JP2017536340A - 抗体−薬物コンジュゲートのネオアジュバント使用 - Google Patents
抗体−薬物コンジュゲートのネオアジュバント使用 Download PDFInfo
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- JP2017536340A JP2017536340A JP2017518446A JP2017518446A JP2017536340A JP 2017536340 A JP2017536340 A JP 2017536340A JP 2017518446 A JP2017518446 A JP 2017518446A JP 2017518446 A JP2017518446 A JP 2017518446A JP 2017536340 A JP2017536340 A JP 2017536340A
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Abstract
Description
本出願は、その文章全体が参照により本明細書に組み込まれる2014年10月7日に出願された仮米国特許出願第62/060,858号の合衆国法典第35巻第119条(e)に基づく利益を主張する。
本出願は、EFS−ウェブを介してASCII形式で提出されている配列表を含み、同配列表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。前記ASCIIコピーは、2015年9月23日に作製され、名称はIMM350WO1_SL.txtであり、サイズは23,226バイトである。
抗体または抗原結合性抗体断片に付着したカンプトテシン治療剤を含むイムノコンジュゲートを調製するための非限定的な方法及び組成物を以下に説明する。好ましい実施形態では、薬物の溶解度は、規定されたポリエチレングリコール(PEG)部分(すなわち、規定数の単量体単位を含有するPEG)を薬物と抗体の間に配置することによって向上し、ここで規定されたPEGは、低分子量PEGであり、好ましくは1〜30単量体単位を含有し、より好ましくは1〜12単量体単位を含有する。
図2は、ADCを形成するためのコンジュゲーションに使用する例示的なアントラサイクリンである、プロ−2−ピロリノドキソルビシン(P2PDox)を示す。親化合物である、2−ピロリノドキソルビシンは、1996年Schallyのグループにより最初に記載され、彼らは、後にそれを前臨床探索のために多くの受容体標的化ペプチドにコンジュゲートするために使用した(Nagy et al.,1996a,Proc Natl Acad Sci USA 93:7269−73;Nagy et al.,1996b,Proc Natl Acad Sci USA 93:2464−9;Nagy et al.,1997,Proc Natl Acad Sci USA 94:652−6;Nagy et al.,1998,Proc Natl Acad Sci USA 95:1794−9)。これはドキソルビシンの誘導体であり、5員エナミンに組み込まれたダウノサミン窒素を有し、極めて強力なアルキル化剤となり、ドキソルビシンの500〜1000倍の細胞毒性を有する。この薬物の超毒性は、安全性のため、アイソレーター内で特別に扱う必要がある。
事実上あらゆる標的抗原に対するモノクローナル抗体を調製するための技術は、当該分野で周知である。例えば、Kohler and Milstein,Nature 256:495(1975)、及びColigan et al.(eds.),CURRENT PROTOCOLS IN IMMUNOLOGY,VOL,1,pages 2.5.1−2.6.7(John Wiley&Sons 1991)を参照されたい。簡潔には、モノクローナル抗体は、抗原を含む組成物をマウスに注射すること、脾臓を取り出してBリンパ球を得ること、Bリンパ球を骨髄腫細胞と融合させてハイブリドーマを産生すること、ハイブリドーマをクローニングすること、抗原に対する抗体を産生する陽性クローンを選択すること、抗原に対する抗体を産生するクローンを培養すること、及び抗体をハイブリドーマ培養物から単離することによって得ることができる。
キメラ抗体とは、ヒト抗体の可変領域が、例えば、マウス抗体の相補性決定領域(CDR)を含むマウス抗体の可変領域により置き換えられている組換えタンパク質である。キメラ抗体は、対象に投与されたとき、低減した免疫原性及び増加した安定性を呈する。キメラ抗体を構築するための方法は、当該分野で周知である(例えば、Leung et al.,1994,Hybridoma 13:469)。
組み合わせアプローチまたはヒト免疫グロブリン遺伝子座を用いて形質転換したトランスジェニック動物のいずれかを用いて完全ヒト抗体を産生するための方法は、当該分野で公知である(例えば、Mancini et al.,2004,New Microbiol.27:315−28;Conrad and Scheller,2005,Comb.Chem.High Throughput Screen.8:117−26;Brekke and Loset,2003,Curr.Opin.Phamacol.3:544−50;各々参照により本明細書に組み込まれる)。このような完全ヒト抗体は、キメラ抗体またはヒト化抗体よりもさらに少ない副作用を呈し、本質的に内在性のヒト抗体としてin vivoで機能すると期待される。ある特定の実施形態では、特許請求する方法及び手順は、このような技術によって産生されるヒト抗体を利用し得る。
抗体断片は、例えば、従来法によって抗体全体のペプシンまたはパパイン消化により得られ得る。例えば、抗体断片は、F(ab’)2と示される5S断片を提供するようにペプシンによる抗体の酵素的切断により産生されてよい。この断片は、チオール還元剤を、及び任意で、ジスルフィド連結の切断から結果的に生じるスルフヒドリル基のブロッキング基を用いてさらに切断して、3.5S Fab’一価断片を産生し得る。あるいは、ペプシンを用いる酵素的切断は、2つの一価Fab断片及びFc断片を産生する。抗体断片を産生するための例示的な方法は、米国特許第4,036,945号、米国特許第4,331,647号、Nisonoff et al.,1960,Arch Biochem Biophys,89:230;Porter,1959,Biochem.J.,73:119;Edelman et al.,1967,METHODS IN ENZYMOLOGY,page 422(Academic Press)、及びColigan et al.(eds.),1991,CURRENT PROTOCOLS IN IMMUNOLOGY,(John Wiley&Sons)において開示されている。
