JP2015519336A - Cll−1に対して特異的な抗体 - Google Patents
Cll−1に対して特異的な抗体 Download PDFInfo
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- JP2015519336A JP2015519336A JP2015511563A JP2015511563A JP2015519336A JP 2015519336 A JP2015519336 A JP 2015519336A JP 2015511563 A JP2015511563 A JP 2015511563A JP 2015511563 A JP2015511563 A JP 2015511563A JP 2015519336 A JP2015519336 A JP 2015519336A
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Abstract
Description
本出願は、2012年5月7日に提出された米国仮出願第61/643,739号、2012年9月10日に提出された米国仮出願第61/699,134号、および2013年3月11日に提出された米国特許出願第13/794,525号の優先権を主張し、それらの開示内容はその全体が参照により組み入れられる。
C型レクチン様分子1(CLL-1)は、AML細胞上、およびさらなる癌細胞を生じうる細胞である癌幹細胞(CSC)上で発現される。
・M26の重鎖CDRおよび軽鎖CDRを含む抗体(実施例1参照);
・M31の重鎖CDRおよび軽鎖CDRを含む抗体;
・G4の重鎖CDRおよび軽鎖CDRを含む抗体;
・M22の重鎖CDRおよび軽鎖CDRを含む抗体;
・M29の重鎖CDRおよび軽鎖CDRを含む抗体;
・M2の重鎖CDRおよび軽鎖CDRを含む抗体;
・M5の重鎖CDRおよび軽鎖CDRを含む抗体;
・G12の重鎖CDRおよび軽鎖CDRを含む抗体;
・M41の重鎖CDRおよび軽鎖CDRを含む抗体;
・E3の重鎖CDRおよび軽鎖CDRを含む抗体;
・B10の重鎖CDRおよび軽鎖CDRを含む抗体;
・G2の重鎖CDRおよび軽鎖CDRを含む抗体;
・G6の重鎖CDRおよび軽鎖CDRを含む抗体;
・G8の重鎖CDRおよび軽鎖CDRを含む抗体;
・G10の重鎖CDRおよび軽鎖CDRを含む抗体;
・G14の重鎖CDRおよび軽鎖CDRを含む抗体;
・G16の重鎖CDRおよび軽鎖CDRを含む抗体;
・G23の重鎖CDRおよび軽鎖CDRを含む抗体;
・G26の重鎖CDRおよび軽鎖CDRを含む抗体;
・G28の重鎖CDRおよび軽鎖CDRを含む抗体;ならびに
・G30の重鎖CDRおよび軽鎖CDRを含む抗体。
・M26の重鎖CDRおよび軽鎖CDRを含む抗体(実施例1参照);
・M31の重鎖CDRおよび軽鎖CDRを含む抗体;
・G4の重鎖CDRおよび軽鎖CDRを含む抗体;
・M22の重鎖CDRおよび軽鎖CDRを含む抗体;
・M29の重鎖CDRおよび軽鎖CDRを含む抗体;
・M2の重鎖CDRおよび軽鎖CDRを含む抗体;
・M5の重鎖CDRおよび軽鎖CDRを含む抗体;
・G12の重鎖CDRおよび軽鎖CDRを含む抗体;
・M41の重鎖CDRおよび軽鎖CDRを含む抗体;
・E3の重鎖CDRおよび軽鎖CDRを含む抗体;
・B10の重鎖CDRおよび軽鎖CDRを含む抗体;
・G2の重鎖CDRおよび軽鎖CDRを含む抗体;
・G6の重鎖CDRおよび軽鎖CDRを含む抗体;
・G8の重鎖CDRおよび軽鎖CDRを含む抗体;
・G10の重鎖CDRおよび軽鎖CDRを含む抗体;
・G14の重鎖CDRおよび軽鎖CDRを含む抗体;
・G16の重鎖CDRおよび軽鎖CDRを含む抗体;
・G23の重鎖CDRおよび軽鎖CDRを含む抗体;
・G26の重鎖CDRおよび軽鎖CDRを含む抗体;
・G28の重鎖CDRおよび軽鎖CDRを含む抗体;ならびに
・G30の重鎖CDRおよび軽鎖CDRを含む抗体、
からなる群より選択される抗体から選択され、ここで、選択されたCDRのいずれか1つまたは複数は、元のCDR配列と比較して1つ、2つまたは3つの保存的アミノ酸置換を有しうる。いくつかの態様において、CLL-1抗体は二重特異性抗体の一部である。いくつかの態様において、CLL-1抗体はサイトトキシンと連結されている。
・M26の可変領域配列(Vh=SEQ ID NO:4;Vl=SEQ ID NO:6)に対して実質的な同一性(少なくとも85、90、95または98%の同一性のいずれか)を有する可変領域配列を含む抗体;
・M31の可変領域配列(Vh=SEQ ID NO:8;Vl=SEQ ID NO:10)に対して実質的な同一性を有する可変領域配列を含む抗体;
・G4の可変領域配列(Vh=SEQ ID NO:12;Vl=SEQ ID NO:14)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M22の可変領域配列(Vh=SEQ ID NO:16;Vl=SEQ ID NO:18)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M29の可変領域配列(Vh=SEQ ID NO:20;Vl=SEQ ID NO:22)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M2の可変領域配列(Vh=SEQ ID NO:24;Vl=SEQ ID NO:26)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M5の可変領域配列(Vh=SEQ ID NO:28;Vl=SEQ ID NO:30)に対して実質的な同一性を有する可変領域配列を含む抗体;
