JP2018527952A - 抗pd−1抗体及びその使用方法 - Google Patents
抗pd−1抗体及びその使用方法 Download PDFInfo
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Abstract
Description
この出願は、米国仮出願第62/212,851号(2015年9月1日出願);同第62/216,043号(2015年9月9日出願);及び同第62/257,195号(2015年11月18日出願)(これらはそれぞれ参照によりその全体として本明細書に加入される)の利益を主張する。
本開示は、ヒトPD-1に特異的に結合する抗体及びその使用方法に関する。
タンパク質プログラム細胞死タンパク質1(PD-1)は、受容体のCD28ファミリーの阻害性メンバーである。PD-1は、活性化されたB細胞、T細胞、及び骨髄細胞で発現される(非特許文献1;非特許文献2;非特許文献3)。PD-1は、Ig遺伝子のスーパーファミリーの一部であり、そして膜近傍免疫受容体阻害性モチーフ(ITIM)及び膜から離れた(membrane distal)チロシン依存性スイッチモチーフ(ITSM)(非特許文献4;非特許文献5)を含有する、55 kDaのI型膜貫通タンパク質である。PD-1についての2つのリガンドPD-L1及びPD-L2が同定されており、これらはPD-1への結合の際にT細胞活性化を下方調節することが示された(非特許文献6;非特許文献7;非特許文献8)。PD-L1は、様々なヒト癌において豊富である(非特許文献9)。PD-1とPD-L1との間の相互作用は、腫瘍浸潤性リンパ球の減少、T細胞受容体媒介増殖の減少、及び癌性細胞による免疫回避を生じる(非特許文献10;非特許文献11;非特許文献12)。この免疫抑制は、PD-1のPD-L1との局所相互作用を阻害することにより逆転され得、そして効果はPD-1のPD-L2との相互作用が遮断される場合も同様に付加的である(非特許文献13;非特許文献14)。
本開示は、ヒトPD-1に特異的に結合し、そしてPD-1機能、例えばPD-1媒介免疫抑制を拮抗する抗体を提供する。これらの抗体を含む医薬組成物、これらの抗体をコードする核酸、これらの抗体を製造するための発現ベクター及び宿主細胞、並びにこれらの抗体を使用して被験体を処置する方法も提供される。本明細書に開示される抗体は、抗原(例えば、腫瘍抗原又は感染性疾患抗原)に応じてT細胞活性化を増加させ、かつ/又はTreg媒介免疫抑制を減少させるため、そしてそれ故、被験体において癌を処置するか、又は被験体において感染性疾患を処置若しくは予防するために特に有用である。
定の実施態様において、抗体は、配列番号74の残基6〜15からなるヒトPD-1のエピトープに結合する。特定の実施態様において、抗体は、配列番号74の残基130〜138を含むか、配列番号74の残基130〜138から本質的になるか、又は配列番号74の残基130〜138からなるヒトPD-1のエピトープに結合する。特定の実施態様において、抗体は、配列番号74の残基130〜138からなるヒトPD-1のエピトープに結合する。特定の実施態様において、抗体は、配列番号74の残基106〜113を含む、配列番号74の残基106〜113から本質的になるか、又は配列番号74の残基106〜113からなるヒトPD-1のエピトープに結合する。特定の実施態様において、抗体は、配列番号74の残基106〜113からなるヒトPD-1のエピトープに結合する。
本開示は、ヒトPD-1に特異的に結合し、そしてPD-1機能、例えばPD-1媒介免疫抑制を拮抗する抗体を提供する。これらの抗体を含む医薬組成物、これらの抗体をコードする核酸、これらの抗体を製造するための発現ベクター及び宿主細胞、並びにこれらの抗体を使用して被験体を処置する方法も提供される。本明細書において開示される抗体は、抗原(例えば、腫瘍抗原又は感染性疾患抗原)に応じたT細胞活性化を増加させるため、そしてそれ故、被験体において癌を処置するか又は被験体において感染性疾患を予防するために特に有用である。本明細書に記載される「単離された抗体」の全ての場合は、単離されていてもよいが単離されていることを必要としない抗体としてさらに考慮される。本明細書に記載される「単離されたポリヌクレオチド」の全ての場合は、単離されていてもよいが単離されていることを必要としないポリヌクレオチドとしてさらに考慮される。本明細書に記載される「抗体」の全ての場合は、単離されていてもよいが単離されていることを必要としない抗体としてさらに考慮される。本明細書に記載される「ポリヌクレオチド」の全ての場合は、単離されていてもよいが単離されていることを必要としないポリヌクレオチドとしてさらに考慮される。
本明細書で使用される用語「約(about)」及び「約(approximately)」は、数値又は数値範囲を修飾するために使用される場合、その値又は範囲を5%〜10%まで上回り、かつその値又は範囲を5%〜10%まで下回る偏差が、依然として示される値又は範囲の意図された意味内であることを示す。
含む。抗体の例としては、モノクローナル抗体、組み換え産生された抗体、単一特異性抗体、多選択性抗体(二重特異性抗体を含む)、ヒト抗体、ヒト化抗体、キメラ抗体、免疫グロブリン、合成抗体、2つの重鎖及び2つの軽鎖分子を含むテトラマー抗体、抗体軽鎖モノマー、抗体重鎖モノマー、抗体軽鎖ダイマー、抗体重鎖ダイマー、抗体軽鎖-抗体重鎖対、細胞内抗体(intrabodies)、ヘテロコンジュゲート抗体、抗体-薬物結合体、単一ドメイン抗体、一価抗体、単鎖抗体又は単鎖Fvs(scFv)、ラクダ化(camelized)抗体、affybodies、Fabフラグメント、F(ab’)2フラグメント、ジスルフィド連結Fvs (sdFv)、抗イディオタイプ(抗Id)抗体(例えば、抗抗Id抗体を含む)、及び上記のいずれかの抗原結合フラグメントが挙げられる。特定の実施態様において、本明細書において記載される抗体は、ポリクローナル抗体集団を指す。抗体は、免疫グロブリン分子のいずれの型(例えば、IgG、IgE、IgM、IgD、IgA又はIgY)でも、いずれのクラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1又はIgA2)でも、いずれのサブクラス(例えば、IgG2a又はIgG2b)のものでもよい。特定の実施態様において、本明細書において記載される抗体はIgG抗体、又はそのクラス(例えば、ヒトIgG1又はIgG4)又はそのサブクラスである。特定の実施態様において、抗体はヒト化モノクローナル抗体である。別の特定の実施態様において、抗体はヒトモノクローナル抗体である。特定の実施態様において、本明細書において記載される抗体は、IgG1又はIgG2抗体である。