ある特定の実施形態では、抗体のFc部分などの抗体の配列は、血清中の半減期など、コンジュゲートの生理学的特徴を最適化するように変動してよい。タンパク質におけるアミノ酸配列を置換する方法は、当該分野で広く公知であり、例えば、部位特異的突然変異誘発による(例えば、Sambrook et al.,Molecular Cloning,A laboratory manual、2nd Ed,1989)。好ましい実施形態では、変動はFc配列中の1つまたは複数のグリコシル化部位の付加または除去を必然的に含み得る(例えば、その実施例項が参照により本明細書に組み込まれる、米国特許第6,254,868号)。他の好ましい実施形態では、Fc配列における特定のアミノ酸置換がなされ得る(例えば、Hornick et al.,2000,J Nucl Med 41:355−62;Hinton et al.,2006,J Immunol 176:346−56;Petkova et al.2006,Int Immunol 18:1759−69;米国特許第7,217,797号;各々参照により本明細書に組み込まれる)。
治療用抗体の免疫原性は、注入反応の危険性の増加及び治療応答の持続時間の低減と関係している(Baert et al.,2003,N Engl J Med 348:602−08)。治療用抗体が宿主において免疫応答を誘導する程度は、抗体のアロタイプによって一部決定され得る(Stickler et al.,2011,Genes and Immunity 12:213−21)。抗体アロタイプは、抗体の定常領域配列における特定の位置にあるアミノ酸配列の変動と関連する。重鎖γ型定常領域を含有するIgG抗体のアロタイプは、Gmアロタイプと命名されている(1976,J Immunol 117:1056−59)。
様々な実施形態では、特許請求する方法及び組成物は、当該分野で公知の様々な抗体のうちのいずれかを利用してよい。使用する抗体は、いくつかの公知の源から商業的に得てよい。例えば、様々な抗体分泌性ハイブリドーマ株は、米国培養細胞系統保存機関(ATCC、バージニア州マナサス)から入手可能である。腫瘍関連抗原を含むがこれらに限定されない様々な疾患標的に対する多数の抗体は、ATCCに寄託されており、かつ/または可変領域配列を公開しており、特許請求する方法及び組成物における使用に利用可能である。例えば、米国特許第7,312,318号;同第7,282,567号;同第7,151,164号;同第7,074,403号;同第7,060,802号;同第7,056,509号;同第7,049,060号;同第7,045,132号;同第7,041,803号;同第7,041,802号;同第7,041,293号;同第7,038,018号;同第7,037,498号;同第7,012,133号;同第7,001,598号;同第6,998,468号;同第6,994,976号;同第6,994,852号;同第6,989,241号;同第6,974,863号;同第6,965,018号;同第6,964,854号;同第6,962,981号;同第6,962,813号;同第6,956,107号;同第6,951,924号;同第6,949,244号;同第6,946,129号;同第6,943,020号;同第6,939,547号;同第6,921,645号;同第6,921,645号;同第6,921,533号;同第6,919,433号;同第6,919,078号;同第6,916,475号;同第6,905,681号;同第6,899,879号;同第6,893,625号;同第6,887,468号;同第6,887,466号;同第6,884,594号;同第6,881,405号;同第6,878,812号;同第6,875,580号;同第6,872,568号;同第6,867,006号;同第6,864,062号;同第6,861,511号;同第6,861,227号;同第6,861,226号;同第6,838,282号;同第6,835,549号;同第6,835,370号;同第6,824,780号;同第6,824,778号;同第6,812,206号;同第6,793,924号;同第6,783,758号;同第6,770,450号;同第6,767,711号;同第6,764,688号;同第6,764,681号;同第6,764,679号;同第6,743,898号;同第6,733,981号;同第6,730,307号;同第6,720,155号;同第6,716,966号;同第6,709,653号;同第6,693,176号;同第6,692,908号;同第6,689,607号;同第6,689,362号;同第6,689,355号;同第6,682,737号;同第6,682,736号;同第6,682,734号;同第6,673,344号;同第6,653,104号;同第6,652,852号;同第6,635,482号;同第6,630,144号;同第6,610,833号;同第6,610,294号;同第6,605,441号;同第6,605,279号;同第6,596,852号;同第6,592,868号;同第6,576,745号;同第6,572,856号;同第6,566,076号;同第6,562,618号;同第6,545,130号;同第6,544,749号;同第6,534,058号;同第6,528,625号;同第6,528,269号;同第6,521,227号;同第6,518,404号;同第6,511,665号;同第6,491,915号;同第6,488,930号;同第6,482,598号;同第6,482,408号;同第6,479,247号;同第6,468,531号;同第6,468,529号;同第6,465,173号;同第6,461,823号;同第6,458,356号;同第6,455,044号;同第6,455,040号、同第6,451,310号;同第6,444,206号;同第6,441,143号;同第6,432,404号;同第6,432,402号;同第6,419,928号;同第6,413,726号;同第6,406,694号;同第6,403,770号;同第6,403,091号;同第6,395,276