JP2022023243A - 非常に特異的な腫瘍細胞表面抗原を標的とするヒト抗体を用いた腫瘍特異的ペイロード送達及び免疫活性化 - Google Patents
非常に特異的な腫瘍細胞表面抗原を標的とするヒト抗体を用いた腫瘍特異的ペイロード送達及び免疫活性化 Download PDFInfo
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Abstract
Description
本出願は、全ての目的で全体が参照により本明細書に組み込まれる、2015年11月30日に出願された米国仮特許出願第62/261,112号の利益及び優先権を主張する。
本発明は、国立衛生研究所から付与された助成金R01 CA129491、R01 CA118919、及びR01 CA171315の下での政府支援によってなされた。政府は、本発明に一定の権利を有する。
、エピルビシン、トレミフェン、レトロゾール、トラスツズマブ、メゲストロールタモキシフェン、パクリタキセル、ドセタキセル、カペシタビン、酢酸ゴセレリン、及びゾレドロン酸からなる群から選択される。
ール、トラスツズマブ、メゲストロールタモキシフェン、パクリタキセル、ドセタキセル、カペシタビン、酢酸ゴセレリン、及びゾレドロン酸からなる群から選択される。
を含む、方法。
用語「患者」には、予防的処置又は治療的処置のいずれかを受けるヒト及び他の哺乳動物対象が含まれる。
0号,第5,216,141号及び第4,469,863号; Angew. (1991年) Chem. Intl. Ed. English 30巻: 423頁; Letsingerら、(1988年) J. Am. Chem. Soc. 110巻:4470頁; Letsingerら、(1994年) Nucleoside & Nucleotide 13巻:1597頁; 2章及び3章, ASC Symposium Series 580,「Carbohydrate Modifications in Antisense Research」, Ed. Y.S. Sanghui and P. Dan Cook; Mesmaekerら(1994年), Bioorganic & Medicinal Chem. Lett. 4巻: 395頁; Jeffsら、(1994年) J. Biomolecular NMR 34巻:17頁; Tetrahedron Lett. 37巻:743頁(1996年))及び非リボース骨格を有するものが含まれ、米国特許第5,235,033号及び第5,034,506号, 6章及び7章, ASC Symposium Series 580, Carbohydrate Modifications in Antisense Research, Ed. Y.S. Sanghui and P. Dan Cookに記載されているものが挙げられる。また、1つ以上の炭素環糖を含有する核酸は、核酸の定義内に含まれる(Jenkinsら、(1995年), Chem. Soc. Rev. 169-176頁参照)。いくつかの核酸類似体は、Rawls, C & E News, 1997年6月2日、35頁に記載されている。リボース-リン酸骨格のこれらの改変は、標識等の付加的な部分の付加を容易にするため、又は生理学的環境におけるこのような分子の安定性及び半減期を増大させるためになされ得る。
1)腫瘍細胞へのペイロード送達(例えば、薬物、siRNA、mRNA、サイトカイン、放射性核種)のための使用;
2)腫瘍の部位で免疫系を選択的に活性化する二重特異性又はオリゴ特異性抗体の成分としての使用;
3)細胞ベースの療法のためのキメラ抗原レセプター(CAR-T)の構築における使用;
4)二重特異性抗体の構築における使用;及び
5)腫瘍検出/定量並びに患者層別化及び結果分析のための診断/病期分類ツールとしての使用。
抗体は、例えば、ALPPL2を発現している癌細胞が組織微小環境に存在する場合、インビトロ及びインサイチュでALPP及び/又はALPPL2に特異的に結合することを発見された。上記に示されるように、このような抗体は、単独での使用した場合、又は「標的化されたエフェクター」を形成するためにエフェクターに結合された場合、癌を標的とするのに有用である。
有用な抗体標的(単数又は複数)としてALPP及び/又はALPP2、及び有用な原型の抗体として、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF抗体を同定すると、ALPP及び/又はALPPL2に結合する他の「関連する」抗体は、ALPP/ALPPL2に結合し、例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFによって結合されるエピトープで、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFの1つ以上と交差反応する抗体について、及び/又は中皮腫細胞(例えば、M28細胞株)に結合させるために、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFの1つ以上と交差反応する抗体についてスクリーニングすることにより容易に同定することができる。
ALPP及び/又はALPPL2に結合し、好ましくはM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFの1つ以上に結合されるエピトープに結合するモノクローナル抗体は、Kohler and Milstein (1975) Nature 256: 495によって報告されている標準的な体細胞ハイブリダイゼーション技術、Bリンパ球のウイルス若しくは腫瘍化形質転換、又はヒト抗体遺伝子のライブラリーを用いるファージディスプレイ技術等の様々な公知の技術を用いて生成され得る。特定の実施形態において、抗体は完全なヒトモノクローナル抗体である。
別のアプローチにおいて、ALPP及び/又はALPPL2に結合する抗体は、本明細書に記載されている「原型の」抗体(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)と同じエピトープに結合するという事実によって同定され得る。このような抗体を同定するために、対象のエピトープを単離する必要はない。特定の実施形態において、例えば、ALPP/ALPP2を発現している細胞(例えば、M28等の中皮腫細胞等)による結合、及び/又はALPP/ALPPL2への結合について、本発明の原型の抗体と競合する抗体に関する抗体ライブラリーをスクリーニングすることができる。
M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFの抗体について公知の配列を用いて、様々なファージディスプレイ(又は酵母ディスプレイ)法が、ALPP/ALPPL2に特異的に結合する、好ましくは同じ又はより大きな親和性でM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFにより結合されるエピトープに結合する、他の抗体を生成するために使用され得る。