・G12の可変領域配列(Vh=SEQ ID NO:32;Vl=SEQ ID NO:34)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M41の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・E3の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・B10の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G2の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G6の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G8の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G10の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G14の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G16の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G23の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G26の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;
・G28の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体;および
・G30の可変領域配列に対して実質的な同一性を有する可変領域配列を含む抗体。いくつかの態様において、実質的に同一な抗体は元の抗体のCDR配列を有する。
・M26の可変領域配列(Vh=SEQ ID NO:4;Vl=SEQ ID NO:6)を含む抗体;
・M31の可変領域配列(Vh=SEQ ID NO:8;Vl=SEQ ID NO:10)を含む抗体;
・G4の可変領域配列(Vh=SEQ ID NO:12;Vl=SEQ ID NO:14)を含む抗体;
・M22の可変領域配列(Vh=SEQ ID NO:16;Vl=SEQ ID NO:18)を含む抗体;
・M29の可変領域配列(Vh=SEQ ID NO:20;Vl=SEQ ID NO:22)を含む抗体;
・M2の可変領域配列(Vh=SEQ ID NO:24;Vl=SEQ ID NO:26)を含む抗体;
・M5の可変領域配列(Vh=SEQ ID NO:28;Vl=SEQ ID NO:30)を含む抗体;
・G12の可変領域配列(Vh=SEQ ID NO:32;Vl=SEQ ID NO:34)を含む抗体;
・M41の可変領域配列を含む抗体;
・E3の可変領域配列を含む抗体;
・B10の可変領域配列を含む抗体;
・G2の可変領域配列を含む抗体;
・G6の可変領域配列を含む抗体;
・G8の可変領域配列を含む抗体;
・G10の可変領域配列を含む抗体;
・G14の可変領域配列を含む抗体;
・G16の可変領域配列を含む抗体;
・G23の可変領域配列を含む抗体;
・G26の可変領域配列を含む抗体;
・G28の可変領域配列を含む抗体;および
・G30の可変領域配列を含む抗体。
・M26の可変領域配列(Vh=SEQ ID NO:4;Vl=SEQ ID NO:6)を含む抗体;
・M31の可変領域配列(Vh=SEQ ID NO:8;Vl=SEQ ID NO:10)を含む抗体;
・G4の可変領域配列(Vh=SEQ ID NO:12;Vl=SEQ ID NO:14)を含む抗体;
・M22の可変領域配列(Vh=SEQ ID NO:16;Vl=SEQ ID NO:18)を含む抗体;
・M29の可変領域配列(Vh=SEQ ID NO:20;Vl=SEQ ID NO:22)を含む抗体;
・M2の可変領域配列(Vh=SEQ ID NO:24;Vl=SEQ ID NO:26)を含む抗体;
・M5の可変領域配列(Vh=SEQ ID NO:28;Vl=SEQ ID NO:30)を含む抗体;
・G12の可変領域配列(Vh=SEQ ID NO:32;Vl=SEQ ID NO:34)を含む抗体;
・M41の可変領域配列を含む抗体;
・E3の可変領域配列を含む抗体;
・B10の可変領域配列を含む抗体;
・G2の可変領域配列を含む抗体;
・G6の可変領域配列を含む抗体;
・G8の可変領域配列を含む抗体;
・G10の可変領域配列を含む抗体;
・G14の可変領域配列を含む抗体;
・G16の可変領域配列を含む抗体;
・G23の可変領域配列を含む抗体;
・G26の可変領域配列を含む抗体;
・G28の可変領域配列を含む抗体;および
・G30の可変領域配列を含む抗体。いくつかの態様において、CLL-1抗体は二重特異性抗体の一部である。いくつかの態様において、CLL-1抗体はサイトトキシンと連結されている。
I.序論
本明細書では、さまざまな有利な特性を備える、CLL-1に対して特異的な抗体を提供する。そのような抗体は、以下の基準の少なくとも1つに基づいて選択された:
・ヒトCLL-1に対する親和性がピコモル濃度からナノモル濃度までの範囲にある;
・AML患者から得られた試料のうち比較的高率の試料との結合(例えば、X357もしくはX1057 CLL-1抗体の場合よりも高率のAML患者、またはAML患者試料の少なくとも50%);
・AML患者試料中の細胞(例えば、末梢血単核細胞(PBMC))のうち比較的高率の細胞との結合(例えば、X357もしくはX1057 CLL-1抗体の場合よりも高率の細胞、またはAML患者試料中の細胞の少なくとも50%);
・抗体薬物複合体(ADC)細胞傷害性アッセイにおいて活性がある;
・補体依存性細胞傷害性(CDC)アッセイにおいて活性がある;
・抗体依存性細胞傷害性(ADCC)アッセイにおいて活性がある;
・インビトロまたはインビボ(異種移植マウスモデル)での抗腫瘍活性;
・AML細胞との特異的結合、およびAML細胞でのADC活性はあるが正常HSCではそうでない;
・動物モデルの種ホモログ(例えば、カニクイザルCLL-1)との結合;
・上記の活性が、キメラ性ヒト形態にある抗体で保たれる。
別に定める場合を除き、本明細書において用いられる技術用語および科学用語は、当業者によって一般的に理解されるのと同じ意味を有する。例えば、Lackie, DICTIONARYOF CELL AND MOLECULAR BIOLOGY, Elsevier(4th ed. 2007);Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press(Cold Springs Harbor, NY 1989)を参照されたい。「1つ(a)」または「1つ(an)」という用語は、「1つまたは複数の」を意図している。「含む(comprise)」およびそれらの変形物、例えば「含む(comprises)」および「含むこと(comprising)」などは、ある段階または要素の叙述の前にある場合、さらなる段階または要素の追加も任意で行え、排除されないことを意味するものとする。本明細書に記載されたものと同様または同等なあらゆる方法、装置および材料を、本発明の実施に用いることができる。以下の定義は、本明細書において頻繁に用いられる。いくつかの特定の用語を理解しやすくするために提供されるものであり、本開示の範囲を限定することは意図していない。
本明細書に記載の抗体は、CLL-1関連障害、すなわち、標準的な対照(例えば、正常細胞、非罹患細胞、非癌性細胞)におけるCLL-1発現と比較して、CLL-1の表面発現の増大または低下と相関づけられる疾患を検出して治療するために用いることができる。CLL-1発現は通常、骨髄細胞系列細胞、例えば、末梢血中および脾臓内の樹状細胞、顆粒球、および単球に限られる。CLL-1レベルの増大は、癌、特に、造血性CSC(例えば、LSC)、ならびにAML(急性骨髄性または骨髄増殖性白血病)、MDS(骨髄異形成症候群)、骨髄線維症、CMML(慢性骨髄単球性白血病)、多発性骨髄腫、形質細胞腫およびCML(慢性骨髄性または骨髄増殖性白血病)などの白血病を含む骨髄増殖性障害と関連性がある。Bakker et al. (2004) Cancer Res. 64:8443;Van Rhenen el al. (2007) Blood 110:2659-66;Zhao el al. (2010) Haematologica (2010) 95:71;Van Rhenen el al. (2007) Leukemia 21:1700;およびHerrmann et al. (2012) Haematologica 97:219を参照。
本明細書では、ヒトCLL-1と、特にCLL-1発現細胞の細胞外ドメインと特異的に結合するCLL-1抗体(すなわち、CLL-1特異的抗体、抗CLL-1)を提供する。いくつかの態様において、CLL-1抗体は、Cレクチンドメインの外側にある構成要素を含むエピトープと結合し、その結果、抗体は、Cレクチンドメインからなるポリペプチドと、CLL-1のCレクチンドメインおよびストークドメイン、またはCLL-1の細胞外ドメインからなるポリペプチドよりも低い親和性で結合する。いくつかの態様において、CLL-1抗体は、CLL-1のC-レクチンドメインからなるポリペプチドと、CLL-1のC-レクチンドメインおよびストークドメインからなるポリペプチドよりも少なくとも5倍の高さのKd(例えば、10倍、20倍、50倍、100倍またはより高い倍率のいずれか)で結合する。例えば、M26およびM31と名付けられたCLL-1抗体は、ヒトCLL-1のアミノ酸101〜265と、ヒトCLL-1のアミノ酸141〜265よりも高い親和性で結合する(SEQ ID NO:2を基準とする)。いくつかの態様において、CLL-1抗体はCレクチンドメインと、完全長CLL-1(またはCLL-1の完全長細胞外ドメイン)よりも少なくとも5倍、10倍、20倍、50倍または100倍の高さであるKdで結合する。
・M26のCDR配列を有する抗体(実施例1、表3参照);
・M31のCDR配列を有する抗体;
・G4のCDR配列を有する抗体;
・M22のCDR配列を有する抗体;
・M29のCDR配列を有する抗体;
・M2のCDR配列を有する抗体;
・M5のCDR配列を有する抗体;および
・G12のCDR配列を有する抗体。