号;同第6,395,274号;同第6,387,350号;同第6,383,759号;同第6,383,484号;同第6,376,654号;同第6,372,215号;同第6,359,126号;同第6,355,481号;同第6,355,444号;同第6,355,245号;同第6,355,244号;同第6,346,246号;同第6,344,198号;同第6,340,571号;同第6,340,459号;同第6,331,175号;同第6,306,393号;同第6,254,868号;同第6,187,287号;同第6,183,744号;同第6,129,914号;同第6,120,767号;同第6,096,289号;同第6,077,499号;同第5,922,302号;同第5,874,540号;同第5,814,440号;同第5,798,229号;同第5,789,554号;同第5,776,456号;同第5,736,119号;同第5,716,595号;同第5,677,136号;同第5,587,459号;同第5,443,953号;同第5,525,338号を参照されたく、この各々の実施例項は参照により本明細書に組み込まれる。これらは、例示的であるに過ぎず、広範な他の抗体及びそれらのハイブリドーマは当該分野で公知である。当業者は、ほぼあらゆる疾患関連抗原に対する抗体配列または抗体分泌性ハイブリドーマを、目的の選択された疾患関連標的に対する抗体について、ATCC、NCBI及び/またはUSPTOのデータベースを簡単に検索することによって得られ得ることを認識するだろう。クローニングされた抗体の抗原結合性ドメインを、当該分野で周知の標準的な技術を用いて、増幅し、切除し、発現ベクターにライゲートし、適応させた宿主細胞にトランスフェクトし、タンパク質産生のために使用し得る(例えば、米国特許第7,531,327号;同第7,537,930号;同第7,608,425号及び同第7,785,880号を参照されたく、これらの各々の実施例項は参照により本明細書に組み込まれる)。
CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD66a−e、CD67、CD70、CD70L、CD74、CD79a、CD80、CD83、CD95、CD126、CD132、CD133、CD138、CD147、CD154、CDC27、CDK−4/m、CDKN2A、CTLA−4、CXCR4、CXCR7、CXCL12、HIF−1α、結腸特異的抗原−p(CSAp)、CEACAM5、CEACAM6、c−Met、DAM、EGFR、EGFRvIII、EGP−1(TROP−2)、EGP−2、ELF2−M、Ep−CAM、線維芽細胞増殖因子(FGF)、Flt−1、Flt−3、葉酸受容体、G250抗原、GAGE、gp100、GRO−β、HLA−DR、HM1.24、ヒト絨毛性ゴナドトロピン(HCG)及びそのサブユニット、HER2/neu、HMGB−1、低酸素誘導因子(HIF−1)、HSP70−2M、HST−2、Ia、IGF−1R、IFN−γ、IFN−α、IFN−β、IFN−λ、IL−4R、IL−6R、IL−13R、IL−15R、IL−17R、IL−18R、IL−2、IL−6、IL−8、IL−12、IL−15、IL−17、IL−18、IL−23、IL−25、インスリン様成長因子−1(IGF−1)、KC4−抗原、KS−1−抗原、KS1−4、Le−Y、LDR/FUT、マクロファージ遊走阻止因子(MIF)、MAGE、MAGE−3、MART−1、MART−2、NY−ESO−1、TRAG−3、mCRP、MCP−1、MIP−1A、MIP−1B、MIF、MUC1、MUC2、MUC3、MUC4、MUC5ac、MUC13、MUC16、MUM−1/2、MUM−3、NCA66、NCA95、NCA90、PAM4抗原、膵臓癌ムチン、PD−1、PD−L1、PD−1受容体、胎盤増殖因子、p53、PLAGL2、前立腺性酸性ホスファターゼ、PSA、PRAME、PSMA、PlGF、ILGF、ILGF−1R、IL−6、IL−25、RS5、RANTES、T101、SAGE、S100、サバイビン、サバイビン−2B、TAC、TAG−72、テネイシン、TRAIL受容体、TNF−α、Tn抗原、トムソン−フリーデンライヒ抗原、腫瘍壊死抗原、VEGFR、ED−Bフィブロネクチン、WT−1、17−1A−抗原、補体因子C3、C3a、C3b、C5a、C5、血管新生マーカー、bcl−2、bcl−6、Kras、発がん遺伝子マーカー及び発がん遺伝子産物が含まれる(例えば、Sensi et al.,Clin Cancer Res 2006,12:5023−32;Parmiani et al.,J Immunol 2007,178:1975−79;Novellino et al.Cancer Immunol Immunother 2005,54:187−207を参照されたい)。
二重特異性抗体は、多くの生物医学用途において有益である。例えば、腫瘍細胞表面抗原及びT細胞表面受容体に対する結合部位を有する二重特異性抗体は、T細胞により特定の腫瘍細胞の溶解をもたらすことができる。神経膠腫及びT細胞上のCD3エピトープを認識する二重特異性抗体は、ヒト患者の脳腫瘍の処置での使用に成功している(Nitta, et al.Lancet.1990;355:368−371)。ある特定の実施形態では、本明細書に開示する治療剤コンジュゲーションのための技術及び組成物は、二重特異性または多重特異性抗体を抗体部分として共に使用してよい。
二重特異性または多重特異性抗体は、前標的化技術においても利用され得る。前標的化は、多段階プロセスであり、元々は、骨髄などの正常組織への望ましくない毒性に寄与する、抗体を直接標的化する際の血液クリアランスの遅さを解決するために開発された。前標的化により、放射性核種または他の治療剤は、数分で血液から排泄される小さな送達分子(標的可能な構築物)に付着する。前標的化二重特異性または多重特異性抗体は、標的可能な構築物ならびに標的抗原に対する結合部位を有し、最初に投与され、遊離抗体は循環から排泄され、次いで標的可能構築物が投与される。