その特定の抗原についての結合及び特異性において使用される。配列の可変性は、相補性決定領域(CDR)と呼ばれる領域に集中するが、可変ドメイン中のより高度に保存された領域は、フレームワーク領域(FR)と呼ばれる。特定の実施態様において、可変領域はヒト可変領域である。特定の実施態様において、可変領域は齧歯動物又はマウスCDR及びヒトフレームワーク領域(FR)を含む。特定の実施態様において、可変領域は霊長類(例えば、非ヒト霊長類)可変領域である。特定の実施態様において、可変領域は、齧歯動物又はマウスCDR及び霊長類(例えば、非ヒト霊長類)フレームワーク領域(FR)を含む。
10-12 M若しくはそれ以下のKdで抗原に結合する。
一局面において、本開示は、ヒトPD-1に特異的に結合し、そしてPD-1機能を拮抗する抗体を提供する。例となる抗体のアミノ酸配列を本明細書の表1〜6に示す。
(a) CDRH1はSYGMH(配列番号1)のアミノ酸配列を含み;かつ/又は
(b) CDRH2はVIWX1DGSNX2YYADSVX3G (配列番号32)のアミノ酸配列を含み、ここで、
X1はY若しくはFであり;
X2はK若しくはEであり;そして
X3はK若しくはMであり;かつ/又は
(c) CDRH3はNX1DX2(配列番号33)のアミノ酸配列を含み、ここで
X1はG若しくはVであり;そして
X2はH若しくはYであり;かつ/又は
(d) CDRL1はRASQSVSSNLA (配列番号4)のアミノ酸配列を含み;かつ/又は
(e) CDRL2はGASTRAT(配列番号5)のアミノ酸配列を含み;かつ/又は
(f) CDRL3はQQYNNWPRT (配列番号6)のアミノ酸配列を含む、
を含む、ヒトPD-1に特異的に結合する単離された抗体を提供する。
(a) CDRH1はSYGMH (配列番号1)のアミノ酸配列を含み;
(b) CDRH2はVIWX1DGSNX2YYADSVX3G (配列番号32)のアミノ酸配列を含み、ここで
X1はY又はFであり;
X2はK又はEであり;そして
X3はK又はMであり;
(c) CDRH3はNX1DX2(配列番号33)のアミノ酸配列を含み、ここで
X1はG又はVであり;そして
X2はH又はYであり;
(d) CDRL1はRASQSVSSNLA (配列番号4)のアミノ酸配列を含み;
(e) CDRL2はGASTRAT(配列番号5)のアミノ酸配列を含み;そして
(f) CDRL3はQQYNNWPRT (配列番号6)のアミノ酸配列を含む。
(a) SYGMH (配列番号1)のアミノ酸配列を含むCDRH1;及び/又は
(b) VIWYDGSNKYYADSVKG (配列番号2)のアミノ酸配列を含むCDRH2;及び/又は
(c) NVDY (配列番号3)若しくはNGDH (配列番号7)のアミノ酸配列を含むCDRH3;及び/又は
(d) RASQSVSSNLA (配列番号4)のアミノ酸配列を含むCDRL1;及び/又は
(e) GASTRAT (配列番号5)のアミノ酸配列を含むCDRL2;及び/又は
(f) QQYNNWPRT (配列番号6)のアミノ酸配列を含むCDRL3
を含む、ヒトPD-1に特異的に結合する単離された抗体を提供する。
る。特定の実施態様において、Ig領域はヒトIgG1である。特定の実施態様において、Ig領域はヒトIgG4である。特定の実施態様において、Ig(例えば、IgG1)は、インビボで成熟野生型IgG1抗体において通常は位置N297(EUナンバリングシステムに従って)に存在するN-連結グリカン部分を欠いている。N297グリカンの欠損は、エフェクター機能の実質的な損失を生じる。N297グリカンの除去は、当該分野で公知のいずれかの方法を使用して達成され得る。例えば、特定の実施態様において、N297グリカンの除去は、グリコシル化部位を除去するためのN297残基の変異により達成される。したがって、特定の実施態様において、本明細書において開示される抗体は、EUナンバリングシステムに従ってN297A変異を含む重鎖定常領域(例えば、ヒトIgG1重鎖定常領域)を含む。特定の実施態様において、本明細書に開示される抗体は、EUナンバリングシステムに従ってN297Q変異を含む重鎖定常領域(例えば、IgG1重鎖定常領域)を含む。特定の実施態様において、本明細書に開示される抗体は、EUナンバリングシステムに従ってD265A変異を含むIgG1重鎖定常領域(例えば、ヒトIgG1重鎖定常領域)を含む。特定の実施態様において、本明細書に開示される抗体は、EUナンバリングシステムに従ってS228P変異を含むIgG4重鎖定常領域(例えば、ヒトIgG4重鎖定常領域)を含む。
るNFATシグナル伝達を、本明細書に記載される(下記の実施例を参照のこと)か又は当業者に公知である方法により評価して、抗体無しで又は非関連抗体(例えば、ヒトPD-1に特異的に結合しない抗体)を用いたPD-L1を発現する標的細胞と共培養されたPD-1を発現するNFAT-ルシフェラーゼレポーター細胞におけるNFATシグナル伝達と比較して、少なくとも約1.2倍、1.3倍、1.4倍、1.5倍、2倍、2.5倍、3倍、3.5倍、4倍、4.5倍、5倍、6倍、7倍、8倍、9倍、10倍、15倍、20倍、30倍、40倍、50倍、60倍、70倍、80倍、90倍、又は100倍増加させる、単離された抗体を提供する。
