発明は、NTB−Aに対して特異的に結合する抗体を提供する。前記抗体は、例えば、様々なNTB−A発現性のがんの処置および診断に、ならびにNTB−Aの検出(例えば、細胞上のNTB−A発現の検出)に有用である。本発明の抗体を用いた、そのような処置、診断、およびNTB−A検出の方法もまた提供される。
異なって指示されない限り、NTB−Aは、ヒトNTB−Aを意味する。代表的なヒト配列は、UniProtKB/Swiss−Protアクセッション番号Q96DU3を割り当てられている。4つのスプライシングバリアントのアイソフォームが公知である。成熟細胞外領域は、Q96DU3の残基22〜226の範囲にある。
1つの局面では、本発明は、成熟NTB−A細胞外領域のエピトープ(例えば、UniProtKB/Swiss−Protアクセッション番号Q96DU3のアミノ酸残基22〜226内に存在するエピトープ)に対して特異的に結合する単離された抗NTBA抗体を提供する。特定の実施態様では、本発明に従った抗NTB−A抗体は、ヒトNTB−A抗原への結合について、本発明者らによって同定および単離された抗NTB−A mAbと同一のVH/VLドメインを有するモノクローナル抗体と競合することができる。特定の局面では、本発明に従った抗NTB−A抗体は、本明細書で同定されるようなマウス抗体、またはそのキメラ形態もしくはヒト化形態である。
(1)非共有的に直接抗原に結合する、
(2)CDR領域に隣接する、
(3)その他の様態でCDR領域と相互作用する(例えば、CDR領域の約6Å以内にある);または
(4)重鎖および軽鎖の間の相互作用を媒介する。
本発明はさらに、上記で説明されたVHドメインおよび/またはVLドメイン(追加的なポリペプチドセグメント(例えば、免疫グロブリン定常領域と対応するポリペプチドセグメント)と連結されたVHドメインおよび/またはVLドメインを含むポリペプチドを含む)のいずれかをコードする核酸を提供する。典型的には、核酸はまた、VHドメインおよび/またはVLドメインを含む成熟ポリペプチドのアミノ末端に融合されたシグナルペプチドもコードする。核酸上のコード配列は、コード配列の発現を確実にするための調節配列(例えば、プロモーター、エンハンサー、リボソーム結合部位、転写終結シグナル等)と作動可能に連結され得る。核酸は、単離された形態で存在し得る、または1つ以上のベクターにクローニングされ得る。核酸は、例えば、固相合成または重複するオリゴヌクレオチドのPCRによって、合成され得る。VHドメインおよびVLドメイン(例えば、分離された重鎖および軽鎖を含む抗体に関して)の両方をコードする複数の核酸は、1つの連続的な核酸として連結されてもよく(例えば、発現ベクター内に)、または分離されてもよい(例えば、それら自体の発現ベクターにそれぞれクローニングされ得る)。
抗NTB−A抗体は、細胞傷害性成分または細胞増殖抑制成分(その薬学的に許容可能な塩を含む)と結合体化され得、抗体薬物結合体(ADC)を形成し得る。抗体との結合体化に特に適切な成分は、細胞傷害性作用物質(例えば、化学療法用作用物質)、プロドラッグ変換酵素、放射性同位体もしくは放射性化合物、または毒素(これらの成分は、集合的に治療的作用物質と呼ばれる)である。例えば、抗NTB−A抗体は、細胞傷害性作用物質(例えば、化学療法用作用物質)、または毒素(例えば、細胞増殖抑制作用物質もしくは細胞致死性作用物質(例えば、アブリン、リシンA、シュードモナス外毒素、またはジフテリア毒素))と結合体化され得る。細胞傷害性作用物質の有用なクラスの例としては、例えば、DNA副溝結合物質、DNAアルキル化作用物質、およびチューブリン阻害物質が挙げられる。代表的な細胞傷害性作用物質としては、例えば、オーリスタチン、カンプトテシン、カリケアミシン、デュオカルマイシン、エトポシド、メイタンシノイド(例えば、DM1、DM2、DM3、DM4)、タキサン、ベンゾジアゼピン(例えば、ピロロ[1,4]ベンゾジアゼピン、インドリノベンゾジアゼピン、およびオキサゾリジノベンゾジアゼピン)およびビンカアルカロイドが挙げられる。
他の局面では、本発明は、NTBA発現性の細胞(例えば、ナチュラルキラー(NK)細胞、NK様T細胞、T細胞、単球、樹状細胞、B細胞、および好酸球を含む)の生物学的活性を調節するために、本明細書で説明される抗NTB−A抗体を用いる方法を提供する。そのような方法には、例えば、NTB−A発現性の細胞の活性を阻害する(例えば、細胞の増殖を阻害する)方法が含まれる。そのような方法にはさらに、例えば、NTB−A発現性の細胞に関係する疾患または障害を処置する方法が含まれる。