ある特定の実施形態では、前標的化での使用のために1つまたは複数の治療剤または診断剤で標識されている標的可能な構築物ペプチドは、標的可能な構築物ペプチドに対する1つまたは複数の結合部位及び疾患または状態に関連する標的抗原に対する1つまたは複数の結合部位を有する二重特異性抗体に結合するように選択され得る。二重特異性抗体は、前標的化技術において使用され得、ここで抗体は、対象に最初に投与され得る。二重特異性抗体が標的抗原に結合し、未結合抗体が循環から排泄されるために十分な時間が許容され得る。次いで、標的可能な構築物、例えば、標識されたペプチドが、対象に投与され、二重特異性抗体への結合が可能になり、疾患細胞または組織で局在化し得る。
好ましい実施形態では、二価または多価抗体が、DOCK−AND−LOCK(商標)(DNL(商標))複合体として形成される(例えば、米国特許第7,521,056号;同第7,527,787号;同第7,534,866号;同第7,550,143号及び同第7,666,400号を参照されたく、その各々の実施例項は参照により本明細書に組み込まれる)。通常、cAMP依存性プロテインキナーゼ(PKA)の調節(R)サブユニットの二量体化及びドッキングドメイン(DDD)配列と、様々なAKAPタンパク質のいずれかに由来するアンカードメイン(AD)配列との間に生じる特異的及び高親和性の結合相互作用を利用する(Baillie et al.,FEBS Letters.2005;579:3264.Wong and Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。DDD及びADペプチドは、任意のタンパク質、ペプチドまたは他の分子に付着し得る。DDD配列が自発的に二量体化し、AD配列に結合するため、本技術は、DDDまたはAD配列に付着し得る任意の選択された分子間の複合体の形成を可能にする。
ある特定の代替の実施形態では、DNL(商標)構築物は、代替的に構築された抗体または抗体断片を使用して形成されてよく、ここでAD部分は、重鎖上のFcのC末端の代わりに、カッパ軽鎖(Ck)のC末端で付着されてよい。代替的に形成されたDNL(商標)構築物は、各々の文書全体が参照により本明細書に組み込まれる、米国仮特許出願第61/654,310号(2012年6月1日に出願)、同第61/662,086号(2012年6月20日に出願)、同第61/673,553号(2012年7月19日に出願)及び同第61/682,531号(2012年8月13日に出願)に開示されるように調製され得る。軽鎖コンジュゲートしたDNL(商標)構築物は、in vitroで向上したFc−エフェクタ機能活性、及びin vivoで改善した薬物動態、安定性及び抗リンパ腫活性を呈した(Rossi et al.,2013,Bioconjug Chem 24:63−71)。
特許請求する組成物及び/または方法のある特定の実施形態は、様々な標的分子、細胞または組織の結合性ペプチド及び/またはペプチド模倣物に関し得る。結合性ペプチドは、ファージディスプレー技術を含むがこれに限定されない当該分野で公知の任意の方法により同定され得る。ペプチドの多様な集団を産生するための様々な方法のファージディスプレー及び技術が当該分野で周知である。例えば、米国特許第5,223,409号;同第5,622,699号及び同第6,068,829号は、ファージライブラリを調製するための方法を開示する。ファージディスプレー技術は、低分子ペプチドがバクテリオファージの表面上に発現することができるようにバクテリオファージを遺伝子操作することを必然的に含む(Smith and Scott,1985,Science 228:1315−1317;Smith and Scott,1993,Meth.Enzymol.21:228−257)。ペプチドに加えて、一本鎖抗体などのより大きなタンパク質ドメインも、ファージ粒子の表面上に呈され得る(Arap et al.,1998,Science 279:377−380)。
ナノボディは、約12〜15kDナノボディは、標的抗原を用いるaの大きさ(約110の長さのアミノ酸)の単一ドメイン抗体である。ナノボディは、フルサイズ抗体のように、標的抗原に選択的に結合でき、抗原と同様の親和性を有する。しかしながら、サイズが非常に小さいため、ナノボディは、固形腫瘍により良好に浸透することができ得る。この小さなサイズは、ナノボディの安定性にも寄与しており、フルサイズ抗体よりもpH及び温度に対する耐性が高くなる(Van Der Linden et al.,1999,Biochim Biophys Act 1431:37−46)。当初、単一のドメイン抗体は、ラクダ類(ラクダ、アルパカ、ラマ)が、軽鎖を伴わずに完全に機能的な抗体を有するとの発見に従って開発された(例えば、Hamsen et al.,2007,Appl Microbiol Biotechnol 77:13−22)。重鎖抗体は、単一の可変ドメイン(VHH)及び2つの定常ドメイン(CH2及びCH3)からなる。抗体のように、ナノボディは、多価及び/または二重特異性の構築物として開発及び使用され得る。IL−6R、vWF、TNF、RSV、RANKL、IL−17A&F及びIgE(例えば、ABLYNX(登録商標)、ベルギー、ヘント)などの様々な標的抗原に標的化されたナノボディのヒト化形態が商業的に開発されており、癌において臨床的に使用される可能性がある(例えば、Saerens et al.,2008,Curr Opin Pharmacol 8:600−8;Muyldermans,2013,Ann Rev Biochem 82:775−97)。
好ましいコンジュゲーションプロトコルは、中性または酸性pHで容易である、チオール−マレイミド、チオール−ビニルスルホン、チオール−ブロモアセトアミド、またはチオール−ヨードアセトアミド反応をベースとする。これは、例えば、活性エステルを使用するときに必要とされるだろうコンジュゲーションのためのより高いpH条件の必要性を取り除く。例示的なコンジュゲーションプロトコルのさらなる詳細を以下に実施例項にて記載する。