生理学的に許容しうる担体、賦形剤又は安定剤(Remington’s Pharmaceutical Sciences (1990) Mack Publishing Co.、Easton、PA)中に、所望の純度を有する本明細書に記載される抗PD-1抗体を含む組成物が本明細書において提供される。許容しうる担体、賦形剤、又は安定剤は、使用される投薬量及び濃度でレシピエントに対して非毒性であり、そしてこれらとしては、リン酸塩、クエン酸塩、及び他の有機酸のような緩衝剤;アスコルビン酸及びメチオニンを含む抗酸化剤;保存料(例えば、オクタデシルジメチルベンジルアンモニウムクロリド;塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェノール、ブチル若しくはベンジルアルコール;メチル若しくはプロピルパラベンのようなアルキルパラベン類;カテコール;レゾルシノール;シクロヘキサノール;3-ペンタノール;及びm-クレゾール);低分子量(約10残基未満)ポリペプチド;血清アルブミン、ゼラチン、又は免疫グロブリンのようなタンパク質;ポリビニルピロリドンのような親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、又はリジンのようなアミノ酸;単糖類、二糖類、及びグルコース、マンノース、又はデキストリンを含む他の炭水化物;EDTAのようなキレート化剤;スクロース、マンニトール、トレハロース若しくはソルビトールのような糖類;ナトリウムのような塩形成対イオン;金属錯体(例えば、Zn-タンパク質複合体);並びに/又はTWEENTM、PLURONICSTM又はポリエチレングリコール(PEG)のような非イオン性界面活性剤が挙げられる。
別の局面において、本開示は、本明細書に開示される抗PD-1抗体を使用して被験体を処置する方法を提供する。PD-1機能の阻害から利益を受けるであろう被験体におけるいずれかの疾患又は障害が、本明細書に開示される抗PD-1抗体を使用して処置され得る。本明細書に開示される抗PD-1抗体は、腫瘍に対して寛容である免疫系を阻害するために特に有用であり、そしてしたがって癌を有する被験体のための免疫療法として使用され得る。例えば、特定の実施態様において、本開示は、被験体において抗原に応じたT細胞活性化を増加させる方法を提供し、該方法は、本明細書に開示される、有効量の抗PD-1抗体又はその医薬組成物を被験体に投与することを含む。特定の実施態様において、本開示は、被験体において癌を処置する方法を提供し、該方法は、本明細書に開示される、有効量の抗体又は医薬組成物を被験体に投与することを含む。本明細書で開示される抗PD-1抗体又は医薬組成物で処置され得る癌としては、限定することなく、黒色腫、頭頚部癌(例えば、頭頸部扁平上皮癌)、肺癌(例えば、非小細胞肺癌及び小細胞肺癌)、乳癌(例えば、ハーセプチン抵抗性乳癌及びトラスツズマブ-DM1(T-DM1)抵抗性乳癌)、前立腺癌、多形神経膠芽腫、結腸直腸癌、肉腫、膀胱癌、子宮頸癌、HPV関連癌、腟癌、外陰癌、陰茎癌、肛門癌、直腸癌、中咽頭癌、多発性骨髄腫、腎細胞癌、卵巣癌、肝細胞癌、子宮内膜癌、膵臓癌、リンパ腫、及び白血病(例えば、高齢白血病、急性骨髄性白血病(AML)、及び高齢AML)が挙げられる。したがって、本発明は、一実施態様において、薬剤としての使用のための、本発明の抗体及び/又は医薬組成物に関する。好ましい実施態様において、本発明は、被験体において癌を処置する方法における使用のため、かつ/又は腫瘍に対する免疫系寛容を阻害するための使用のため、かつ/又は癌を有する被験体の免疫療法における使用のため、かつ/又は被験体における抗原に応じたT細胞活性化を増加させる方法における使用のための、薬剤の製造のための、本発明の抗体及び/又は医薬組成物の使用に関する。好ましい実施態様において、癌は、黒色腫、頭頚部癌(例えば、頭頸部扁平上皮癌)、肺癌(例えば、非小細胞肺癌及び小細胞肺癌)、乳癌(例えば、ハーセプチン抵抗性乳癌及びトラスツズマブ-DM1(T-DM1)抵抗性乳癌)、前立腺癌、多形神経膠芽腫、結腸直腸癌、肉腫、膀胱癌、子宮頸癌、HPV関連癌、腟癌、外陰癌、陰茎癌、肛門癌、直腸癌、中咽頭癌、多発性骨髄腫、腎細胞癌、卵巣癌、肝細胞癌、子宮内膜癌、膵臓癌、リンパ腫、及び白血病(例えば、高齢白血病、急性骨髄性白血病(AML)、及び高齢AML)からなる群より選択される。
ル封入された又は捕捉された抗原、3脱O-アシル化モノホスホリルリピドA(3 D-MPL)、免疫賦活性オリゴヌクレオチド、toll様受容体(TLR)リガンド、マンナン結合レクチン(MBL)リガンド、STINGアゴニスト、免疫賦活性複合体、例えばサポニン、Quil A、QS-21、QS-7、ISCOMATRIX、及びその他が挙げられる。他のアジュバントとしては、CpGオリゴヌクレオチド並びにポリ(A)及びポリ(U)のような二本鎖標準RNA分子が挙げられる。上記アジュバントの組み合わせも使用され得る。例えば、米国特許第6,645,495号;同第7,029,678号;及び同第7,858,589号(これらは全て参照によりそれら全体として本明細書に加入される)を参照のこと。一実施態様において、本明細書で使用されるアジュバントはQS-21 STIMULONである。
別の局面において、PD-1(例えば、ヒトPD-1)抗原に特異的に結合する本明細書に記載される抗体又はそのフラグメント(例えば、軽鎖可変領域及び/又は重鎖可変領域)をコードするヌクレオチド配列を含むポリヌクレオチド、及び宿主細胞(例えば、E. coli及び哺乳動物細胞)における組み換え発現のためのベクター、例えば上記ポリヌクレオチドを含むベクターが本明細書において提供される。本明細書に提供される抗体のいずれかの重鎖及び/又は軽鎖をコードするヌクレオチド配列を含むポリヌクレオチド、さらには上記ポリヌクレオチド配列を含むベクター、例えば、宿主細胞、例えば哺乳動物細胞におけるそれらの有効な発現のための発現ベクターが本明細書に提供される。
有する抗体を製造するために使用され得るこのようなシステムの例である。