Amo−1、JJN−3、Karpas−620、KMS−12−BM、MOLP−8、OPM−2(DSMZ;RPMI1640+20%FBS)、L−363(DSMZ;RPMI1640+15%FBS)、LP−1、SK−MM−2(DSMZ;RPMI1640+10%FBS)、EJM(DSMZ;EMEM+20%FBS)、MM.1R、MM.1S、NCI−H929、RPMI−8226(ATCC;RPMI1640+10%FBS)、およびU−266(ATCC;RPMI1640+15%FBS)細胞株を、5%CO2、37℃で培養した。500,000細胞を、FACsバッファー(PBS+3%FBS+0.02%アジ化ナトリウム)中で45分間、氷上で、抗NTB−A抗体NT−7および11A1を用いて染色した。PE結合体化二次抗体を検出に用いた。FACSCaliburフローサイトメーター(Becton Dickinson)を用いて、染色された細胞を分析した。
凍結ヒト多発性骨髄腫患者骨髄吸引サンプル(500万〜1000万細胞)を、BioServe(Beltsville,MD)、AllCells(Emeryville,CA),Conversant Healthcare Systems(Huntsville,AL)、およびProteoGenex(Culver City,CA)から購入した。MM患者骨髄細胞を37℃で解凍し、予め温められたRPMI1640培地に移し、そして細胞の凝集を最小化するために室温で10分間DNaseI(0.05mg/ml)により処理した。次に、細胞を遠心分離(1,400rpm;5分)し、RPMI1640+10%FBSに再懸濁し、そして、トリパンブルー排除法によって細胞数/生存を測定した。次に、患者細胞を遠心分離し、氷上のFACsバッファー(PBS+3%FBS、+0.02%アジ化ナトリウム)に再懸濁し、いかなる残骸も取り除くように100μmセルストレーナーによってろ過し、そして100μLの細胞懸濁液を染色のためにV底96ウェルプレートのウェルに分注した(1.2×105〜1.0×106生存細胞数/ウェル)。患者骨髄吸引細胞を、抗hCD38−FITC、抗hCD45−APC、およびPE結合体化抗NTB−A(クローン:NT−7)もしくはアイソタイプ対照IgGにより3重染色した(氷上で30分)。染色した細胞を、FACsバッファー中で2回洗浄し、FACsCaliburフローサイトメーターを用いてフローサイトメトリーによる分析を行った。NTB−Aの細胞表面の発現を、多発性骨髄腫細胞CD38+/CD45−にゲーティングされた亜集団について定量した。CD138(クローン:1D4)陽性対照多発性骨髄腫抗原の発現もまた測定した。
NTB−A抗体産生マウスの脾臓およびリンパ節から回収したリンパ球を、骨髄腫細胞に融合した。融合細胞を、ハイブリドーマ生育培地中で一晩回復させた。回復に続いて、細胞をスピンダウンし、次に半固体培地中に播種した。ハイブリドーマをインキュベートし、IgG産生ハイブリドーマクローンを選び取った。ハイブリドーマ培養上清をスクリーニングし、NTB−A陽性細胞の表面上の蛍光シグナルの測定によって、478中313のハイブリドーマクローンが、NTB−A細胞外ドメインに対して特異的に結合することが見出された。細胞外ドメインNTB−Aへの蛍光標識ADCの特異的結合を、2.0μg/mlの濃度のNTB−A発現性の多発性骨髄腫細胞のパネルを用いて、フローサイトメトリー(BD Biosciences FACSCalibur)によって確認した。NTB−Aに結合する313のハイブリドーマを、国際出願第2011/109308号において説明される方法を用いてvc−MMAEと直接結合体化するために、展開した。直接結合体化された抗体のパネルを、結合アッセイおよび細胞傷害アッセイにおいて試験した。多発性骨髄腫細胞株との細胞傷害について、313のNTBA−A結合ADCをスクリーニングした。細胞傷害研究を、適切な生育培地にウェルあたり15,000の多発性骨髄腫細胞を播種することにより行った。細胞ベースの結合アッセイのために、抗NTB−A vcMMAE4−ロード抗体薬物結合体を、細胞上で12.5、50.0、および200ng/mLの最終濃度で試験し、37℃で合計96時間インキュベートした。細胞の生存を、Cell Titer Glo(Promega)蛍光アッセイを用いて測定し、ADCの効能を、非処理対照細胞に対する生存のパーセントに基づいて評価した。IC50値を、Prismソフトウェア(GraphPad)を用いて作った用量曲線から生成した。細胞傷害の閾値は、50ng/ml以下のIC50に設定した。ADCとして最も強力な69の抗NTBAモノクローナル抗体が、次へ進んだ。69の最も強力なADCのうち6つのみが、12.5ng/mlより小さいIC50値を示した。飽和結合曲線およびKd値を、高度に細胞傷害性の抗NTB−A ADCの小さいパネルについてフローサイトメトリーによって測定した。抗NTB−A 11A1および26B7抗体を有するADCが、最も細胞傷害性であることが決定された。
マウス11A1抗体mcMMAF結合体を、そのNTB−A+細胞株U−266中に内部移行する能力について評価した(図1)。