・M26の可変領域配列(Vh=SEQ ID NO:4;Vl=SEQ ID NO:6)に対して実質的な同一性(少なくとも(85、90、95または98%の同一性)を有する可変領域配列を含む抗体;
・M31の可変領域配列(Vh=SEQ ID NO:8;Vl=SEQ ID NO:10)に対して実質的な同一性を有する可変領域配列を含む抗体;
・G4の可変領域配列(Vh=SEQ ID NO:12;Vl=SEQ ID NO:14)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M22の可変領域配列(Vh=SEQ ID NO:16;Vl=SEQ ID NO:18)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M29の可変領域配列(Vh=SEQ ID NO:20;Vl=SEQ ID NO:22)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M2の可変領域配列(Vh=SEQ ID NO:24;Vl=SEQ ID NO:26)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M5の可変領域配列(Vh=SEQ ID NO:28;Vl=SEQ ID NO:30)に対して実質的な同一性を有する可変領域配列を含む抗体;および
・G12の可変領域配列(Vh=SEQ ID NO:32;Vl=SEQ ID NO:4)に対して実質的な同一性を有する可変領域配列を含む抗体。いくつかの態様において、実質的に同一な抗体は、元の抗体と同じ重鎖および軽鎖CDR配列を有する。
・M26のCDR配列を有する抗体(実施例1、表3参照);
・M31のCDR配列を有する抗体;
・G4のCDR配列を有する抗体;
・M22のCDR配列を有する抗体;
・M29のCDR配列を有する抗体;
・M2のCDR配列を有する抗体;
・M5のCDR配列を有する抗体;および
・G12のCDR配列を有する抗体。
・M26のCDR配列を有する抗体(実施例1、表3参照);
・M31のCDR配列を有する抗体;
・G4のCDR配列を有する抗体;
・M22のCDR配列を有する抗体;
・M29のCDR配列を有する抗体;
・M2のCDR配列を有する抗体;
・M5のCDR配列を有する抗体;および
・G12のCDR配列を有する抗体。いくつかの態様において、CDR配列の任意の1つまたは複数は、元の抗体のCDR配列と比較して1個、2個または3個の保存的アミノ酸置換を含む。
・M26の可変領域配列(Vh=SEQ ID NO:4;Vl=SEQ ID NO:6)に対して実質的な同一性(少なくとも85、90、95、または98%の同一性)を有する可変領域配列を含む抗体;
・M31の可変領域配列(Vh=SEQ ID NO:8;Vl=SEQ ID NO:10)に対して実質的な同一性を有する可変領域配列を含む抗体;
・G4の可変領域配列(Vh=SEQ ID NO:12;Vl=SEQ ID NO:14)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M22の可変領域配列(Vh=SEQ ID NO:16;Vl=SEQ ID NO:18)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M29の可変領域配列(Vh=SEQ ID NO:20;Vl=SEQ ID NO:22)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M2の可変領域配列(Vh=SEQ ID NO:24;Vl=SEQ ID NO:26)に対して実質的な同一性を有する可変領域配列を含む抗体;
・M5の可変領域配列(Vh=SEQ ID NO:28;Vl=SEQ ID NO:30)に対して実質的な同一性を有する可変領域配列を含む抗体;および
・G12の可変領域配列(Vh=SEQ ID NO:32;Vl=SEQ ID NO:34)に対して実質的な同一性を有する可変領域配列を含む抗体。
・10nMまたはそれ未満、例えば、1nMまたはそれ未満、1〜10nM、100〜1000pM、10〜1000pM、約1nMまたはそれ未満、1〜500pMなどのKdでヒトCLL-1と結合する;
・HL60細胞またはAML患者由来のCLL-1発現性AML細胞を用いたCDCアッセイにおけるEC50が200ng/mLまたはそれ未満;
・HL60細胞またはAML患者由来のCLL-1発現性AML細胞を用いたADCアッセイにおけるEC50が100pMまたはそれ未満(100pM of less);および
・抗体の非存在下における細胞増殖と比較して、CLL-1発現細胞(例えば、HL60細胞、AML細胞)の細胞増殖を低下させる。