in Molecular Biology、(2002) 5th Ed.、Ausubel FM et al.、eds.、John Wiley and Sons、New York、におけるChapter 11(これは参照によりその全体として本明細書に加入される)を参照のこと)。
assay)(ELISA)のようなインビトロ結合アッセイにより決定する。
本明細書に記載される1つ又はそれ以上の抗体、又はその医薬組成物若しくは結合体を含むキットも提供される。特定の実施態様において、本明細書に提供される1つ又はそれ以上の抗体のような本明細書に記載される医薬組成物の成分の1つ又はそれ以上で満たされた1つ又はそれ以上の容器を含む医薬パック又はキットが本明細書において提供される。いくつかの実施態様において、キットは、本明細書に記載される医薬組成物及び本明細書に記載されるもののようないずれかの予防的又は治療的薬剤を含む。特定の実施態様において、キットは、T細胞マイトジェン、例えば、フィトヘマグルチニン(PHA)及び/若しくは酢酸ミリスチン酸ホルボール(PMA)、又はTCR複合体刺激抗体、例えば抗CD3抗体及び抗CD28抗体を含有し得る。医薬品又は生物学的製品の製造、使用又は販売を規制する行政機関により規定される形態の通知を場合によりこのような容器に添付してもよく、この通知は、ヒト投与に関する製造、使用又は販売の機関による承認を反映する。
このセクション(すなわち、セクション6)における実施例は、説明として提供されるものであり、限定としてではない。
この実施例は、ヒトPD-1に特異的に結合する抗体、特にAGEN2033w、AGEN2034w、AGEN2046w、及びAGEN2047wと指定された抗体の特徴づけを記載する。AGEN2033w及びAGEN2046wは、同じ重鎖可変領域アミノ酸配列(配列番号15)及び同じ軽鎖可変領域アミノ酸配列(配列番号16)を共有する。AGEN2034w及びAGEN2047wは、同じ重鎖可変領域アミノ酸配列(配列番号17)及び同じ軽鎖可変領域アミノ酸配列(配列番号16)を共有する。AGEN2033w及びAGEN2034wは、EUナンバリングシステムに従ってS228P変異(すなわち、野生型IgG4定常領域と比較して位置228におけるセリンのプロリンでの置換)を含有するヒトIgG4抗体であり、AGEN2046w及びAGEN2047wは、ヒトIgG1抗体である。さらに、AGEN2047wの3つのFc変異体もまた特徴づけられた:EUナンバリングシステムに従って番号付けされた、N297A変異体、S267E/L328F二重変異体、及びS239D/A330L/I332E三重変異体。
抗PD-1抗体AGEN2046w、AGEN2047w、及びAGEN2034wを、活性化末梢血単核球(PBMC)への結合についてフローサイトメトリーにより調べた。未精製バフィコートから製造した凍結保存したヒトPBMC(Research Blood Components、カタログ番号(Cat#) 002)又は凍結保存したカニクイザルPBMC(Worldwide Primates Inc.、顧客注文)を、NormocinTM (InvivoGen、Cat# ant-nr-1)及び10%熱不活化FBS(Gibco、Cat# 16140063)を追加したRPMI1640培地に96ウェルNUNCLONデルタ表面プレート(NUNCTM)において105細胞/ウェルでプレーティングした。細胞を、100 ng/mlのブドウ球菌エンテロトキシンA(SEA;ヒトPBMC用) (Toxin Technologies、Cat# at101red)又はブドウ球菌エンテロトキシンB (SEB;カニクイザルPBMC用) (Toxin Technology、Cat# bt202red)の存在下で5日間37℃、5% CO2、及び湿度97%で培養した。次いで、サンプル緩衝液(PBS + 2% FBS + 0.09%アジ化ナトリウム)で細胞を1回洗浄し、そして段階希釈した抗体又はアイソタイプ対照 100 μl(10、1、0.1、0.01、0.001、及び0.0001 μg/mlのAGEN2046w、AGEN2047w、又はヒトIgG1アイソタイプ対照(LifeTein LLC、Cat# LT12031);又は25、5、1、0.2、0.04、0.008、0.0016、0.00032、及び0.000064 μg/mlのAGEN2034w又はヒトIgG4アイソタイプ対照(LifeTein LLC、Cat# LT12034))とともに暗所にて氷上でインキュベートした。45分後に、サンプル緩衝液で細胞を2回洗浄し、次いでLIVE/DEAD(R)固定化可能近IR死滅細胞染色(Life Technologies、Cat# L10119)、CD4-BV421 (Biolegend、Cat# 317434)、及びヤギF(ab')2抗ヒトIgG+A+M、R-PE (Life Technologies、Cat# AHI1707)とともに30分間インキュベートした。サンプル緩衝液で細胞を2回洗浄し、次いでサンプル緩衝液に再懸濁し、そしてFACS Fortessa血球計算機(Becton Dickinson)で分析した。CD4+ T細胞をゲーティングし、そして平均蛍光強度(MFI)を記録した。
PD-1に対するAGEN2034wの選択性を、同族タンパク質に対してサスペンションアレイ技術を使用して評価した。
抗PD-1抗体がリガンドPD-L1及びPD-L2の結合を遮断するかどうかを決定するために、ランキングアッセイ設定を、サスペンションアレイ技術を使用して行った。5 μlアッセイ緩衝液中の1200 Luminex(R)ビーズ(Luminex Corp、Cat# 48 LC10014-48)を、96ウェルハーフエリアプレート(Corning、Inc.、Cat# 3884)の各ウェルに加えた。ビーズをPD-1抗原PD-1-Fcキメラ(R&D systems、Cat# 1086-PD)とアミンカップリングを介してCOOHビーズ表面にカップリングした。カップリング反応を、1mlあたりPD-1抗原50 μg/ml及び1 x