抗体変異体を作製する1つのアプローチは、ファージディスプレイ又は酵母ディスプレイのライブラリーにおいて新たなパートナー(チェーンシャッフリング)(Clacksonら、(1991年) Nature. 352巻: 624~628頁)を作製するために、本来のVH又はVL遺伝子をV遺伝子のレパートリーに置換することであった。チェーンシャッフリング及びファージディスプレイを用いて、ハプテンフェニルオキサゾロン(phOx)に結合するヒトscFv抗体断片の親和性は、300nMから1nM(300倍)に増大した(Marksら、(1992年) Bio/Technology 10巻: 779~783頁)。
アミノ酸側鎖に接触する多数の抗原は、典型的には、相補性決定領域(CDR)に位置され、VHに3つ(CDR1、CDR2、及びCDR3)及びVLに3つ(CDR1、CDR2、及びCDR3)に位置する(Chothiaら、(1987年) J. Mol. Biol.,196巻: 901~917頁; Chothiaら、(1986年) Science, 233巻: 755~8; Nhanら、(1991年) J. Mol. Biol., 217巻: 133~151頁)。これら残基は、抗原のための抗体親和性の原因となる、多数の結合エネルギーに寄与する。他の分子において、リガンドに接触するアミノ酸の突然変異は、その結合パートナーのために1つのタンパク質分子の親和性を増大させるのに有効な手段であることが示されている(Lowmanら、(1993年) J. Mol. Biol., 234巻: 564~578頁; Wells (1990年) Biochemistry, 29巻: 8509~8516頁)。例えば、本明細書に記載されているように、CDRの部位特異的突然変異誘発、及びALPP/ALPPL2を発現している細胞/細胞株に対するスクリーニングは、結合親和性が改善された抗体を生成することができる。
単純な部位特異的突然変異誘発の拡張において、突然変異体抗体ライブラリーが作製され得、この場合、部分的又は全体のCDRは無作為化される(VL CDRl、CDR2及び/若しくはCDR3並びに/又はVH CDR1、CDR2及び/若しくはCDR3)。一実施形態において、各CDRは、鋳型として公知の抗体(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)を用いて、別個のライブラリーにおいて無作為化される。各CDRライブラリーからの最も高い親和性突然変異体のCDR配列は、親和性の付加的な増加を得るために組み合わせられる。同様の方法が、3.4×10-10から9.0×10-13Mまで1500倍を超えて、増殖ホルモン受容体のためにヒト増殖ホルモン(hGH)の親和性を増大させるために使用されている(Lowmanら、(1993年) J. Mol. Biol., 234巻: 564~578頁)。
一実施形態において、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF抗体に由来する部分的な抗体配列は、構造的及び機能的に関連する抗体を生成するために使用され得る。例えば、抗体は、優位に、6つの重鎖及び軽鎖の相補性決定領域(CDR)に位置するアミノ酸残基を介して、標的抗原と相互に作用する。この理由により、CDR内のアミノ酸配列は、CDRの外側の配列よりも、個々の抗体間において多様である。CDR配列が大部分の抗体-抗原相互作用に起因するため、異なる特性を有する異なる抗体からフレームワーク配列上に移植された特定の天然に存在する抗体からのCDR配列を含む、発現ベクターを構築することにより、特定の天然に存在する抗体の特性を模倣する組換え抗体を発現することが可能である(例えば、Riechmannら、(1998年) Nature 332巻: 323~327頁; Jonesら、(1986年) Nature 321巻: 522~525頁;Queenら、(1989年) Proc. Natl. Acad. Sci. USA, 86巻: 10029~10033頁を参照されたい)。このようなフレームワーク配列は、生殖系列抗体遺伝子配列を含む公的なDNAデータベースから得ることができる。
M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)の重鎖及び/又は軽鎖のCDR1を含む抗体が生成される。更に、抗体は、本発明の抗体(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)の他の重鎖及び/又は軽鎖CDRを含み得る。
る。
様々な実施形態において、本明細書に記載されている抗体は、化学合成により生成され得、又は組換え的に発現され得る。
本明細書に提供されている配列情報を用いて、本明細書に記載される抗ALPPL2特異抗体(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)、又はその変異体が、ペプチド合成の周知の方法を用いて化学的に合成され得る。配列のC末端アミノ酸が不溶性支持体に結合され、その後、配列中の残りのアミノ酸が連続的に付加される固相合成は、一本鎖抗体の化学合成のための好ましい1つの方法である。固相合成のための技術は、Barany and Merrifield, Solid Phase Peptide Synthesis; 3~284頁 in The Peptides: Analysis, Synthesis, Biology. 2巻: Special Methods in Peptide Synthesis, Part A., Merrifieldら、(1963年) J. Am. Chem. Soc., 85巻: 2149~2156頁, Stewartら、(1984年) Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem. Co., Rockford, Illに記載されている。
特定の実施形態において、本明細書に記載されている抗ALPPL2/ALPPL特異抗体(例えばM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)、又はその変異体が、当業者に周知の方法を用いて組換え発現される。例えば、本明細書に提供されているM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFの配列情報を用いて、所望の抗体をコード化する核酸が、当業者に公知である多数の標準的方法に従って調製され得る。核酸は、次に所望の抗体又は鎖を発現する宿主細胞にトランスフェクトされる。
本明細書において提供される一本鎖抗体の公知の及び/又は同定された配列(例えば、VH及び/又はVL配列)を用いて、他の抗体形態を容易に作製することができる。このような形態は、限定されないが、多価抗体、完全抗体、scFv、(scFv')2、Fab、(Fab')2、キメラ抗体等を含む。
例えば、(scFv')2抗体を作製するために、2つの抗ALPP/ALPPL2抗体は、リンカー(例えば、炭素リンカー、ペプチド等)を介して、又は、例えば、2つのシステイン間のジスルフィド結合を介して接続される。したがって、例えば、ジスルフィドが連結したscFvを作製するために、システイン残基は、本明細書に記載されている抗体のカルボキシ末端での部位特異的突然変異誘発により導入され得る。