別の態様では、本発明は、対象を処置する方法であって、本明細書に記載の治療有効量の治療用コンジュゲートを対象に投与することを含む、前記方法に関する。本明細書に記載の治療用コンジュゲートを用いて処置され得る疾患には、B細胞悪性腫瘍(例えば、非ホジキンリンパ腫、マントル細胞リンパ腫、多発性骨髄腫、ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫、バーキットリンパ腫、濾胞性リンパ腫、急性リンパ性白血病、慢性リンパ性白血病、毛髪様細胞白血病)を含むがこれに限定されず、例えば、別のCD22エピトープ(hRFB4)に対するhLL2 MAb(エプラツズマブ、米国特許第6,183,744を参照されたい)などの抗CD22抗体、またはCD19、CD20、CD21、CD22、CD23、CD37、CD40、CD40L、CD52、CD74、CD80またはHLA−DRなどの他のB細胞抗原に対する抗体を使用する。他の疾患には、内胚葉由来消化系上皮の腺癌、乳癌及び非小細胞肺癌などの癌、ならびに他の癌腫、肉腫、グリア系腫瘍、骨髄性白血病等を含むが、これらに限定されない。具体的には、悪性固形腫瘍または造血器腫瘍、例えば、消化管、胃、結腸、食道、肝臓、肺、乳房、膵臓、肝臓、前立腺、卵巣、精巣、脳、骨もしくはリンパ系腫瘍、肉腫または黒色腫により産生されたまたはこれに関連する抗原、例えば、癌胎児性抗原に対する抗体は、有利に使用される。そのような治療剤は、疾患状態及びコンジュゲートの忍容性に応じて、1回または反復して与えられることができ、外科手術、外照射、放射免疫療法、免疫療法、化学療法、アンチセンス療法、干渉RNA療法、遺伝子療法等の他の治療様式と任意で組み合わせて使用することもできる。各組み合わせは、腫瘍のタイプ、ステージ、患者の状態及び以前の治療ならびに担当医により考慮される他の因子に適合されるだろう。
コンジュゲートの好適な投与経路には、経口、非経口、皮下、直腸、経粘膜、腸投与、筋肉内、髄内、くも膜下腔内、直接心室内、静脈内、硝子体内、腹腔内、鼻腔内、または眼球内注射が含まれるが、これらに制限されるものではない。好ましい投与経路は、非経口である。あるいは、例えば、固形腫瘍内に直接化合物を注射することを介して、全身様式よりむしろ局所にて化合物を投与してよい。
特定の実施形態では、本発明は、トリプルネガティブ乳癌のネオアジュバント処置のためのADCイムノコンジュゲートの使用に関する。TNBCは、用語が示すように、エストロゲン受容体及びプロゲステロン受容体(ER、PR)、ならびにHER2(ERBB2)の発現を欠いている乳癌を指す。この種は、全侵襲性乳癌の約15〜20%を構成し、非常に悪性である。TNBC患者は、他の乳癌と比較して遠隔再発及び死亡の割合が高く(Millikan et al.,Breast Cancer Res Treat 2008;109:123−139)、転移性疾患を伴うこれらの生存期間中央値はたった13カ月である(Kassam et al.,Clin Breast Cancer 2009;9:29−33)。罹病率に関しては、TNBCは、若年患者、BRCA1突然変異保有者、ならびに特定の民族、例えばアフリカ系アメリカ人及びヒスパニック系の女性においてより頻繁にみられる(Bauer et al.,Cancer 2007,109:1721−1728;Sorlie et al.,Proc Natl Acad Sci USA 2003,100:8418−8423;26−28;Foulkes et al.,N Engl J Med 2010,363:1938−1948)。これは、生殖細胞系列遺伝的背景が、TNBCの転写及び分化において役割を果たしていることを示す。組織学的に、大半のTNBC腫瘍は、侵襲性乳管腫であり、組織学的グレードが高く、腫瘍サイズが大きく、診断時にはリンパ節転移陽性であることが非常に多い(Dent et al.,Clin Cancer Res 2007,13:4429−4434)。予後は、転移の挙動に関連し、サブタイプにより転移のパターンは異なる。乳癌は、一般的に、骨に転移するが、基底様疾患は、脳、肺、及び遠隔リンパ節への転移が多数を占める(Kennecke et al.,J Clin Oncol 2010,28:3271−3277;Sihto et al.,Breast Cancer Res 2011,13:R87)。非基底形態は、類似したパターンの転移を示すが、肝臓への転移がより頻繁である。
ある特定の実施形態は、抗TROP−2 hRS7抗体に付着しているSN−38カンプトテシン型薬物の多数のコピーを含むADCである、IMMU−132のTNBCにおけるネオアジュバント使用に関する。SN−38は、CPT−11(イリノテカン)の活性代謝産物であり、乳癌における標準的な薬物ではないが、TNBCにおいて固有の治療的利益を提供し得る。BRCA1突然変異を発現する癌に対してTNBCがその表現型において類似しており、それゆえ、BRCAに伴うDNA修復機序における欠失に起因して、かかるBRCA1患者において有効である、プラチナ製剤及びアルキル化剤、ならびにトポイソメラーゼI阻害剤(例えば、トポテカン及びイリノテカンのようなカンプトテシン)などの、薬剤に反応性である可能性があると想定されている。これらは、二重鎖DNAの切断を誘導し、DNA修復に影響を与え、細胞死を引き起こすことにより作用する(Hastak et al.,Cancer Res 2010;70:7970−7980)。ポリ(アデノシン二リン酸リボース)ポリメラーゼ(PARP)を阻害する同様の作用機序は、BRCA同様、DNA修復においても重要な役割を果たすが、PARP阻害剤は、DNAの1つの鎖に損傷を引き起こし、これは、BRCA突然変異及びPARP阻害のために、相同組換えにより修復することができない。
pCRは、TNBCを有する患者におけるネオアジュバント療法治験の容認エンドポイントとなっている(Bardia&Baselga,Clin Cancer Res 2013 Dec 1;19(23):6360−6370;Ademuyiwa et al.,J Onc 2013;2013:219869;Food and Drug Administration。業界用ドラフトガイダンス:Pathologic Complete Response in Neoadjuvant Treatment of High−Risk Early−Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.May 2012)。pCRは、FDAガイダンス書類において「ネオアジュバント全身療法の完了後に、摘出した乳房検体及び[全ての採取した]同側リンパ節のヘマトキシリン・エオシン評価上でいずれの侵襲性癌も残存しない(すなわち、現行のAJCC病期分類システムにおいてypT0ypN0である)として」既定されている(Food and Drug Administration.