107 Luminexビーズを使用して行った。標準NHSエステル化学を使用して、抗原の第一級アミン基とビーズ表面上のカルボキシル基との間にカルボジイミド結合を形成した(Luminex Xmap説明書3章)。
初代ヒトT細胞に対する抗PD-1抗体の機能的活性を、SEA刺激後に評価した。未精製バフィコートから製造した凍結保存したヒトPBMC(Research Blood Components、Cat# 002)を、96ウェルNUNCLONデルタ表面プレート(NUNCTM)において、NormocinTM (InvivoGen、Cat# ant-nr-1)及び10%熱不活化FBS(Gibco、Cat# 16140063)を追加したRPMI1640培地中105細胞/ウェルでプレーティングした。固定濃度(10 μg/ml)又は用量範囲量の抗体(50、10、2、0.4、0.08、0.016、及び0.0032 μg/ml)及び固定量のSEA (100 ng/ml、Toxin Technology、Cat# at101red)の存在下で5日間37℃、5% CO2、及び湿度97%で細胞を培養した。試験した抗体は、AGEN2033w、AGEN2034w、AGEN2046w、AGEN2047w、及びIgG1アイソタイプ対照であった。上清を集め、そして分析まで-80℃で保存した。IL-2の力価を電気化学発光(MSD)により測定した。
この実施例において、抗PD-1抗体の拮抗的活性に対するFcγR結合の効果を調べた。
次に、抗PD-1抗体AGEN2034wを、混合リンパ球反応で調べた。樹状細胞は、凍結保存されたHLA-A2+ ヒトPBMCから得られた単離されたCD14+細胞(Stemcell Technologies、Cat# 18058)由来であり、そして最初に500 U/ml IL-4 (Peprotech、Cat# 200-04-20UG)及び1000 U/ml GM-CSF (Peprotech、Cat# 300-03-20UG)の存在下で24時間、次いで1000 U/ml TNFα (Peprotech、Cat# 300-01A-50UG)、10 ng/ml IL-1β (Peprotech、Cat# 200-01B-10UG)、10 ng/ml IL-6 (Peprotech、Cat# 200-06-20UG)、及び1 μM PGE2 (Sigma、Cat# P0409-5MG)の存在下でさらに24時間分化させた。同種HLA-A2- ヒトPBMCドナーからMACSカラム精製(Miltenyi Biotec、Cat# 130-096-535)により精製した50,000 pan T細胞を、いずれの抗体も存在しない場合又は10 μg/ml ヒトIgG4アイソタイプ対照抗体 (Biolegend、Cat# 403402)若しくは10 μg/ml AGEN2034wの存在下で、5% ヒトAB血清(Corning、Cat# 35-060-CI)及びペニシリン/ストレプトマイシン(Gibco、Cat# 15140-122)を含有するRPMI(Corning、Cat# 10-040-CM)中で10,000樹状細胞とともに共培養した。培養物を5日間37℃及び5% CO2でインキュベートした。上清を、定常状態濃度のIFNγについてAlphaLISA (Perkin
Elmer、Cat# AL217C)を使用して評価した。
この実施例において、抗PD-1抗体 AGEN2034wを、卵巣癌腹水により誘導されるT細胞増殖の抑制を軽減するその能力について試験した。手短には、初代ヒトPBMCをCFSE (Biolegend、Cat# 423801)で標識し、次いで増加する濃度(0.00000102〜50 μg/ml)のAGEN2034w又はIgG4アイソタイプ対照抗体 (Biolegend、Cat# 317434)の存在下で4〜5日間、1 μg/ml 抗CD3抗体(eBioscience、Cat# 16-0037-85)及び50%体積/体積の卵巣癌腹水で刺激した。細胞を、抗ヒトCD4抗体 (Biolegend、Cat# 317434)又は抗ヒトCD8抗体 (Biolegend、Cat# 344710)及びLIVE-DEAD生存率染色(Life Technologies、Cat# L10119)で免疫染色した。CFSE希釈により示されるCD4+又はCD8+ T細胞の増殖を、BD Fortessa (Becton Dickinson)を使用してフローサイトメトリーにより測定した。
さらに、レポーターアッセイを利用して、AGEN2034wの拮抗的活性を調べた。詳細には、このレポーターアッセイにおいて、PD-L1を発現する標的細胞及びPD-1を発現するレポーター細胞の共培養は、レポーター細胞におけるNFAT-ルシフェラーゼレポーター遺伝子の発現を阻害した。抗PD-1抗体によるPD-1/PD-L1相互作用の遮断は、阻害性シグナルを軽減することができ、ルシフェラーゼ発現をもたらした。
この実施例において、以下の6つのさらなる抗PD-1抗体を特徴づけした:AGEN2001w、AGEN2002w、EP11_pl1_B03、EP11_pl1_B05、EP11_pl1_C02、及びEP11_pl1_C03。これらの抗体の可変重鎖及び可変軽鎖配列を表6に開示する。
上記の6つの抗PD-1抗体の親和性を、表面プラズモン共鳴により分析した。6つの抗体は全て組み換えヒトPD-1に結合した(データは示していない)。
ヒトPBMCに対する抗PD-1抗体 AGEN2002wの機能的活性を、セクション6.1.4に記載されるものと同様のアッセイにおいて試験した。手短には、未精製バフィコートから製造した凍結保存したヒトPBMC(Research Blood Components、Cat# 002)を、抗PD-1抗体AGEN2002w
10 μg/ml又はアイソタイプ対照抗体(HEL IgG1、LifeTein、Cat# LT12031)及び SEAペプチド(Toxin Technologies、Cat# at101red)100 ng/mlの存在下で4日間37℃、5% CO2、及