本明細書において意図される抗体はまた、「キメラ」抗体を含み、そこでは、重鎖及び/又は軽鎖の一部が、特定の種に由来し、又は特定の抗体クラス若しくはサブクラスに属している抗体における、対応する配列と同一である又はそれに相同であり、一方、鎖(単数又は複数)の残りは、別の種に由来し、又は別の抗体クラス若しくはサブクラスに属している抗体、並びにこのような抗体の断片における、対応する配列と同一である又はそれに相同であるが、それらが所望の生物活性を示す場合に限る(例えば、米国特許第4,816,567号;Morrisonら、(1984年) Proc. Natl. Acad. Sci. 81巻: 6851~6855頁等を参照されたい)。
別の実施形態において、本発明は、インタクトな完全なヒト抗ALPP/ALPPL2抗体を提供する。このような抗体は、キメラなヒト化抗体の作製と同様の方法で容易に生成することができる。この例において、本明細書に記載されているVH及びVLドメインは、完全にヒトであり、実質的に完全な抗体(例えば、IgG、IgA、IgM等)に容易に操作され得る。
特定の実施形態において、本明細書に記載されているVH及びVLドメインの1以上を含有するダイアボディが意図される。用語「ダイアボディ」とは、典型的には、2つの抗原結合部位を有する抗体断片を指す。断片は、典型的には、同じポリペプチド鎖(VH-VL)において軽鎖可変ドメイン(VL)に連結される重鎖可変ドメイン(VH)を含む。同じ鎖上の2つのドメイン間で対にすることを可能にするには短すぎるリンカーの使用によって、ドメインは、別の鎖の相補的なドメインと対になり、2つの抗原結合部位を作製することを強いられる。ダイアボディは、例えば、欧州特許第404,097号;国際公開第93/11161号、及びHolligerら、(1993年) Proc. Natl. Acad. Sci. USA 90巻: 6444~6448頁においてより詳細に記載される。
特定の実施形態において、本明細書において提供される配列情報を用いて、抗ALPP/ALPPL2抗体はユニボディとして構築され得る。ユニボディは、特定の小さな抗体のフォーマットよりも長い治療濃度域が予測される、安定した、より小さな抗体のフォーマットを生成する抗体技術である。特定の実施形態において、ユニボディは、抗体のヒンジ領域の排除によりIgG4抗体から生成される。完全な大きさのIgG4抗体とは異なり、分子断片の半分は、非常に安定しており、ユニボディと称される。IgG4分子を半分にすることで、ユニボディ上に、標的に結合することができる領域が1つだけ残る。ユニボディを生成する方法は、PCT国際公開第2007/059782号において詳細に記載され、これはその全体において参照により本明細書に組み込まれる(例えば、Kolfschotenら、(2007年) Science 317巻: 1554~1557頁もまた参照されたい)。
特定の実施形態において、本明細書において提供される配列情報は、ALPP/ALPPL2に結合するアフィボディ分子を構築するために使用される。アフィボディ分子は、ブドウ球菌タンパク質AのIgG結合ドメインの1つに由来する、58-アミノ酸残基タンパク質ドメインに基づく、親和性タンパク質のクラスである。この3つのヘリックス束のドメインは、組み合わせのファージミドライブラリーの構築のための足場として使用され、これらのライブラリーからは、所望の分子を標的化するアフィボディ変異体が、ファージディスプレイ技術を用いて選択され得る(例えば、Nordら、(1997年) Nat. Biotechnol. 15巻: 772~777頁; Ronmarkら、(2002年) Eur. J. Biochem., 269巻: 2647~2655頁を参照されたい)。アフィボディの詳細及び製造方法は、当業者に公知である(例えば、全体において参照により本明細書に組み込まれる、米国特許第5,831,012号を参照されたい)。
上記で説明したように、結合活性の増大のための選択は、標的抗原のための抗体(例えば、ALPPL2、特に、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLFの1つ以上に結合されるエピトープ)の親和性の測定を伴うことができる。このような測定を行う方法は、当業者に周知である。簡潔には、例えば、抗体のKdは、例えばBIAcore、表面プラズモン共鳴に基づくバイオセンサーにおいて標的細胞に結合する動力学から決定される。この技術のために、抗原又は細胞(例えば、ALPPL2を発現している細胞)は、質量変化を検出することができる、誘導体化されたセンサチップに繋がれる。抗体がセンサチップ上を通過すると、抗体は、定量化可能な質量の増加を結果としてもたらす抗原に結合する。抗体の濃度に応じた結合速度の測定を用いて、結合速度定数(kon)を計算することができる。結合フェーズ後、緩衝液がチップの上を通過し、抗体の解離の速度(Koff)が決定される。Konは典型的に1.0×102から5.0×106の範囲で、Koffは1.0×10-1から1.0×10-6の範囲で測定される。平衡定数Kdは頻繁に、Koff/konとして計算され、したがって、典型的には、10-5から10-12の範囲で測定される。この方法で測定される親和性は、蛍光消光滴定により溶液中で測定される親和性と十分に相関する。
本明細書に記載されている原型の抗ALPP/ALPPL2抗体(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)は、ALPPL2を発現している癌細胞(例えば、限定されないが、中皮腫、精巣癌、子宮内膜癌、卵巣癌、膵臓癌、及び非小細胞肺癌等の癌の細胞)に特異的に結合する。抗体は、(例えば、ALPPL2を発現している癌細胞の成長及び/又は増殖を阻害するために)治療として単独で使用することができ、又は、ALPPL2を発現する様々な癌細胞(例えば、単離細胞、癌幹細胞、転移細胞、固形腫瘍細胞等)へのエフェクター(例えば、細胞毒素、標識、放射性核種、リガンド、抗体、薬物、リポソーム、ナノ粒子、ウイルス粒子、サイトカイン、免疫調節分子等)の効果的及び特異的な送達をもたらす、エフェクター形成イムノコンジュゲートに結合され得る。
検出可能な標識-撮像組成物
特定の実施形態において、抗ALPP/ALPPL2イムノコンジュゲートは、腫瘍部位に検出可能な標識を指向するために使用され得る。これにより、腫瘍の検出及び/又は局在化を促進することができる。それは、原発腫瘍、又は特定の実施形態において、ALPPL2を発現している癌によって生成される二次腫瘍(例えば、限定されないが、中皮腫、精巣癌、子宮内膜癌、卵巣癌、膵臓癌、及び非小細胞肺癌等の癌の細胞)を検出するために効果的であり得る。
別の実施形態において、エフェクターは、細胞上でイオン化放射線の細胞毒性効果を増強する放射線増感剤を含み得る(例えば、60Co又はX線供給源により生成され得るもの等)。多数の放射線増感剤が公知であり、限定されないが、ベンゾポルフィリン誘導体化合物(例えば米国特許第5,945,439号を参照)、1,2,4-ベンゾトリアジンオキシド(例えば米国特許第5,849,738号を参照)、特定のジアミンを含有する化合物(例えば米国特許第5,700,825号を参照)、BCNT(例えば米国特許第5,872,107号を参照)、放射線増感性ニトロ安息香酸アミド誘導体(例えば米国特許第4,474,814号を参照)、様々な複素環誘導体(例えば米国特許第5,064,849号を参照)、白金錯体(例えば米国特許第4,921,963号を参照)等を含む。