本明細書に記載の抗体、例えば、組換え抗体、モノクローナル抗体、またはポリクローナル抗体の調製のためには、当技術分野において公知の多くの手法を用いることができる(例えば、Kohler & Miistem, 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Coding, 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を細胞からクローニングし、例えば、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て、組換えモノクローナル抗体を作製するために用いることができる。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。重鎖および軽鎖の遺伝子産物のランダムな組み合わせにより、種々の抗原特異性を有する抗体の大規模なプールが生じる(例えば、Kuby, Immunology (3rd ed. 1997)を参照)。単鎖抗体または組換え抗体の作製のための手法(米国特許第4,946,778号、米国特許第4,816,567号)を、本発明のポリペプチドに対する抗体を作製するために応用することができる。また、トランスジェニックマウス、または他の哺乳動物などの他の生物を、ヒト化抗体またはヒト抗体を発現させるために用いることもできる(例えば、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用いて、選択した抗原と特異的に結合する抗体およびヘテロマーFab断片を同定することもできる(例えば、McCafferty et al., Nature 348:552-554 (1990);Marks et ah , Biotechnology 10:779-783 (1992)を参照)。抗体を二重特異性のもの、すなわち、2つの異なる抗原を認識しうるものとして作製することもできる(例えば、WO 93/08829号、Traunecker et al., EMBO J. 10:3655-3659 (1991);およびSuresh et al., Methods in Enzymology 121:210 (1986)を参照)。抗体が、ヘテロ複合体、例えば共有結合性に連結された2つの抗体、またはイムノトキシンであってもよい(例えば、米国特許第4,676,980号、WO 91/00360号;WO 92/200373号;およびEP 03089号を参照)。
結合の特異性は、環境または非関連分子全般における抗体および他の材料に対しての解離定数と比較した場合の、標的に対する抗体(または他の標的指向性部分)の解離定数(Kd)の比較の点から定義することができる。典型的には、非関連材料に対しての抗体のKdは、標的に対してのKdよりも少なくとも2倍、3倍、4倍、5倍、10倍、20倍、50倍、100倍、200倍の高さであるか、またはより高いと考えられる。
CLL-1に対する抗体結合の部位は、エピトープマッピングのための公知の手法を用いてマッピングすることができる。当業者は、エピトープマッピングのために用いられるアプローチが、例えば、抗原が細胞内で発現されるか、一次ポリペプチド配列の翻訳後修飾、および異なる細胞上または異なる環境内での抗原構造の違いというように、抗原に応じて異なりうることを理解しているであろう。
本明細書に記載の抗体は、CLL-1を発現する細胞の細胞依存性細胞傷害作用(CDC)、抗体依存性細胞媒介性細胞傷害作用(ADCC)、および抗体薬物複合体細胞傷害作用(ADC)に対して有効である。CLL-1を発現する例示的な細胞には、異種性の組換えCLL-1(例えば、ヒトCLL-1)を発現する細胞株;HL60、THP1、TF1-α、U937、およびOCIAML-5などのヒトAML細胞株(最初の4つはATCCから入手可能である);1人または複数のAML患者由来の初代細胞(例えば、PBMCまたは生着した腫瘍細胞);K562およびKU812などのヒトCML細胞株(ATCCから入手可能);ならびに1人または複数のCML患者またはMDS患者由来の初代細胞が含まれる。
本明細書に記載のCLL-1抗体は、CLL-1 AML細胞を含むCLL-1発現細胞へ内部移行することができる。すなわち、CLL-1発現細胞は本明細書に記載の抗体を内部移行させることができる。本明細書に記載のCLL-1抗体は、例えば、検出可能な複合体または細胞傷害性複合体により、そのような細胞を標的化するための有効な手段を与える。
本明細書に記載のCLL-1抗体は、CLL-1発現細胞と特異的に結合する。このため、CLL-1抗体を、CLL-1発現細胞(例えば、AML細胞およびAML CSC)を検出するための、インビトロおよびインビボでの診断アッセイのために用いることができる。例えば、試料(例えば、血液試料または組織生検試料)を患者から得て、CLL-1抗体と接触させた上で、患者試料中のCLL-1発現細胞の存在を、抗体結合を検出することによって判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(例えば、抗体自体が標識である場合)、または第2の検出物質、例えば二次抗体などを用いることによって検出することもできる。検出用標識は、直接的に、または間接的に、例えばキレート剤またはリンカーを介して、本発明の抗体に付随させることができる。
CLL-1抗体を含む診断用物質には、例えば、以下の参考文献に提示されているような、当技術分野において公知であるあらゆる診断用物質が含まれうる: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)。診断用物質は、検出可能なシグナルを与える、および/または増強する作用物質としてのものを含む、種々のやり方によって検出することができる。検出可能なシグナルには、γ線放射性、放射性、エコー源性、光学的、蛍光性、吸収性、磁気または断層撮影シグナルが非限定的に含まれる。診断用物質の画像化のための手法には、単一光子放出型コンピュータ断層撮影法(SPECT)、磁気共鳴撮像法(MRI)、光学撮像法、ポジトロン放出断層撮影法(PET)、コンピュータ断層撮影法(CT)、X線撮像法、γ線撮像法などが非限定的に含まれうる。「検出可能な作用物質」、「検出可能な部分」、「標識」、「造影剤」および類似の用語などの用語は、本明細書において同義に用いられる。