び湿度97%で培養した。上清を集め、そして分析まで-80℃で保存した。IL-2の力価を電気化学発光(MSD)により測定した。
抗PD-1抗体AGEN2034wのエピトープを、水素-重水素交換(HDX)質量分析及びPepscan分析を使用して特徴づけした。
AGEN2034wのFabフラグメント(AGEN2034w-Fab)のヒトPD-1の細胞外ドメインとの相互作用を、水素-重水素交換(HDX)質量分析により調べた。
抗PD-1抗体AGEN2034wの結合を、チップ結合ペプチドアレイとして製造された合成PD-1ペプチドフラグメントに対して測定した。Pepscan Presto BV、Lelystad、the Netherlandsにより分析を行った。手短には、ヒトPD-1のエピトープを再構築するために、ペプチドのライブラリーを合成した。アミノ官能基化ポリプロピレン支持体を、専用の親水性ポリマー製剤でグラフティングし、続いて、ジシクロヘキシルカルボジイミド(DCC)を使用してNヒドロキシベンゾトリアゾール(HOBt)を用いてt-ブチルオキシカルボニル-ヘキサメチレンジアミン(BocHMDA)と反応させ、その後、トリフルオロ酢酸(TFA)を使用してBoc基を切断した。標準的Fmocペプチド合成を使用して、顧客改変したJANUS液体操作ステーション(Perkin Elmer)によりアミノ官能基化個体支持体上でペプチドを合成した。構造的模倣物の合成を、Pepscanの専用の足場上の化学的に連結されたペプチド(Chemically Linked Peptides on Scaffolds)(CLIPS)技術を使用して行った。CLIPS技術は、ペプチドを、単一ループ、二重ループ、三重ループ、シート様折り畳み、らせん様折り畳み及びそれらの組み合わせを構築することが可能である。合成されたペプチドの各々への抗体の結合を、PEPSCANベースのELISAで試験した。ペプチドアレイを、一次抗体溶液とともに終夜4℃でインキュベートした。洗浄後に、ペプチドアレイを、ヤギ抗ヒトHRP結合体(Southern Biotech、Cat# 2010-05)とともに1時間25℃でインキュベートした。洗浄後に、ペルオキシダーゼ基質2,2’-アジノ-ジ-3-エチルベンズチアゾリンスルホネート(ABTS)及び20 μl/ml 3% H2O2を加えた。1時間後、発色を測定し、そして電荷結合素子(CCD) - カメラ及び画像処理システムを用いて測定し定量した。
Claims (86)
- 相補性決定領域CDRH1、CDRH2、及びCDRH3を含む重鎖可変領域並びに相補性決定領域CDRL1、CDRL2、及びCDRL3を含む軽鎖可変領域を含む相補性決定領域を含む、ヒトPD−1に特異的に結合する単離された抗体であって、ここで:
(a) CDRH1はSYGMH(配列番号1)のアミノ酸配列を含み;
(b) CDRH2はVIWX1DGSNX2YYADSVX3G(配列番号32)のアミノ酸配列を含み、ここで
X1はY又はFであり;
X2はK又はEであり;そして
X3はK又はMであり;
(c) CDRH3はNX1DX2(配列番号33)のアミノ酸配列を含み、ここで
X1はG又はVであり;そして
X2はH又はYであり;
(d) CDRL1はRASQSVSSNLA(配列番号4)のアミノ酸配列を含み;
(e) CDRL2はGASTRAT(配列番号5)のアミノ酸配列を含み;そして
(f) CDRL3はQQYNNWPRT(配列番号6)のアミノ酸配列を含む、
上記単離された抗体。 - CDRH2は、配列番号2及び34〜36からなる群より選択されるアミノ酸配列を含む、請求項1に記載の単離された抗体。
- CDRH3は、配列番号3、7、及び37からなる群より選択されるアミノ酸配列を含む、請求項1又は2に記載の単離された抗体。
- CDRH1、CDRH2及びCDRH3は、それぞれ配列番号1、2、及び3;1、2、及び7;1、2、及び37;1、34、及び7;1、35、及び7;又は1、36、及び7に示されるCDRH1、CDRH2及びCDRH3アミノ酸配列を含む、請求項1〜3のいずれか1項に記載の単離された抗体。
- 相補性決定領域CDRH1、CDRH2及びCDRH3を含む重鎖可変領域、並びに相補性決定領域CDRL1、CDRL2及びCDRL3を含む軽鎖可変領域を含む、ヒトPD−1に特異的に結合する単離された抗体であって、ここでCDRH1、CDRH2、CDRH3、CDRL1、CDRL2、及びCDRL3は、それぞれ配列番号1、2、3、4、5、及び6に示されるアミノ酸配列を含む、上記単離された抗体。
- 相補性決定領域CDRH1、CDRH2及びCDRH3を含む重鎖可変領域、並びに相補性決定領域CDRL1、CDRL2及びCDRL3を含む軽鎖可変領域を含む、ヒトPD−1に特異的に結合する単離された抗体であって、ここでCDRH1、CDRH2、CDRH3、CDRL1、CDRL2、及びCDRL3は、それぞれ配列番号1、2、7、4、5、及び6に示されるアミノ酸配列を含む、上記単離された抗体。
- 配列番号49のアミノ酸配列を含む重鎖可変領域を含む、請求項1〜6のいずれか1項に記載の単離された抗体。
- 抗体は、配列番号15、17、及び26〜31からなる群より選択されるアミノ酸配列に対して少なくとも75%、80%、85%、90%、95%、又は100%同一であるアミノ酸配列を含む重鎖可変領域を含む、請求項1〜6のいずれか1項に記載の単離された抗体。
- 重鎖可変領域は、配列番号15、17、及び26〜31からなる群より選択されるアミノ酸配列を含む、請求項8に記載の単離された抗体。
- 重鎖可変領域は、配列番号15のアミノ酸配列を含む、請求項9に記載の単離された抗体。
- 重鎖可変領域は、配列番号17のアミノ酸配列を含む、請求項9に記載の単離された抗体。
- 配列番号52のアミノ酸配列を含む重鎖を含む、請求項10に記載の単離された抗体。
- 配列番号54のアミノ酸配列を含む重鎖を含む、請求項10に記載の単離された抗体。
- 配列番号53のアミノ酸配列を含む重鎖を含む、請求項11に記載の単離された抗体。