特定の実施形態において、エフェクターは、αエミッタ、即ち、アルファ粒子を放出する放射性同位体を含み得る。アルファエミッタは、癌の治療に有効であることが、近年において示されている(例えば、McDevittら、(2001年) Science 294巻:1537~1540頁; Ballangrudら(2001年) Cancer Res. 61巻: 2008~2014頁; Borchardtら、(2003年) Cancer Res. 63巻: 5084~50頁を参照されたい)。適切なアルファエミッタには、限定されないが、Bi、213Bi、211At等が含まれる。
本明細書に記載されている医薬及び/又は放射標識の多くは、キレートとして提供され得る。キレート分子は、典型的には、本明細書に記載されている抗ALPP/ALPPL2抗体(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)に結合されるエピトープタグに特異的に結合する、分子(例えば、ビオチン、アビジン、ストレプトアビジン等)に結合される。
本明細に記載されている抗ALPP/ALPPL2(例えば、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA、及び/又はM25wtLF)は、治療剤、放射線を放出する化合物、植物、真菌又は細菌起源の細胞毒性分子、生物学的タンパク質、及びそれらの混合物を含む様々な細胞毒性剤及び/又は細胞増殖抑制剤を送達するために使用することができる。特定の実施形態において、細胞毒性剤は、例えば、小有機分子、細胞毒性タンパク質又はペプチド、放射線エミッタ、例えば、上記される短距離高エネルギーαエミッタ等である細胞内活性型細胞毒性剤を含み得る。さらなる代表的な治療剤には、放射性同位体、化学療法剤、免疫調節剤、抗血管新生剤、抗増殖剤、アポトーシス促進剤及び細胞溶解酵素(例えば、RNAse)が含まれる。薬剤はまた、免疫調節剤、抗血管新生剤、抗増殖剤、又はアポトーシス促進剤をコードする遺伝子等の治療用核酸を含むことができる。これらの薬物に関する記載は相互排他的ではなく、したがって、治療剤は、上記用語の1つ以上を用いて記載することができる。例えば、選択された放射性同位元素はまた細胞毒素である。種々の実施形態において、治療剤は、上記のいずれかの薬学的に許容される塩、酸又は誘導体として調製され得る。
ある特定の実施形態では、抗ALPP/ALPPL2抗体を免疫調節性に結合し、癌細胞/腫瘍部位で免疫調節性を局在化するように機能させる。免疫応答を活性化し得る多くの免疫調節剤が当業者に公知である。例示的であるが、非限定的な一実施形態では、免疫調節性は、抗CD3抗体を含む。抗CD3モノクローナル抗体は、インビトロでヒトT細胞の細胞増殖を誘発し、ヒトT細胞クローン及びヒト末梢血リンパ球による特異的及び非特異的細胞溶解を活性化する。抗CD3のインビボ投与は、UV誘発マウス線維肉腫の腫瘍増殖を防ぐ。
ある特定の実施形態では、エフェクターは、ウイルス粒子(例えば繊維状ファージ、アデノ関連ウイルス(AAV:adeno-associated virus)、レンチウイルス等)を含む。抗体は、ウイルス粒子にコンジュゲートしてもよく、及び/又はウイルス粒子(例えば繊維状ファージ)の表面上に発現させてもよい。ウイルス粒子は加えて、標的細胞(例えばALPPL2を発現する癌細胞)に送達される核酸を含んでもよい。細胞に核酸を送達するためのウイルス粒子の使用は、WO99/55720、米国特許第6,670,188号、同第6,642,051号及び同第6,669,936号で詳細に記載されている。
ある特定の実施形態では、エフェクターは、別の抗体(例えば第2の抗体)を含む。本明細書に記載する抗ALPPL2抗体への抗体エフェクターの結合は、二重特異性抗体を提供し得る。ある特定の実施形態では、抗体エフェクターは、(抗ALPPL2抗体により結合されるエピトープとは)異なるALPPL2のエピトープ、又はALPPL2を発現する細胞上の異なる標的に結合する抗体を含む。したがって、ある特定の実施形態では、エフェクターは、中皮腫細胞、精巣癌細胞、子宮内膜癌細胞並びにある特定の膵臓癌細胞、卵巣癌細胞及び非小細胞肺癌細胞等の癌細胞の表面上に発現するマーカーに結合する抗体を含む。
当業者は、本明細書に記載する抗ALPP/ALPPL2抗体(例えばM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLF)及びエフェクター分子が、任意の順序で共に接続され得ることを理解する。したがって、抗体が単鎖ポリペプチドである場合、エフェクター分子は、標的化分子のアミノ末端又はカルボキシ末端のいずれかに接続してもよい。抗体が1つを超えるアミノ酸鎖を含む場合、エフェクター分子は、抗体を構成する任意のペプチドのアミノ末端又はカルボキシル末端のいずれかに接続してもよい。また、結合が分子の各々の活性を妨害しない限り、抗体は、エフェクター分子の内部領域に接続してもよく、又は反対にエフェクター分子は、抗体の内部位置に接続してもよい。
ある特定の実施形態では、本明細書に記載する抗ALPP/ALPPL2抗体(例えばM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLF)は、エフェクター分子(例えば細胞毒、標識、リガンド、薬物、リポソーム等)に化学的にコンジュゲートすることができる。分子を化学的にコンジュゲートする手段は、当業者に周知である。
(CO-Alk1-Sp1-Ar-Sp2-Alk2-C(Z1=Q-Sp)
を有するリンカーが挙げられるが、これに限定されず、式中、Alk1及びAlk2は独立して、結合又は分岐若しくは非分岐(C1~C10)アルキレン鎖であり;Sp1は、結合、--S--、--O--、--CONH--、--NHCO--、--NR'--、--N(CH2CH2)2N--又は--X--Ar--Y--(CH2)n--Zであり、ここで、X、Y及びZは独立して、結合、--NR'--、--S--又は--O--であり、ただしn=0である場合、Y及びZの少なくとも1つは、結合でなければならず、Ar'は、任意選択で(C1~C5)アルキル、(C1~C4)アルコキシ、(C1~C4)チオアルコキシ、ハロゲン、ニトロ、--COOR'、--CONHR'、--(CH2)nCOOR'、--S(CH2)nCOOR'、--O(CH2)nCONHR'又は--S(CH2)nCONHR'のうちの1つ、2つ又は3つの基で置換される1,2-、1,3-又は1,4-フェニレンであり、ただし、Alk'が結合である場合、Sp1は結合であり;nは、0~5の整数であり;R'は、任意選択で--OH、(C1~C4)アルコキシ、(C1~C4)チオアルコキシ、ハロゲン、ニトロ、(C1~C3)ジアルキルアミノ又は(C1~C3)トリアルキルアンモニウム-A-のうちの1つ又は2つの基により置換される分岐又は非分岐(C1~C5)鎖であり、ここで、A-は、塩を完成する薬学的に許容されるアニオンであり;Arは、任意選択で、n及びR'が本明細書中上記に定義される通りである(C1~C6)アルキル、(C1~C5)アルコキシ、(C1~C4)チオアルコキシ、ハロゲン、ニトロ、--COOR'、--CONHR'、--O(CH2)nCOOR'、--S(CH2)nCOOR'、--O(CH2)nCONHR'若しくは--S(CH2)nCONHR'又は1,2-、1,3-、1,4-、1,5-、1,6-、1,7-、1,8-、2,3-、2,6-若しくは2,7-ナフチリデン若しくは