検出用物質および治療用物質を抗体と結合させるための手法は周知である(例えば、Arnon 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., 62:1 19-58 (1982)を参照)。
本明細書に記載のCLL-1抗体を用いて、AML細胞などのCLL-1発現細胞を標的化することができる。CLL-1発現は、AML細胞およびCSC(例えば、AML CSC)上で増大している。CLL-1は正常CD34+ 造血幹細胞(HSC)上で著しくは発現されないことから、本CLL-1抗体を用いて、CSCをHSCと識別することができる。AML細胞に共通するCLL-1エピトープを認識し、それ故にAML細胞とあまねく結合することができる高親和性CLL-1抗体は、AMLの再発率が非常に高いことから、特に有益である。上述したように、CLL-1抗体を含む治療用組成物は、例えば、CLL-1発現細胞の検出および位置決定、ならびに治療効果のモニタリングのためのセラノスティック組成物を形成するために検出用標識をさらに含む。
A.実施例1:CLL-1抗体の配列および構造の特徴づけ
ヒトCLL-1を用いて、マウスにおいて抗体を生じさせた。CLL-1に対して特異的な抗体を選択し、モノクローナル抗体の安定した産生のためにハイブリドーマにクローニングした。CLL-1に対して特異的な抗体をいくつかクローニングし、配列および抗体構造に関して特徴づけた。これらのデータは以下の表1〜3に示されている。重鎖および軽鎖の可変領域配列は配列表に示されている。
CDR H1:SEQ ID NO:51〜58
CDR H2:SEQ ID NO:59〜66
CDR H3:SEQ ID NO:67〜74
CDR L1:SEQ ID NO:75〜82
CDR L2:SEQ ID NO:83〜90
CDR L3:SEQ ID NO:91〜98
いくつかのクローンに関して、エピトープマッピングを実施し、公知の抗体に関するCLL-1との結合の位置と比較した。これらの抗体には、Nuvelo/X1057(US20100285037号)、Crucell/X357(米国特許第7741443号)、およびヤギ抗CLL-1が含まれる。概要は以下の表4に示されている。CLL-1またはCLL-1のCレクチンドメインを293T細胞において発現させた。トランスフェクトされていない293T細胞、またはマウスCLL-1をトランスフェクトした293T細胞を対照として用いた。
CLL-1抗体クローンについて親和性試験を実施した。手短に述べると、ビオチン化CLL-1(25ug/ml)をストレプトアビジンセンサーチップにロードして、22Cで2時間おいた。1:1グローバルカーブフィッティングを用いて、各抗体について3つの異なる濃度(10、30および90ug/ml)でAb-Ag解離曲線を作成した。結果は以下の表6に示されている。
CLL-1抗体を、ヒトCLL-1を発現する組換え293細胞、ならびに2種のAML細胞株、HL60およびOCI AML-5に対する結合に関して試験した。FACSによって検出した、抗体結合を伴う生細胞の比率を、以下の表7に示している。
以前に特徴づけられたCLL-1抗体は、典型的には、初代AML細胞と高いばらつきを伴って結合し、これは患者試料に広く用いる上では問題であった。中には、特定の患者由来の試料と検出可能なようには結合しないものもある。本明細書に開示された抗体を、AML患者由来の初代細胞試料に対する結合に関して、FACSによって試験した。2群の試料を試験した:第1のものは患者6人からなり、もう一方は37人という、より大規模なコホートからなる。各抗体クローンを群内のあらゆる試料に対する結合に関して試験したわけではない。結合の結果は表8に示されている。M26およびM31はAML患者の初代細胞試料からの90%またはそれを上回る細胞と結合することが、FACSによってさらに見いだされた。
抗体薬物複合体(ADC)アッセイを、AML細胞株HL60およびOCI AML-5、ならびにCLL-1を発現する組換え293細胞に対して実施した。手短に述べると、細胞をさまざまな濃度のサポリン結合抗体とともに37Cで48〜72時間インキュベートした。細胞生存度をDHL比色アッセイによって決定して、EC50値を求めた。
補体依存性細胞傷害性アッセイを、AML患者由来の初代細胞に対して実施した。初代AML細胞を、補体の存在下で、さまざまな濃度のCLL-1抗体とともに37Cで2時間インキュベートした。細胞生存度を比色Cellglowアッセイ(Promega)によって決定した。
2組のインビボ有効性試験を実施した。第1のものは、CLL-1陽性HL60 AMLヒト細胞株をマウスに用いる皮下(SC)腫瘍生着・成長モデルであった。第2のものは、CLL-1陽性OCI AML-5ヒトAML細胞株を用いる同所性(骨髄、血液、脾臓およびリンパ節)腫瘍生着・増生モデルであった。