抗体−薬物結合体(ADC)を、マウス抗NTB−Aモノクローナル抗体11A1および26B7について調製した。抗有糸分裂作用物質モノメチルオーリスタチンE(MMAE)を、カテプシンで切断可能なバリン−シトルリン(vc)リンカーを介して抗NTB−A mAbに結合体化し、モノメチルオーリスタチンF(MMAF)を、マレイミドカプロイル(mc)リンカーを介して、米国特許第7,659,241号および第7,498298号において説明されるように、システイン結合を介した抗体あたり薬物4つのストイキオメトリに結合体化した。抗NTB−A−vc−MMAE(4)ADCおよび抗NTB−A−mc−MMAF(4)ADCを、10点の用量曲線(1,000ng/mL〜0.05081ng/mL)を作製するために、培地中で3倍に連続的に希釈し、96ウェルアッセイプレート中で培養した多発性骨髄腫細胞にアプライした。Karpas−620、EJM、MM.1R、MM.1S、U−266(NTB−A+)、およびL363(NTB−A−)多発性骨髄腫細胞株を、抗NTB−A ADCにより4連で処理し、37℃、5%CO2で96時間インキュベートした。細胞を、Cell Titer Glo蛍光細胞傷害アッセイ(Promega)を用いて生存についてアッセイし、そしてEnVisionプレートリーダー(Perkin Elmer)を用いてデータを収集した。用量効果曲線およびIC50値を、GraphPad Prismソフトウェアを用いて計算した。
本実施例で説明されるアッセイは、11A1マウス抗体と結合について競合するサンプル抗体の能力を評価するために用いられる方法を詳述する。この特定の研究のために、26B7抗体およびNT−7抗体(クローン:NT−7(Biolegend #317208))の11A1抗体と競合する能力を評価した。また11A1抗体のそれ自体と競合する能力についても評価した。アッセイは、マウス11A1 IgG1抗体を含む「リファレンス抗体」(すなわち、天然(native)(天然(natural))の抗体の2価構造中のVHドメインおよびVLドメイン、すなわち、イムノグロブリン鎖の2つの同一のペアからなる4量体であって、それぞれのペアは、1つの軽鎖および1つの重鎖を有する)を利用する。
Alexa Fluor 647と結合体化したマウス抗ヒトNTB−A抗体(11A1および26B7)の用量滴定を用いて、飽和結合曲線を生成した。抗原陽性Ramos細胞を、96ウェルV底プレート(Thermo Scientific,Rochester,NY)に、ウェルあたり1×105細胞で播種した。2倍濃縮抗体の3倍連続希釈をFACsバッファー(PBS+2%ウシ胎児血清+0.02%アジ化物)中で調製し、2連で細胞に加えた。抗体溶液を氷上で1時間、光から保護して細胞とインキュベートした。細胞をFACsバッファーで2回洗浄し、そしてLSRIIフローサイトメーター(BD BioSciences,San Jose,CA)上で分析した。GraphPad Prismソフトウェア(La Jolla,CA)によりKD値を決定した。
NODscidIL2レセプターガンマ鎖ノックアウト(NSG)マウスを用いて、腫瘍細胞が骨髄区画に局在化する、多発性骨髄腫の播種性細胞株モデルを開発する。100万個のMM.1R多発性骨髄腫細胞または500万個のU−266多発性骨髄腫細胞をマウスに移植し、次に、腫瘍細胞移植の5日後に抗NTB−A抗体薬物結合体を投薬する。
4つのvcMMAE分子をロードしたvcMMAE抗NTB−A抗体薬物結合体を、1.0および3.0mg/kgの単回用量で腹腔内注射によりマウスに送達する。多発性骨髄腫腫瘍細胞により分泌される循環ラムダ軽鎖Igのレベルについて、抗体薬物結合体の投薬後、2から3週間ごとにELISAアッセイによりマウス血清をモニターする。それぞれの研究グループのマウスは、疾患進行の徴候、および罹患率について評価し、疾患の進行した徴候により屠殺する。対照および処置研究グループについて、Kaplan−Meier生存プロットを生成し、それぞれのADC用量レベルにおいて観察された抗腫瘍活性の、ビヒクル対照もしくは非結合対照ADCに対する有意性を決定するために統計的分析を行う。
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US20110171204A1 (en) * | 2006-08-28 | 2011-07-14 | Arca Biopharma, Inc. | Antibodies to ntb-a |
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US10435468B2 (en) | 2019-10-08 |
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JP6449777B2 (ja) | 2019-01-09 |
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JP2020055870A (ja) | 2020-04-09 |
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