Arは、任意選択で、n及びR'が本明細書中上記に定義される通りである(C1~C6)アルキル、(C1~C5)アルコキシ、(C1~C4)チオアルコキシ、ハロゲン、ニトロ、--COOR'、--CONHR'、--O(CH2)nCOOR'、--S(CH2)nCOOR'、--O(CH2)nCONHR'若しくは--S(CH2)nCONHR'のうちの1つ、2つ若しくは3つの基で置換される1,2-、1,3-若しくは1,4-フェニレンであるか、又はArは、各々任意選択で(C1~C6)アルキル、(C1~C5)アルコキシ、(C1~C4)チオアルコキシ、ハロゲン、ニトロ、--COOR'、--CONHR'、--O(CH2)nCOOR'、--S(CH2)nCOOR'、--O(CH2)nCONHR'若しくは--S(CH2)nCONHR'のうちの1つ、2つ、3つ若しくは4つの基で置換される1,2-、1,3-、1,4-、1,5-、1,6-、1,7-、1,8-、2,3-、2,6-若しくは2,7-ナフチリデンであり;
Z1は、任意選択で(C1~C5)アルキル、(C1~C4)アルコキシ、(C1~C4)チオアルコキシ、ハロゲン、ニトロ、--COOR'、--CONHR'、--O(CH2)nCOOR'、--S(CH2)nCOOR'、--O(CH2)nCONHR'又は--S(CH2)nCONHR'のうちの1つ、2つ又は3つの基で置換される(C1~C5)アルキル又はフェニルであり;Alk2及びSp2は共に結合であり;Sp及びQは上記に定義される通りである。
様々な実施形態で、療法剤は、例えば上記に記載するように、抗体に化学的にコンジュゲートされるが、他の実施形態では、エフェクターは、療法組成物、例えば薬物、核酸(例えばアンチセンス核酸及びRNAi又は細胞に送達されるべき別の核酸)又は好ましくは循環系への直接的な曝露から遮蔽される別の療法部分を含有する被包システム、例えばウイルスキャプシド、リポソーム又はミセルを含み得る。抗体に結合したリポソームを調製する手段は、当業者に周知である(例えば米国特許第4,957,735号;Connorら(1985年)、Pharm. Ther., 28、341~365頁等を参照のこと)。
ある特定の実施形態では、エフェクターは、抗体に、又はエピトープタグに結合されるキレートを含む。抗ALPP/ALPPL2抗体は、対応するエピトープタグ又は抗体を有するため、キレートへの抗体の単純な接触は抗体とエフェクターとの結合をもたらす。部分が使用される前に組み合わせ工程を行ってもよく(標的化策)、又はキレートが送達される前に標的組織を抗体に結合してもよい。様々な標的化部分にカップリングするために好適なキレートを生成する方法は、当業者に周知である(例えば米国特許第6,190,923号、同第6,187,285号、同第6,183,721号、同第6,177,562号、同第6,159,445号、同第6,153,775号、同第6,149,890号、同第6,143,276号、同第6,143,274号、同第6,139,819号、同第6,132,764号、同第6,123,923号、同第6,123,921号、同第6,120,768号、同第6,120,751号、同第6,117,412号、同第6,106,866号、同第6,096,290号、同第6,093,382号、同第6,090,800号、同第6,090,408号、同第6,088,613号、同第6,077,499号、同第6,075,010号、同第6,071,494号、同第6,071,490号、同第6,060,040号、同第6,056,939号、同第6,051,207号、同第6,048,979号、同第6,045,821号、同第6,045,775号、同第6,030,840号、同第6,028,066号、同第6,022,966号、同第6,022,523号、同第6,022,522号、同第6,017,522号、同第6,015,897号、同第6,010,682号、同第6,010,681号、同第6,004,533号及び同第6,001,329号を参照のこと)。
抗体及び/又はエフェクターが比較的短い場合(例えば約50個未満のアミノ酸)、それらは標準の化学ペプチド合成技術を使用して合成することができる。両方の分子が比較的短い場合、キメラ分子は、単一の隣接したポリペプチドとして合成することができる。或いは、標的化分子及びエフェクター分子を、別々に合成し、その後、1つの分子のアミノ末端と他の分子のカルボキシル末端との縮合により融合させ、これによりペプチド結合を形成してもよい。或いは、標的化分子及びエフェクター分子を、各々、ペプチドスペーサー分子の一端と縮合させ、これにより隣接した融合タンパク質を形成してもよい。
本明細書に記載する抗ALPP/ALPPL2抗体(例えばM25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLF)及び/又はそれらのイムノコンジュゲートは、予防処置のための、しかし主には療法処置のための非経口、局所、経口若しくは局部投与(例えば腫瘍部位に注射される)、エアロゾル投与又は経皮投与に有用である。医薬組成物は、投与方法によって様々な単位投与形態で投与することができる。例えば、経口投与に好適な単位投与形態は、粉末、錠剤、丸薬、カプセル及びトローチ剤を含む。本明細書に記載する抗体及び/又はそのイムノコンジュゲート並びに本明細書に記載する抗体及び/又はそのイムノコンジュゲートを含む医薬組成物は、経口投与される場合、好ましくは消化から保護されることが認識される。これは当業者に公知のいくつかの手段により、例えばタンパク質を酸性加水分解及び酵素加水分解に抵抗性にするためにタンパク質を組成物と複合体化することにより、又はリポソーム等の適切な抵抗性担体中にタンパク質を包装することにより、達成することができる。タンパク質を消化から保護する手段は、本分野で周知である。
放射性又は他のエフェクターが診断及び/又は療法剤として使用される場合、放射標識化合物は多くの場合貯蔵寿命が乏しいこと及び/又は使用される放射性核種の短い半減期のために、すぐ使用できる組成物を使用者の自由に使用できる状態にしておくことは多くの場合不可能である。かかる場合、使用者は、病院、医師の執務室又は検査室で放射性核種での標識化反応を行うことができる。次いで、この目的又は他の目的のために、様々な反応成分は、いわゆる「キット」の形態で使用者に提供され得る。キットは好ましくは、使用者が、自分が自由に使用できる施設を使用することによりキットから所望の組成物を調製することができるように、所望の反応を行うために必要な操作は可能な限り単純であるべきであるように設計される。それゆえ、また、本発明は、本発明に従う組成物を調製するためのキットに関連する。
ある特定の実施形態では、本明細書に記載する抗体は、CAR-T細胞療法のための構築物/細胞の創出で利用することができる。CAR-T細胞療法は、癌を有する哺乳動物(例えば癌患者)への、キメラ抗原受容体(CAR)を発現し、(CARと相互作用する)腫瘍細胞に働き、腫瘍細胞のアポトーシスをもたらす遺伝子操作した細胞(例えばT細胞、ナチュラルキラー(NK:natural killer)細胞、細胞傷害性Tリンパ球(CTL:cytotoxic T lymphocyte)、調節性T細胞等)の投与を含む細胞免疫療法である。