- 配列番号55のアミノ酸配列を含む重鎖を含む、請求項11に記載の単離された抗体。
- 配列番号56のアミノ酸配列を含む重鎖を含む、請求項11に記載の単離された抗体。
- ヒトIGHV3−33生殖系列配列由来のアミノ酸配列を有する重鎖可変領域を含む、請求項1〜8のいずれか1項に記載の単離された抗体。
- 配列番号16のアミノ酸配列に対して少なくとも75%、80%、85%、90%、95%、又は100%同一であるアミノ酸配列を含む軽鎖可変領域を含む、請求項1〜17のいずれか1項に記載の単離された抗体。
- 軽鎖可変領域は、配列番号16のアミノ酸配列を含む、請求項18に記載の単離された抗体。
- 配列番号19のアミノ酸配列を含む軽鎖を含む、請求項19に記載の単離された抗体。
- ヒトIGKV3−15生殖系列配列由来のアミノ酸配列を有する軽鎖可変領域を含む、請求項1〜18のいずれか1項に記載の単離された抗体。
- 重鎖可変領域及び軽鎖可変領域が、それぞれ、配列番号15及び16;17及び16;26及び16;27及び16;28及び16;29及び16;30及び16;又は31及び16に示されるアミノ酸配列を含む、請求項1に記載の単離された抗体。
- (a) 配列番号15のアミノ酸配列を含む重鎖可変領域、及び
(b) 配列番号16のアミノ酸配列を含む軽鎖可変領域
を含む、ヒトPD−1に特異的に結合する単離された抗体。 - (a) 配列番号17のアミノ酸配列を含む重鎖可変領域、及び
(b) 配列番号16のアミノ酸配列を含む軽鎖可変領域
を含む、ヒトPD−1に特異的に結合する、単離された抗体。 - 配列番号15、17、及び26〜31からなる群より選択されるアミノ酸配列を含む重鎖可変領域を含む、ヒトPD−1に特異的に結合する単離された抗体。
- 配列番号16のアミノ酸配列を含む軽鎖可変領域を含む、ヒトPD−1に特異的に特異的に結合する単離された抗体。
- (a) 配列番号52のアミノ酸配列を含む重鎖;及び
(b) 配列番号19のアミノ酸配列を含む軽鎖
を含む、ヒトPD−1に特異的に結合する、単離された抗体。 - (a) 配列番号53のアミノ酸配列を含む重鎖;及び
(b) 配列番号19のアミノ酸配列を含む軽鎖
を含む、ヒトPD−1に特異的に結合する単離された抗体。 - (a) 配列番号54のアミノ酸配列を含む重鎖;及び
(b) 配列番号19のアミノ酸配列を含む軽鎖
を含む、ヒトPD−1に特異的に結合する単離された抗体。 - (a) 配列番号55のアミノ酸配列を含む重鎖;及び
(b) 配列番号19のアミノ酸配列を含む軽鎖
を含む、ヒトPD−1に特異的に結合する単離された抗体。 - (a) 配列番号56のアミノ酸配列を含む重鎖;及び
(b) 配列番号19のアミノ酸配列を含む軽鎖
を含む、ヒトPD−1に特異的に結合する単離された抗体。 - 請求項1〜31のいずれか1項に記載の抗体と、ヒトPD−1への結合について交差競合する、単離された抗体。
- 請求項1〜31のいずれか1項に記載の抗体と同じヒトPD−1のエピトープに結合する、単離された抗体。
- 配列番号74の残基107〜122からなるエピトープに結合する、請求項1〜33のいずれか1項に記載の単離された抗体。
- 配列番号74の残基5〜22からなるエピトープに結合する、請求項1〜34のいずれか1項に記載の単離された抗体。
- 配列番号74の残基6〜15からなるエピトープに結合する、請求項1〜35のいずれか1項に記載の単離された抗体。
- 配列番号74の残基130〜138からなるエピトープに結合する、請求項1〜36のいずれか1項に記載の単離された抗体。
- 配列番号74の残基106〜113からなるエピトープに結合する、請求項1〜37のいずれか1項に記載の単離された抗体。
- ヒトIgG1、IgG2、IgG3、IgG4、IgA1、及びIgA2からなる群より選択される重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- ヒトIgG1重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- EUナンバリングシステムに従って位置N297のグリカン部分を欠いたヒトIgG1重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- EUナンバリングシステムに従って、N297A変異を含むヒトIgG1重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- EUナンバリングシステムに従って、N297Q変異を含むヒトIgG1重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- EUナンバリングシステムに従って、D265A変異を含むヒトIgG1重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- EUナンバリングシステムに従って、S228P変異を含むヒトIgG4重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体。
- 野生型ヒトIgG重鎖定常領域の変異体であるヒトIgG 重鎖定常領域を含む、請求項1〜11、17〜26、及び32〜38のいずれか1項に記載の単離された抗体であって、ここで変異ヒトIgG重鎖定常領域は、野生型ヒトIgG重鎖定常領域がヒトFc受容体に結合するよりも低い親和性でヒトFc受容体に結合する、上記単離された抗体。
- ヒトFc受容体がFcγRである、請求項46に記載の単離された抗体。
- FcγRがFcγRIIBである、請求項47に記載の単離された抗体。
- FcγRが、樹状細胞、単球、マクロファージ、好中球、顆粒球、B細胞、及びナチュラルキラー細胞からなる群より選択される細胞で発現される、請求項47に記載の単離された抗体。
- 変異ヒトIgG重鎖定常領域が、変異ヒトIgG1、変異ヒトIgG2、又は変異ヒトIgG4重鎖定常領域である、請求項46〜49のいずれか1項に記載の単離された抗体。