業界用ドラフトガイダンス:Pathologic Complete Response in Neoadjuvant Treatment of High−Risk Early−Stage Breast Cancer:Use as an Endpoint to Support Accelerated Approval.May 2012)(イタリック強調を追加)[訳者注:[全ての採取した]が強調されている箇所である]。これにより、転移性疾患の設定よりも比較的少数の患者で素早く薬物を検査することが可能になるが、ネオアジュバント療法の開始後6カ月以内またはそれより早期の外科手術の結果に基づく迅速な(暫定的な)薬物承認をもたらす可能性がある外科手術での有効性の評価、治療成功期間(EFS)及び全生存(OS)率を決定するための経過観察は、最終的な薬物承認につながる臨床的利益を実証するために依然として必要とされている。承認の迅速化のためのこの道筋は、遥かに早く一般使用に薬物を利用可能にし、様々な臨床試験及び設定におけるその包含を拡大し、これがTNBCの外科手術に直面している女性に非常に迅速な利益を提供することができることを意味する。IMMU−132の毒性プロファイルが、同様の作用機序を扱うプラチナ製剤及びPARP薬物よりも真に優れているならば、この新規治療剤の追加は、TNBC治療のネオアジュバントにおける(ならびに、おそらく補助剤及び転移性設定でも)パラダイムシフトを引き起こす可能性がある。また、IMMU−132の標的であるTROP−2が、非トリプルネガティブ(TN)腫瘍においても高率で発現されるため、この薬剤は、これらの他の乳癌型においても特有の活性を示し得る。転移性及び早期TNBCの治療における有望な結果は、非TN癌を有する患者においてもこの薬剤の研究を奨励するだろう。
様々な実施形態は、患者を処置するために好適な構成要素を含有するキットに関し得る。例示的なキットは、本明細書に記載の少なくとも1つのコンジュゲートされた抗体または他の標的化部分を含有してよい。投与するための成分を含有する組成物が、経口送達によるものなどの消化管を介する送達用に製剤化されていない場合、いくつかの他の経路を通してキット構成要素を送達することができるデバイスが含まれ得る。非経口送達などの用途のためのデバイスの1タイプは、組成物を対象の体内に注入するために使用されるシリンジである。吸入デバイスも使用してよい。
CL2A−SN−38の合成のための好ましい反応スキームでは、EEDQ(0.382g)を、市販されているFmoc−Lys(MMT)−OH(0.943g)及びp−アミノベンジルアルコール(0.190g)の混合物を含む塩化メチレン(10mL)に、室温で加え、4時間撹拌した。抽出処理、その後フラッシュクロマトグラフにより、1.051gの物質を白色泡状物として得た。エレクトロスプレー質量スペクトルは、ピークをm/e745.8(M+H)及びm/e780.3(M+Cl−)で示し、これは構造と一致した。Lys(MMT)−PABOH中間体(0.93g)を、ジエチルアミン(10mL)中に溶解し、2時間撹拌した。溶媒除去後、残渣をヘキサン中で洗浄して、0.6gの中間体を無色沈査として得た(HPLCにより91.6%純度)。HPLC保持時間:2.06分。エレクトロスプレー質量スペクトルは、ピークをm/e523.8(M+H)、m/e546.2(M+Na)及びm/e522.5(M−H)で示した。
抗CEACAM5ヒト化MabであるhMN−14、抗CD22ヒト化MabであるhLL2、抗CD20ヒト化MabであるhA20、抗EGP−1ヒト化MabであるhRS7、及び抗ムチンヒト化MabであるhPAM4を、CL2A−SN−38にコンジュゲートしてイムノコンジュゲートを調製した。各抗体を、トリス(2−カルボキシエチル)ホスフィン(TCEP)を含むリン酸緩衝液で7〜7.4の範囲のpHで穏やかに還元し、pHを6.5に調整し、約10倍モル過剰のCL2A−SN−38と、DMSOを5〜10%v/vで共溶媒として使用して反応させ、20分間にわたって周囲温度でインキュベートした。抗体に関して10倍モル過剰で水溶液として使用されるN−エチルマレイミドで過剰チオールはいずれもキャップした。
In vitro特徴づけ−TROP−2陽性ヒト前立腺癌腫細胞株である、PC−3を標的として使用して、非コンジュゲートhRS7 IgGと比較してIMMU−132による抗原結合における潜在的な変化を評価した。3つの別々の場合で測定したとき、IMMU−132及び非コンジュゲートhRS7 IgGの結合性の間で有意差はなかった(KD値、それぞれ、0.658±0.140nM対0.564±0.055nM)。
IMMU−132を、MDA−MB−468 TNBC腫瘍を有するマウスにおいて評価した(図4A;用量は、SN−38当量で示す)。IMMU−132(0.2mg/kg)は、食塩水、イリノテカン(6mg/kg)、または対照抗CD20 ADC、hA20−CL2A−SN−38と比較したとき、有意な腫瘍退縮を引き起こした(P<0.0012、AUC)。用量を0.12mg/kgまで低下させたときでさえ、IMMU−132は、マウスにおいて有意に腫瘍体積を減少させた(P<0.0017、AUC)。重要なことに、この低量のIMMU−132で与えられたSN−38当量の総量は、たった9.6μgであり、一方でマウスに投与された6mg/kgは62.5倍の利益を表した(600μg累積用量)。しかしながら、イリノテカン群における最初のマウスが疾患進行のために失われたとき、IMMU−132(0.12mg/kg)で処置したマウスにおける腫瘍体積(TV)は、イリノテカンで処置したマウスのものよりも有意に小さかった。(それぞれ、TV=0.17±0.12cm3対0.53±0.29cm3;P=0.0094、両側T検定)。他の固形腫瘍モデルにおいて見いだされるように、IMMU−132を用いる腫瘍に対する少量のSN−38の特異的標的は、遥かに多い用量の非標的薬物よりも遥かに有効である。