様々な実施形態では、キメラ抗原受容体構築物は、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLF抗体により結合されるALPPに及び/若しくはALPPL2に並びに/又はALPPのドメインに及び/若しくはALPPL2に特異的に結合する標的特異的結合エレメント(そうでなければ抗原結合性部分とも呼ばれる)を含む。ある特定の実施形態では、標的特異的結合エレメントは、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLF抗体からの結合ドメインを含む。ある特定の実施形態では、標的特異的結合エレメントは、M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M2
5AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLF抗体を含む。
膜貫通ドメインについて、CARは、CARの細胞外ドメインに融合される膜貫通ドメインを含むように設計され得る。一実施形態では、天然でCARのドメインの1つと関連している膜貫通ドメインが使用される。一部の場合、膜貫通ドメインは、受容体複合体の他のメンバーとの相互作用を最小限にするために、かかるドメインの、同じ又は異なる表面膜タンパク質の膜貫通ドメインへの結合を避けるようにアミノ酸置換により選択又は改変してもよい。
CARの細胞質ドメイン又はそうでなければ細胞内シグナルドメインは、CARが入れられた免疫細胞の正常なエフェクター機能の少なくとも1つの活性化の要因である。「エフェクター機能」という用語は、細胞の特殊化機能を指す。例えば、T細胞のエフェクター機能は、細胞溶解活性又はサイトカインの分泌を含むヘルパー活性であり得る。したがって、「細胞内シグナルドメイン」という用語は、エフェクター機能シグナルを伝達し、細胞が特殊化機能を行うことをもたらすタンパク質の部分を指す。通常、細胞内シグナルドメインの全体が使用され得るが、多くの場合、鎖全てを使用する必要はない。細胞内シグナルドメインのトランケートされた部分が使用される点で、かかるトランケートされた部分は、それがエフェクター機能シグナルを伝達する限り、インタクトな鎖の代わりに使用することができる。細胞内シグナルドメインという用語はしたがって、エフェクター機能シグナルを伝達するのに十分な細胞内シグナルドメインの任意のトランケートされた部分を含むことを意味する。
様々な実施形態では、本明細書に記載するCARの配列を含むDNA構築物が提供される。ある特定の実施形態では、CARは、抗体M25ADLF、M25ADLFEG、M25ADLFDS、M25FYIA、M25FYIAEG、M25FYIADS、M25、M25EG、M25DS、M25AELF、M25AELFEG、M25AELFDS、M25ADL99P、M25ADL99G、M25ADS95R、M25ADD28G、M25ADS91G、M25ADY93H、M25ADYHSRLF、M25GRITSGFYGDwtLC、M25FSITSGFYGDwtLC、M253018IA、M253018LF、M25AD、M25ADX、ALPPL2rd3_1、ALPPL2rd3_2、M25AGIA、M25AGLF、M25ASIA、M25ASLF、M25ASwt、M25AVIA、M25AVLF、M25ALIA、M25ALLF、M25wtIA及び/又はM25wtLFにより結合されるALPPに、及び/若しくはALPPL2に、並びに/又はALPP及び/若しくはALPPL2のドメインに特異的に結合する抗原結合性部分を含み、抗原結合性部分の核酸配列は、細胞内ドメインの核酸配列に作動可能に連結される。本発明のCARで使用することができる例示的な細胞内ドメインとして、CD3ゼータ、CD28、4-1BB等の細胞内ドメインが挙げられるが、これらに限定されない。一部の場合、CARは、CD3ゼータ、CD28、4-1BB等の任意の組合せを含み得る。
ある特定の実施形態では、本発明の本明細書に記載する免疫細胞(例えばT細胞)の増殖(expansion)及び遺伝子改変の前に、T細胞源を対象から得る。T細胞は、末梢血単核球、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位からの組織、腹水、胸水、脾臓組織及び腫瘍を含むいくつかの供給源から得ることができる。本発明のある特定の実施形態では、本分野で入手可能な任意の数のT細胞株を使用してもよい。本発明のある特定の実施形態では、T細胞は、当業者に公知の任意の数の技術、例えばFICOLL(商標)分離を使用して対象から回収される一単位の血液から得ることができる。例示的な一実施形態では、個人の循環血液からの細胞はアフェレーシスにより得られる。アフェレーシス生成物は典型的に、T細胞、単球、顆粒球、B細胞を含むリンパ球、他の有核白血球、赤血球及び血小板を含有する。一実施形態では、アフェレーシスにより回収した細胞は、血漿画分を除去するために、及び細胞を次の加工工程のために適切な緩衝液又は媒体に入れるために洗浄してもよい。本発明の一実施形態では、細胞をリン酸緩衝液(PBS:phosphate buffered saline)で洗浄する。代替の実施形態では、洗浄溶液はカルシウムを欠き、かつマグネシウムを欠く場合があるか、又は全てではないとしても多くの二価カチオンを欠く場合がある。ここでもまた、驚くべきことに、カルシウムの非存在下での初期活性化工程は、活性化の拡大をもたらし得る。当業者が容易に理解するように、洗浄工程は、当業者に公知の方法により、例えば製造業者の使用説明書に従って半自動化「フロースルー」遠心分離(例えばCobe 2991 cell processor、Baxter CytoMate又はHaemonetics Cell Saver 5)を使用することにより達成することができる。洗浄後、細胞を様々な生体適合性緩衝液、例えばCa2+非含有Mg2+非含有PBS、PlasmaLyte A又は緩衝液を伴う若しくは伴わない他の生理食塩水中に再懸濁してもよい。或いは、アフェレーシス試料の望ましくない成分を除去し、細胞を培養培地中に直接再懸濁してもよい。
望ましいCAR(例えば本明細書に記載するCAR)を発現するためのT細胞の遺伝子改変の前であろうと、又は後であろうと、T細胞は、例えば米国特許第6,352,694号、同第6,534,055号、同第6,905,680号、同第6,692,964号、同第5,858,358号、同第6,887,466号、同第6,905,681号、同第7,144,575号、同第7,067,318号、同第7,172,869号、同第7,232,566号、同第7,175,843号、同第5,883,223号、同第6,905,874号、同第6,797,514号、同第6,867,041号及び米国特許公開公報第2006/0121005号で記載されている方法を一般的に使用して活性化及び増殖させることができる。
様々な実施形態では、本明細書に記載するCARをコードするベクターを形質導入した細胞が提供される。例示的な一実施形態では、レンチウイルスベクター(LV:lentiviral vector)を形質導入したT細胞が提供され、LVは本明細書に記載する抗ALPP/ALPPL2 CARをコードする。それゆえ、一部の場合、形質導入したT細胞は、CAR媒介T細胞応答を誘発し得る。