M26 CLL-1抗体を、サポリンと結合させた上で、ADCアッセイにおいて特異的死滅に関して試験した。ヒト対象の骨髄から単離した初代患者AML細胞または正常CD34陽性造血幹細胞を、軟寒天コロニー形成アッセイ用に播種した(細胞100,000個/プレート)。続いて細胞を、CLL-1-サポリン毒素結合モノクローナル抗体クローンM26の存在下で14日間インキュベートした。図4に示されているように、CLL-1抗体-サポリン複合体は、AML幹細胞のクローン性増殖の選択的な特異的阻害を引き起こしたが、正常HSCには影響しなかった。陰性対照は未処理とするか、または関連のないIgG-サポリン複合体で処理した。これらの結果は、サイトトキシンと結合させたCLL-1抗体が、HSCコロニー形成を阻害することなく、AML細胞コロニー形成を約80%減少させることを実証している。これらの結果は、本明細書に開示されたCLL-1抗体を、AML細胞上に発現されたCLL-1を特異的に標的化するために安全に治療的に用いうることを示している。
CLL-1抗体クローンM26、M31およびG4の可変領域(Fab)を用いて、ヒトIgG1由来の定常領域(Fc)を有するキメラ抗体を作製した。これらのヒトキメラ抗体を、ChiM26、ChiM31、およびChiG4(またはChi31G4)と称する。ヒトキメラ抗体の特異性を親マウス抗体と比較して検討するために、これらの抗体を用いてヒトPBMCの異なる集団を染色した。PBMCを2人のヒトドナーから得て、Ficoll勾配によって分離した上でプールした。約2×105個の単核細胞を3%ヒト血清でブロックし、続いて、系列マーカーCD89(顆粒球)、CD14(単球および顆粒球)、CD3(リンパ系)およびCD19(B細胞)に対して特異的な抗体で染色した。図5は、ライブゲーティングを行った細胞に関するFACSの結果を示している。ヒトキメラCLL-1抗体は、マウスCLL-1抗体と同じ骨髄細胞系列集団を染色する。
ヒトキメラ抗体の特異性を親マウス抗体と比較して検討するために、これらの抗体を用いてカニクイザルPBMCの異なる集団を染色した。PBMCを3体のドナーから得て、Ficoll勾配によって分離した上でプールした。約2×105個の単核細胞を3%ヒト血清でブロックし、続いて、系列マーカーCD3(リンパ系)、CD19(B細胞)、CD14(顆粒球)、CD14(単球)およびCD89(顆粒球)に対して特異的な抗体で染色した。図6は、ライブゲーティングを行った細胞に関するFACSの結果を示している。ヒトキメラCLL-1抗体は、マウスCLL-1抗体と同じ骨髄細胞系列集団を染色する。
ヒトキメラCLL-1抗体が内部移行してADCを媒介する能力を、CLL-1を発現する293細胞に対してインビトロで検討した。細胞を、さまざまな濃度の指定の抗体と接触させた。適合するIgGアイソタイプ抗体を陰性対照に用いた。続いて、サポリン結合二次抗体(Mousezap(登録商標)またはHumzap(登録商標))を2:1比で添加し、細胞を72時間インキュベートした。Cell Titre-Glo(登録商標)を各培養ウェルに添加し、5〜10分間混合して、発光プレートリーダーで検出した。細胞生存度は発光シグナルによって決定した。図7は、ヒトキメラCLL-1抗体(7B)がマウスCLL-1抗体クローン(7A)とほぼ同一なADC活性を有することを示している。
ヒトキメラCLL-1抗体ChiM26、ChiM31、およびChiG4(Chi31G4)がADCCを媒介する能力を、CLL-1を発現する293細胞に対して判定した。標的細胞を96穴丸底ウェルに添加し、さまざまな濃度の指定の抗体、およびエフェクター細胞(Promega(登録商標))とともに37Cで6時間インキュベートした。生細胞をPromega ADCC Reporter Assay(登録商標)を用いて検出した。結果は図8に示されている。ヒトIgGアイソタイプ対照は検出可能な活性を有しなかったが、ChiM26、ChiM31、およびChi31G4に関するEC50は、ng/ml単位でそれぞれ79、143および105であることが明らかになった。
2組のインビボ異種移植試験を、マウスおよびヒトのキメラCLL-1抗体を用いて実施した。いずれの試験にも、第0日にヒトAML細胞の尾静脈注射を受ける1日前に照射を行ったNOD/SCIDマウスを用いた。いずれの試験にも、約3週間の経過にわたる8回の抗体注射と、その後の骨髄細胞における腫瘍成長の検出を含めた。
Claims (22)
- ヒトC型レクチン様分子1(CLL-1)の細胞外ドメインと特異的に結合する単離された抗体であって、ヒトCLL-1のC-レクチンドメインおよびストークドメインからなるポリペプチドよりも少なくとも5倍の高さのKdで、ヒトCLL-1のC-レクチンドメインからなるポリペプチドと結合する、単離された抗体。
- ヒトまたはカニクイザルのCLL-1と1000pMまたはそれ未満のKdで結合する、請求項1記載の単離された抗体。
- AMLの個体由来の急性骨髄性白血病(AML)細胞の試料中の細胞の少なくとも50%と結合する、請求項1記載の単離された抗体。
- 静止状態のCLL-1発現細胞と結合する、請求項1記載の単離された抗体。
- 以下のものからなる群より選択される、請求項1記載の単離された抗体:
SEQ ID NO:51、59および67の重鎖相補性決定領域(CDR)と、SEQ ID NO:75、83および91の軽鎖CDRとを含む抗体;
SEQ ID NO:52、60および68の重鎖CDRと、SEQ ID NO:76、84および92の軽鎖CDRとを含む抗体;および
SEQ ID NO:53、61および69の重鎖CDRと、SEQ ID NO:77、85および93の軽鎖CDRとを含む抗体。 - ヒト化されている、請求項1記載の単離された抗体。
- Fv抗体フラグメントである、請求項1記載の単離された抗体。