- ヒトIgGκ及びIgGλからなる群より選択される軽鎖定常領域を含む、請求項1〜19、21〜26、及び32〜50のいずれか1項に記載の単離された抗体。
- ヒト抗体である、請求項1〜51のいずれか1項に記載の単離された抗体。
- ヒトPD−1に対して拮抗的である、請求項1〜52のいずれか1項に記載の単離された抗体。
- ヒトPD−1の活性を不活性化するか、低減するか、又は阻害する、請求項53に記載の単離された抗体。
- ヒトPD−1のヒトPD−L1又はヒトPD−L2への結合を阻害する、請求項53に記載の単離された抗体。
- ブドウ球菌エンテロトキシンA(SEA)で刺激された末梢血単核球(PBMC)によるIL−2産生を増加させる、請求項53に記載の単離された抗体。
- ヒトT細胞及び同種樹状細胞の共培養のIFNγ産生を増加させる、請求項53に記載の単離された抗体。
- 卵巣癌腹水とともに共培養された抗CD3抗体刺激CD4+又はCD8+T細胞の増殖を増加させる、請求項53に記載の単離された抗体。
- PD−L1を発現する標的細胞とともに共培養されたPD−1を発現するNFAT−ルシフェラーゼレポーター細胞におけるNFATシグナル伝達を増加させる、請求項53に記載の単離された抗体。
- 細胞傷害性薬物、細胞分裂阻害剤、毒素、放射性核種、又は検出可能な標識に結合された、請求項1〜59のいずれか1項に記載の単離された抗体。
- 請求項1〜60のいずれか1項に記載の抗体及び薬学的に許容しうる担体又は賦形剤を含む、医薬組成物。
- 請求項1〜60のいずれか1項に記載の抗体の重鎖及び/又は軽鎖をコードする単離されたポリヌクレオチド。
- 請求項62に記載のポリヌクレオチドを含むベクター。
- 請求項62に記載のポリヌクレオチド又は請求項63に記載のベクターを含む、組み換え宿主細胞。
- ヒトPD−1に結合する抗体を製造する方法であって、請求項64に記載の宿主細胞を、ポリヌクレオチドが発現され、そして抗体が産生されるように培養することを含む、上記方法。
- 被験体における抗原に応じたT細胞活性化を増加させる方法であって、有効量の請求項1〜61のいずれか1項に記載の抗体又は医薬組成物を被験体に投与することを含む、上記方法。
- 有効量の請求項1〜61のいずれか1項に記載の抗体又は医薬組成物を被験体に投与することを含む、被験体において癌を処置する方法。
- 癌が、黒色腫、頭頸部癌、肺癌、乳癌、前立腺癌、多形神経膠芽腫、結腸直腸癌、肉腫、膀胱癌、子宮頸癌、HPV関連癌、腟癌、外陰癌、陰茎癌、肛門癌、直腸癌、中咽頭癌、多発性骨髄腫、腎細胞癌、卵巣癌、肝細胞癌、子宮内膜癌、膵臓癌、リンパ腫、及び白血病からなる群より選択される、請求項67に記載の方法。
- 抗体又は医薬組成物は、皮下投与又は静脈内投与される、請求項66〜68のいずれか1項に記載の方法。
- 抗体又は医薬組成物が腫瘍内投与される、請求項66〜68のいずれか1項に記載の方法。
- さらなる治療剤を被験体に投与することをさらに含む、請求項66〜70のいずれか1項に記載の方法。
- さらなる治療剤が、化学療法剤、放射線治療薬、又はチェックポイントターゲッティング剤である、請求項71に記載の方法。
- チェックポイントターゲッティング剤が、アンタゴニスト抗PD−1抗体、アンタゴニスト抗PD−L1抗体、アンタゴニスト抗PD−L2抗体、アンタゴニスト抗CTLA−4抗体、アンタゴニスト抗TIM−3抗体、アンタゴニスト抗LAG−3抗体、アンタゴニスト抗CEACAM1抗体、アンタゴニスト抗TIGIT抗体、アゴニスト抗CD137抗体、アゴニスト抗ICOS抗体、アゴニスト抗GITR抗体、及びアゴニスト抗OX40抗体からなる群より選択される、請求項72に記載の方法。
- さらなる治療剤が、インドールアミン−2,3−ジオキシゲナーゼ(IDO)の阻害剤である、請求項71に記載の方法。
- 阻害剤が、エパカドスタット、F001287、インドキシモド、及びNLG919からなる群より選択される、請求項74に記載の方法。
- さらなる治療剤がワクチンである、請求項71に記載の方法。
- ワクチンが、抗原性ペプチドと複合体化した熱ショックタンパク質を含む熱ショックタンパク質ペプチド複合体(HSPPC)を含む、請求項76に記載の方法。
- 熱ショックタンパク質がhsc70であり、そして腫瘍関連抗原性ペプチドと複合体化している、請求項77に記載の方法。
- 熱ショックタンパク質がgp96であり、そして腫瘍関連抗原性ペプチドと複合体化しており、ここでHSPPCは被験体から得られた腫瘍由来である、請求項77に記載の方法。
- さらなる治療剤がTCRを含む、請求項71に記載の方法。
- さらなる治療剤が可溶性TCRである、請求項80に記載の方法。
- さらなる治療剤が、TCRを発現する細胞である、請求項80に記載の方法。
- さらなる治療剤が、キメラ抗原受容体を発現する細胞である、請求項71に記載の方法。
- さらなる治療剤が、ペプチド−MHC複合体に特異的に結合する抗体である、請求項71に記載の方法。
- 癌又は感染性疾患の処置における使用のための、請求項1〜60のいずれか1項に記載の単離された抗体。
- 癌又は感染性疾患を処置するための医薬組成物又は薬剤を製造するための、請求項1〜60のいずれか1項に記載の単離された抗体の使用。
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JP2022513029A (ja) * | 2018-11-14 | 2022-02-07 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | 皮膚がんを治療するためのpd-1阻害剤の病変内投与 |
JP7469305B2 (ja) | 2018-11-19 | 2024-04-16 | バイオサイトジェン ファーマシューティカルズ (ベイジン) カンパニー リミテッド | 抗pd-1抗体およびその使用 |
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