本願発明者らは、現存の腫瘍細胞及び天然組織微小環境に存在している原位置の腫瘍細胞に高い特異性で結合するヒトモノクローナル抗体を特定するためにサブトラクティブファージ抗体ディスプレイライブラリー選択を以前に使用した。不治の奇病である中皮腫についての本願発明者らの研究で、本願発明者らは、中皮腫細胞株及び組織に特異的に結合するが、研究した任意の他の細胞株には結合しない新しい抗体を特定した。
Claims (32)
- ヒトの胎盤に発現するALPPL2に特異的に結合する、単離された抗体又はその断片であって、少なくとも1つの重鎖可変領域(VH)及び少なくとも1つの軽鎖可変領域(VL)を含み、前記重鎖可変領域及び前記軽鎖可変領域が、アミノ酸配列GFTFSSYAからなるVH CDR1、アミノ酸配列ISYDGSNKからなるVH CDR2、及びアミノ酸配列AKEGDSSRWSYDLからなるVH CDR3、並びにアミノ酸配列SSDVGGYNYからなるVL CDR1、アミノ酸配列DVTからなるVL CDR2、及びアミノ酸配列SSYTSTSTLVVからなるVL CDR3を含む、抗体又はその断片。
- アミノ酸配列QVQLQQSGGGLVKPGGSLRLSCAAS GFTFSSYAMHWVRQAPGKGLEWVAV ISYDGSNKYYADSVKGRFTISRDNS KNTLYLQMDSLRAEDTAVYFCAKEG DSSRWSYDLWGRGTLVTVSSからなる重鎖可変領域(VH)、及び
アミノ酸配列QSALTQPASVSGSPGQSITISCTGTS SDVGGYNYVSWYQQHPGKAPKVMIYD VTNRPSGVSNRFSGSKSGNTASLTIS GLQAEDEADYYCSSYTSTSTLVVFGG GTKLTVLからなる軽鎖可変領域(VL)を含む、請求項1に記載の抗体。 - 実質的にインタクトな免疫グロブリンである、請求項1又は2に記載の抗体。
- IgA、IgE又はIgGを含む、請求項3に記載の抗体。
- IgGを含む、請求項3に記載の抗体。
- IgG1を含む、請求項3に記載の抗体。
- Fv、Fab、(Fab')2、(Fab')3、IgGΔCH2、及びミニボディからなる群から選択される、請求項1又は2に記載の抗体。
- 一本鎖抗体である、請求項1又は2に記載の抗体。
- ヒトscFvである、請求項8に記載の抗体。
- 前記重鎖可変領域が、アミノ酸配列(Gly4Ser)3(配列番号82)を含むか又はそれからなるリンカーによって前記軽鎖可変領域に接続されている、請求項9に記載の抗体。
- 第2の抗体、検出可能な標識、細胞毒性剤又は細胞増殖抑制剤、薬物を含有するリポソーム、放射性核種、薬物、プロドラッグ、免疫調節剤、ウイルス粒子、サイトカイン、及びキレートからなる群から選択されるエフェクターに結合している、請求項1~10のいずれか一項に記載の抗体を含むイムノコンジュゲート。
- 前記抗体が、細胞毒性剤及び/又は細胞増殖抑制剤に結合している、請求項11に記載のイムノコンジュゲート。
- 前記抗体が、直接的に又はリンカーを介して、以下:
前記薬物;
前記薬物を含有する脂質又はリポソーム;
前記薬物を含む高分子薬物担体;及び
前記薬物を含むナノ粒子薬物担体
の1つ以上に結合している、請求項11に記載のイムノコンジュゲート。 - 前記薬物が抗癌剤である、請求項12又は13に記載のイムノコンジュゲート。
- 前記薬物が、オーリスタチン、ドラスタチン-10、天然物であるドラスタチン-10の合成誘導体、及びメイタンシン又はメイタンシン誘導体からなる群から選択される薬物を含むか;又は
前記薬物が、モノメチルオーリスタチンF(MMAF)、オーリスタチンE(AE)、モノメチルオーリスタチンE(MMAE)、vcMMAE、及びvcMMAFからなる群から選択される薬物を含むか;又は
前記薬物が、メルタンシン(DM1)、DM3、及びDM4からなる群から選択されるメイタンシンを含むか;又は
前記薬物が、カリケアマイシン、デュオカルマイシン、及びピロロベンゾジアゼピンからなる群から選択されるか;又は
前記薬物が、カリケアマイシン又はカリケアマイシン類似体を含むか;又は
前記薬物がデュオカルマイシンを含むか;又は
前記薬物が、デュオカルマイシンA、デュオカルマイシンB1、デュオカルマイシンB2、デュオカルマイシンC1、デュオカルマイシンC2、デュオカルマイシンD、デュオカルマイシンSA、シクロプロピルベンゾインドールデュオカルマイシン(CC-1065)、センタナマイシン、ラケルマイシン、アドゼレシン、ビゼレシン、及びカルゼレシンからなる群から選択されるデュオカルマイシンを含むか;又は
前記薬物が、ピロロベンゾジアゼピンを含むか;又は
前記薬物が、アントラマイシン、マゼトラマイシン、トマイマイシン、プロトラカルシン、チカマイシン、ネオトラマイシンA、ネオトラマイシンB、DC-81、シビロマイシン、ポロトラマイシンA、ポロトラマイシンB、シバノマイシン、アブベイマイシン、SG2000、及びSG2285からなる群から選択される薬物を含むか;又は
前記薬物が、オーリスタチン、ドラスタチン、コルヒチン、コンブレタスタチン、及びmTOR/PI3K阻害剤からなる群から選択されるか;又は
前記薬物が、フルオロウラシル(5-FU)、カペシタビン、5-トリフルオロメチル-2'-デオキシウリジン、メトトレキセートナトリウム、ラルチトレキセド、ペメトレキセド、シトシンアラビノシド、6-メルカプトプリン、アザチオプリン、6-チオグアニン(6-TG)、ペントスタチン、リン酸フルダラビン、クラドリビン、フロクスウリジン(5-フルオロ-2)、リボヌクレオチドレダクターゼ阻害剤(RNR)、シクロホスファミド、ネオサル、イフォスファミド、チオテパ、1,3-ビス(2-クロロエチル)-1-ニトロソウレア(BCNU)、1-(2-クロロエチル)-3-シクロヘキシル-1ニトロソウレア、メチル(CCNU)、ヘキサメチルメラミン、ブスルファン、プロカルバジンHCL、ダカルバジン(DTIC)、クロラムブシル、メルファラン、シスプラチン、カルボプラチン、オキサリプラチン、ベンダムスチン、カルムスチン、クロロメチン、ダカルバジン(DTIC)、フォテムスチン、ロムスチン、マンノスルファン、ネダプラチン、ニムスチン、プレドニムスチン、ラニムスチン、サトラプラチン、セムスチン、ストレプトゾシン、テモゾロミド、トレオスルファン、トリアジクオン、トリエチレンメラミン、チオTEPA、四硝酸トリプラチン、トロフォスファミド、ウラムスチン、ドキソルビシン、クエン酸ダウノルビシン、ミトキサントロン、アクチノマイシンD、エトポシド、トポテカンHCL、テニポシド(VM-26)、イリノテカンHCL(CPT-11)、カンプトテシン、ベロテカン、ルビテカン、ビンクリスチン、硫酸ビンブラスチン、酒石酸ビノレルビン、硫酸ビンデシン、パクリタキセル、ドセタキセル、ナノ粒子パクリタキセル、アブラキサン、イクサベピロン、ラロタキセル、オルタタキセル、テセタキセル、ビンフルニン、レチノイン酸、レチノイン酸誘導体、ドキシルビシン、ビンブラスチン、ビンクリスチン、イフォスファミド、シスプラチン、5-フルオロウラシル、カンプトテシン誘導体、インターフェロン、タモキシフェン、及びタキソールからなる群、又はパミドロネート二ナトリウム、アナストロゾール、エキセメスタン、エピルビシン、トレミフェン、レトロゾール、トラスツズマブ、メゲストロールタモキシフェン、酢酸ゴセレリン、及びゾレドロン酸からなる抗癌化合物の群から選択される、
請求項14に記載のイムノコンジュゲート。 - 前記抗体が細胞毒素に結合しているか;又は
前記抗体が、ジフテリア毒素、シュードモナス外毒素、リシン、アブリン、サポリン、及びチミジンキナーゼからなる群から選択される細胞毒素に結合しているか;又は