IMMU−132は、最近の治療後に再発して中央値で3つの治療を以前に受けた、多様な転移性固形癌を有する25人の患者における用量設定第I相試験を完了している。25人のうち23人は、コンピュータ断層撮影(CT)によりRECIST1.1について評価可能であり、知見は以下の通りであった。(1)8〜10mg/kg/用量を与える21日間のサイクルの1日目及び8日目の処置の用量スケジュールは、忍容性を示し、有効であった。(2)G−CSF造血支持は最低限必要であるが、時折の投与遅延及び/または用量減少を伴って、最大10カ月までさえも、反復サイクルを投与することができる。(3)治療の反復施行にもかかわらず、抗薬物抗体または抗抗体抗体は感受性ELISA試験によって検出されなかった。(4)主要な毒性は、好中球減少症、下痢、及び脱毛症であり、単独で与えられるときのSN−38の親化合物であるイリノテカンのそれと一致しているが、IMMU−132ではより管理可能であった。(5)IMMU−132は、13人の患者で安定疾患、3例で部分奏効(TNBC、小細胞肺癌、及び結腸直腸癌)、7例で進行性疾患を、最良奏効として達成することにより、in vivoでヒト対象において抗腫瘍活性を示した。最長無増悪期間は、第I相試験で転移性ホルモン難治性前立腺癌を有する患者における、約57週間であった。
忍容可能な好中球減少症(神経障害またはアドリアマイシン、タキサン、及びプラチナ薬剤に顕著な他の副作用のエビデンスがない)は、特に、ネオアジュバント設定において処置未経験患者で、IMMU−132がこれらの薬剤のうちの1つまたは複数と併用できることを示す。ドキソルビシン+シクロホスファミドの前後でのパクリタキセルの長期使用を考えると、本発明者らは、IMMU−132がパクリタキセルと併用して12週間にわたって与えられるべきだと考えた。この場合、IMMU−132の典型的なサイクルは、8mg/kgを21日毎の1日目及び8日目に与えるものである。パクリタキセル±IMMU−132の12週間処置レジメンを完了後、ドキソルビシン及びシクロホスファミドを、4コースにわたって、隔週で投与し、使用される標準的なプロトコルに従う(下記例)。IMMU−132が追加される治験群と同じように、対照群は、パクリタキセル、ドキソルビシン+シクロホスファミドを用いる治療のみを受ける。好中球減少症を制限し、発熱性好中球減少症を回避するために、そのレジメンにおけるIMMU−132の用量減少は、併用により経験される好中球減少症の等級及び持続期間に従って許容される。現在の経験におけるように、パクリタキセルも減少が必要である場合があり、G−CSF(例えば、ニューポジェン)を用いた造血支持の選択肢が、最初の治療コースについて担当医の裁量にゆだねられる。しかしながら、本発明者らは、ドキソルビシン+シクロホスファミドの第二群の開始後の予防的G−CSF療法を要求する(共同研究者の推奨に基づく)。
上述の第I相試験では、血清試料を、各処置について、「ピーク」レベルを表す注入終了の30分以内に(ほとんどの注入は2〜3.5時間続いた)、次いで「トラフ」レベルを表す次の用量の直前に回収した。2回のELISAアッセイを使用してピーク及びトラフ血清試料を測定した。一方のアッセイは、抗SN−38抗体で被覆されたプレート(Immunomedicsにより開発された)を使用してインタクトなコンジュゲート(ADC)に付着したSN−38を結合することにより生成物を捕捉する。結合した生成物を、次いで、特異的抗イディオタイプ抗体(すなわち、抗hRS7 IgG)を使用して目的の抗体であるとして同定する。ゆえに、このアッセイは、インタクトなコンジュゲートを測定する。他方のアッセイは、血清中のhRS7 IgGを検出するように構成される。図6Aは、4つの用量レベルにおけるIgG及びADCピークレベルを示す。ピークレベルを患者の体重に正規化するとき(すなわち、μg/mL/kg)、用量が増加するにつれて濃度が増加する傾向が見られる(図6B)。
臨床的に、IMMU−132は、8mg/kgで投与されている(すなわち、約0.16μg/kg SN−38当量)。ヒト用量の8mg/kgは、マウス用量にすると、98.4mg/kgまたは20gのマウスに対しておおよそ2mgである。この用量は、3つのうちの1つ異なる投薬スキームに分割され、動物の1群は2回の1mgのIMMU−132用量(1及び15日目)を受け、これは隔週投薬レジメンを表し、1群は、4用量の500μg(1、8、22、及び29日目)を与えられ、これは21日間の処置サイクルにおける2週間にわたる週1回を表し、最後の群は、8用量の250μg(1、4、8、11、22、25、29、及び32日目)を与えられ、これは21日間の処置サイクルにおける2週間にわたる週2回を表す。これらの投薬スキームを、ヒト胃癌腫及び膵臓腺癌異種移植モデルにおいて試験した(図8)。
マウス及びカニクイザルを両方とも活用して、IMMU−132の毒性動力学を評価した(Cardillo et al.,Clin Cancer Res 2011;17:3157−3169)。Swiss−Websterマウスにおいて、4、8、または12mg/kgのSN−38当量(250、500、または750mg/kgタンパク質用量)での2用量のIMMU−132を、3日間離して投与した。体重減少がないことから示されるように動物にて毒性の明白な兆候は観察されなかった(結果はファイル上)。造血器毒性は生じておらず、血清化学はアスパラギン酸トランスアミナーゼ(AST)及びアラニントランスアミナーゼ(ALT)レベルが二回目の注射の7日後に上昇したことを明らかにしたのみであった。しかしながら、これらの酵素は正常に戻り、病理組織検査で肝病変のエビデンスはなかった。
一般に、癌細胞は、外因性または内因性アポトーシス経路と称される2つの主経路のうちの1つを介してアポトーシスを起こすことができる(Fulda&Debatin,Oncogene 2006;25(34):4798−4811)。外因性経路は、細胞表面の細胞死受容体(例えば、TNFファミリー受容体)の係合を特徴とし、これはカスパーゼ−8の活性化をもたらし、これがカスパーゼ3などの下流カスパーゼの活性化をもたらし、最終的にポリ−ADP−リボースポリメラーゼ(PARP)を切断し、DNAを断片化し、細胞死をもたらす。反対に、内因性経路は、ミトコンドリアから細胞質内へのシトクロムc放出をもたらす直接的なDNA損傷(例えば、電離放射線)または他の細胞のストレス(例えば、細胞周期停止)のいずれかにより引き起こされることができる。シトクロムcは、次いで、アポトーシスプロテアーゼ活性化因子−1(APAF−1)と複合体を形成し、これがカスパーゼ−9を活性化するプラットフォームとして作用し、その後カスパーゼ−3及び−7を含むカスパーゼ活性化カスケードを開始し、PARP切断、ならびに細胞死がもたらされる。