- 治療用化合物と結合されている、請求項1記載の単離された抗体。
- 検出用部分と結合されている、請求項1記載の単離された抗体。
- 細胞がC型レクチン様分子1(CLL-1)を発現するか否かを判定する方法であって、以下の段階を含む、方法:
請求項9記載の抗体を細胞と接触させる段階;および
抗体の細胞との結合を検出する段階であって、抗体の細胞との結合によって細胞がCLL-1を発現することが示される、段階;および
細胞がCLL-1を発現するか否かを判定する段階。 - 細胞が、造血細胞を含む個体由来の生物試料中にある、請求項10記載の方法。
- 細胞がCD34またはCD38を発現するか否かを判定する段階をさらに含む、請求項10記載の方法。
- C型レクチン様分子1(CLL-1)を発現する細胞の生存を阻害するための方法であって、以下の段階を含む、方法:
請求項1記載の抗体を細胞と接触させる段階であって、それによって細胞の生存を阻害する、段階。 - 接触させる段階が、抗体を個体に投与することを含み、細胞が個体内にある、請求項13記載の方法。
- 個体が骨髄増殖性障害と診断されている、請求項13記載の方法。
- 骨髄増殖性障害が、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、慢性骨髄単球性白血病(CMML)、骨髄異形成症候群(MDS)、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13記載の方法。
- 請求項1記載の単離された抗体と、薬学的に許容される担体とを含む薬学的組成物。
- 個体における骨髄増殖性障害を治療する方法であって、以下の段階を含む、方法:
個体に対して請求項17記載の薬学的組成物を投与する段階であって、それによって個体におけるAMLを治療する、段階。 - 抗体が治療用化合物と結合されている、請求項18記載の方法。
- 個体が骨髄増殖性障害と診断されているか、または骨髄増殖性障害に対する治療法を受けたことがある、請求項18記載の方法。
- 骨髄増殖性障害が、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、慢性骨髄単球性白血病(CMML)、骨髄異形成症候群(MDS)、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18記載の方法。
- 以下のものからなる群より選択される、ヒトC型レクチン様分子1(CLL-1)と結合する単離された抗体:
SEQ ID NO:51、59および67の重鎖相補性決定領域(CDR)と、SEQ ID NO:75、83および91の軽鎖CDRとを含む抗体;
SEQ ID NO:52、60および68の重鎖CDRと、SEQ ID NO:76、84および92の軽鎖CDRとを含む抗体;および
SEQ ID NO:53、61および69の重鎖CDRと、SEQ ID NO:77、85および93の軽鎖CDRとを含む抗体。
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JP2022505921A (ja) * | 2018-10-26 | 2022-01-14 | カファ セラピューティクス リミテッド | Cll1を標的とする抗体およびその応用 |
JP2023509821A (ja) * | 2020-12-11 | 2023-03-10 | 広州百▲ジ▼基因科技有限公司 | 抗cll1抗体およびその使用 |
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JP2020202867A (ja) * | 2016-04-01 | 2020-12-24 | カイト ファーマ インコーポレイテッドKite Pharma, Inc | キメラ受容体及びその使用方法 |
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JP2022169740A (ja) * | 2016-04-01 | 2022-11-09 | カイト ファーマ インコーポレイテッド | キメラ受容体及びその使用方法 |
JP7451627B2 (ja) | 2016-04-01 | 2024-03-18 | カイト ファーマ インコーポレイテッド | キメラ受容体及びその使用方法 |
JP2022505921A (ja) * | 2018-10-26 | 2022-01-14 | カファ セラピューティクス リミテッド | Cll1を標的とする抗体およびその応用 |
JP2023509821A (ja) * | 2020-12-11 | 2023-03-10 | 広州百▲ジ▼基因科技有限公司 | 抗cll1抗体およびその使用 |
JP7384493B2 (ja) | 2020-12-11 | 2023-11-21 | 広州百▲ジ▼基因科技有限公司 | 抗cll1抗体およびその使用 |
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US9850314B2 (en) | 2017-12-26 |
CN104736562B (zh) | 2018-05-01 |
US20130295118A1 (en) | 2013-11-07 |
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