前記抗体が、免疫調節剤に結合しているか;又は
前記抗体が、抗CD3抗体を含む免疫調節剤に結合しているか;又は
前記抗体が、免疫チェックポイントを阻止する免疫調節剤に結合しているか;又は
前記抗体が、抗CTLA4抗体、抗PDL1抗体、抗PDL2抗体、抗ICOS抗体、及び抗BTLA抗体からなる群から選択される抗体を含む免疫調節剤に結合しているか;又は
前記抗体が、イピリムマブ、ニボルマブ、及びペンブロリズマブからなる群から選択される抗体のVH及びVLドメインを含む抗体である免疫調節剤に結合している、
請求項11に記載のイムノコンジュゲート。 - 前記抗体が、99Tc、97Ru、95Ru、94Tc、90Y、89Zr、86Y、77Br、77As、76Br、75Se、72As、68Ga、67Ga、67Cu、64Cu、62Cu、59Fe、58Co、57Co、52Mn、52Fe、51Cr、47Sc、3H、35S、33P、32P、225Ac、224Ac、223Ra、213Bi、212Pb、212Bi、211At、203Pb、203Hg、201Tl、199Au、198Au、197Pt、18F、189Re、188Re、186Re、177Lu、175Yb、172Tm、169Yb、169Er、168Tm、167Tm、166Ho、166Dy、165Tm、165Dy、161Tb、15O、15N、159Gd、157Gd、153Sm、153Pb、151Pm、14C、149Pm、143Pr、142Pr、13N、133I、131In、131I、127Te、126I、125Te、125I、124I、123I、122Te、121Te、121Sn、11C、113In、111In、111Ag、109Pd、107Hg、105Ru、105Rh、及び103Ruからなる群から選択される同位体を含むキレートに結合している、請求項11に記載のイムノコンジュゲート。
- 前記抗体が検出可能な標識に結合している、請求項11に記載のイムノコンジュゲート。
- 薬学的に許容される担体及び請求項1~10のいずれか一項に記載の抗体;及び/又は
薬学的に許容される担体及び請求項11~18のいずれか一項に記載のイムノコンジュゲート
を含む医薬製剤。 - 経口投与、経鼻投与、直腸投与、腹腔内注射、血管内注射、皮下注射、経皮投与、及び筋肉内注射からなる群から選択される経路を介した投与用に製剤化される、請求項19に記載の医薬製剤。
- 請求項11~18のいずれか一項に記載の抗ALPPL2イムノコンジュゲートを含む、細胞集団における腫瘍開始細胞を減少する、並びに/又はALPPL2を発現する細胞の成長及び/若しくは増殖を阻害するための組成物であって、前記イムノコンジュゲートを含むエフェクターが、細胞増殖抑制活性及び/又は細胞毒性活性及び/又は免疫調節活性を有する、組成物。
- 前記細胞が、中皮腫、精巣癌、子宮内膜癌、並びに卵巣癌、膵臓癌、及び非小細胞肺癌のサブセットからなる群から選択される癌細胞である、請求項21に記載の組成物。
- 請求項1~10のいずれか一項に記載の抗体を含むキメラ抗原受容体(CAR)。
- 前記抗体;
膜貫通ドメイン;
少なくとも1つの共刺激シグナル伝達領域;及び
CD3ゼータシグナル伝達ドメイン
を含む、請求項23に記載のキメラ抗原受容体。 - 前記共刺激シグナル伝達領域が、CD27、CD2S、4-1 BB、OX40、CD30、CD40、PD-1、ICOS、リンパ球機能関連抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、CD83と特異的に結合するリガンド、及びそれらの任意の組み合わせからなる群から選択される共刺激分子の細胞内ドメインを含む、請求項24に記載のキメラ抗原受容体。
- 前記膜貫通ドメインが、CD8ヒンジドメイン又はその断片を含む、請求項24又は25に記載のキメラ抗原受容体。
- 請求項23~26のいずれか一項に記載のキメラ抗原受容体(CAR)をコードする核酸配列を含む細胞。
- T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、及び調節性T細胞からなる群から選択される;及び/又は
抗原結合ドメインがALPPL2を発現する細胞に結合する場合に、前記細胞が抗癌免疫応答を示す、請求項27に記載の細胞。 - 請求項27又は28に記載の遺伝子操作された細胞(CAR-T細胞)、及び薬学的に許容される担体を含む、哺乳動物において癌を治療するための医薬組成物。
- 請求項1~10のいずれか一項に記載の単離された抗体若しくはその断片、又は請求項23~26のいずれか一項に記載のキメラ抗原受容体(CAR)を発現するように遺伝子改変された細胞を含む組成物であって、
哺乳動物において、ALPPL2、又はその断片を発現する標的細胞集団又は組織に対するT細胞媒介性免疫応答を刺激するための;又は
ALPPL2、又はその断片を発現する腫瘍に対する抗腫瘍免疫を付与するための;又は
ALPPL2、又はその断片を発現する細胞を含む癌を有する哺乳動物を治療するための;又は
癌と診断された哺乳動物において遺伝子操作されたT細胞の持続的集団を生成するための;又は
癌と診断された哺乳動物において、遺伝子操作されたT細胞の集団を増殖させるための;又は
癌を治療するための、
組成物。 - 請求項11~17のいずれか一項に記載の抗ALPPL2イムノコンジュゲートを含む組成物であって、前記イムノコンジュゲートを含むエフェクターが、細胞増殖抑制活性及び/又は細胞毒性活性を有する、組成物の、細胞集団における腫瘍開始細胞を減少する、並びに/又はALPPL2を発現する細胞の成長及び/若しくは増殖を阻害するための医薬の製造における使用。
- 請求項23~26のいずれか一項に記載のキメラ抗原受容体(CAR)を発現するように遺伝子改変された細胞を含む組成物の、
哺乳動物において、ALPPL2、又はその断片を発現する標的細胞集団又は組織に対するT細胞媒介性免疫応答を刺激するための;又は
哺乳動物において、ALPPL2、又はその断片を発現する腫瘍に対する抗腫瘍免疫を付与するための;又は
ALPPL2、又はその断片を発現する細胞を含む癌を有する哺乳動物を治療するための;又は
癌と診断された哺乳動物において遺伝子操作されたT細胞の持続的集団を生成するための;又は
癌と診断された哺乳動物において、遺伝子操作されたT細胞の集団を増殖させるための;又は
癌を治療するための、
医薬の製造における使用。
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EP3383920A1 (en) | 2018-10-10 |
EP3383920B1 (en) | 2024-01-10 |
EP3383920A4 (en) | 2019-10-16 |
WO2017095823A1 (en) | 2017-06-08 |
JP2019505172A (ja) | 2019-02-28 |
JP7206360B2 (ja) | 2023-01-17 |
US20210236650A1 (en) | 2021-08-05 |
CA3006759A1 (en) | 2017-06-08 |
DK3383920T3 (da) | 2024-04-02 |
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