組織におけるSN−38のクリアランス及び取込みを、40mg/kgのイリノテカン(773μg;総SN−38当量=448μg)またはIMMU−132(1.0mg、DAR=7.6、SN−38当量=20μg)を静脈内注射されたCapan−1膵臓癌異種移植片(約0.06〜0.27g)を有するヌードマウスにおいて調べた。イリノテカン用量は、マウスのMTDであり、ヒトでは3.25mg/kgまたは約126mg/m2が当量である。マウスにおいてIMMU−132用量はMTDを十分に下回り、約4mg/kg IMMU−132のヒト当量用量を表す(80μg/kg SN−38当量)。動物の群(n=3)を5つの間隔で病理解剖した;イリノテカンについては、5分、1時間、2時間、6時間、及び24時間ならびにIMMU−132については、1時間、6時間、24時間、48時間、72時間。動物から採取した血清を水中で1:2に希釈し、次いで、等分のメタノール:エチレングリコール:1M ZnSO4で抽出した。この培地では、SN−38、SN−38G(グルクロン酸抱合)、及びイリノテカンは有機相に取込まれ、一方でタンパク質は沈殿する。ゆえに、IgGに結合したSN−38はいずれも沈殿し、検出されなくなる。
CD74は、内部移行し、抗体結合の後に再循環するので、抗体−薬物コンジュゲート(ADC)のための魅力的な標的である。CD74の多くは、血液癌に関連しているが、固形癌でも発現される。従って、CD74を発現する固形腫瘍の治療に関するヒト化抗CD74抗体、ミラツズマブと調製されたADCの有用性を調べた。ミラツズマブ−ドキソルビシン及び2つのミラツズマブ−SN−38コンジュゲートを、切断可能リンカー(CL2A及びCL2E)と共に調製したが、これらは血清におけるその安定性及びどのようにSN−38をリソソーム中に放出するかにおいて異なる。CD74発現を、フローサイトメトリー及び免疫組織学により決定した。In vitro細胞毒性及びin vivo治療試験をヒト癌細胞株A−375(黒色腫)、HuH−7及びHep−G2(肝がん)、Capan−1(膵臓)、及びNCI−N87(胃)、及びRajiバーキットリンパ腫において行った。ミラツズマブ−SN−38ADCを抗TROP−2及び抗CEACAM6抗体と調製したSN−38ADCとそれらの標的抗原を発現している異種移植片において比較した。
ヒト腫瘍細胞株。Rajiバーキットリンパ腫、A−375(黒色腫)、Capan−1(膵臓腺癌)、NCI−N87(胃癌腫)、Hep−G2肝がん及びMC/CAR骨髄腫細胞株をAmerican Tissue Culture Collection(バージニア州、マナサス)から購入した。HuH−7肝がん細胞株を日本ヒューマンサイエンス研究資源バンク(Japan Health Science Research Resources Bank)(日本、大阪府)から購入した。全ての細胞株は、加湿されたCO2インキュベーター(5%)内、37℃で、10%〜20%仔牛血清及びサプリメントを含有する推奨培地内で培養した。細胞を50回未満で継代し、マイコプラズマについて定期的に検査した。
ヒト腫瘍細胞株及び異種移植片におけるCD74発現。固形腫瘍細胞株における膜のみのCD74のMFIが、バックグラウンドMFIよりも非常に頻繁に2倍未満で高かったため(A−375黒色腫細胞株を除く)、4つの異なる固形腫瘍型に由来する6つの細胞株を、透過処理した細胞の分析に主に基づいてCD74陽性であると同定した(表4)。Rajiにおける表面CD74発現は、固形腫瘍細胞株よりも5倍超高かったが、透過処理したRaji細胞における総CD74は、固形腫瘍細胞株の大半と同様であった。
患者は、mCRCを有する62歳の女性であり、2012年1月に転移性疾患を最初に呈した。女性は、診断の数週間後に最初の治療として腹腔鏡下での回腸横行結腸切除術を受け、次いで、4サイクルのFOLFOX(ロイコボリン、5−フルオロウラシル、オキサリプラチン)化学療法をネオアジュバント設定で受け、その後、肝臓の右葉にある転移性病変を除去するために2012年3月に右肝切除を受けた。この後、合計で12サイクルのFOLFOXにわたるアジュバントFOLFOXレジメンを2012年6月に再開した。8月に、オキサリプラチンを、悪化する神経毒性のために、レジメンから除去した。女性の5−FUの最後のサイクルは2012年9月25日であった。
患者は、57歳の女性であり、ステージIV、トリプルネガティブ、乳癌(ER/PRネガティブ、HER−neuネガティブ)を有し、2005年に最初に診断された。女性は、2005年に左乳房の腫瘍摘出手術を受け、その後、2005年9月に投与集中ACTをアジュバント設定で受けた。次いで、女性は、放射線療法を受け、これは11月に完了した。2012年初期に患者が対側(右)乳房にしこりを触診したときに疾患の局所再発が認められ、その後CMF(シクロホスファミド、メトトレキサート、5−フルオロウラシル)化学療法を用いて処置された。女性の疾患は同年に再発し、胸壁の皮膚の転移性病変を伴った。次いで、女性は、カルボプラチン+TAXOL(登録商標)化学療法レジメンを受け、その間に、血小板減少症が生じた。女性の疾患は進行し、女性は週1回ドキソルビシンを開始し、これを6用量にわたって継続した。皮膚疾患も進行していた。FDG−PETスキャンを2012年9月26日に行い、胸壁上への疾患の進行及び固形腋窩結節の肥大が示された。患者は疼痛制御のためにオキシコドンを投与された。
本試験は、手術可能なTNBC、ステージII及びIIIを有する18歳以上の女性を対象とする。適格な患者が登録され、コンピュータによって2つの治療群のうちの1つに無作為化される。この治療群は、一方の群が、以下の処置レジメンに示すように、併用療法の最初のコースでIMMU−132をパクリタキセルに追加する点を除いて同一である(図11)。用量減少及び用量遅延のルールは、IMMU−132について、毒性が先行治験から予測されるそれを超えた場合に、可能であればパクリタキセルを処方量に維持するように、確立された。G−CSFなどの骨髄増殖因子の使用は、治験群のこの最初の併用コースについては担当医師の裁量にあるが、患者が、最後の化学療法コースとして外科手術の前にドキソルビシン及びシクロホスファミドの併用を受けているときは、発熱性好中球減少症のリスクを低下させるためにG−CSFの予防的投与が義務づけられる。
組み入れ基準
1.18歳以上で侵襲性乳癌と診断された女性により記載されたインフォームドコンセント。
2.コア針生検または切開(摘出でない)生検により組織学的に確認された侵襲性乳癌。身体検査または放射線検査により臨床ステージT2−4N0−2またはT1N1−2。
3.乳癌遺伝子(BRCA)生殖細胞系列突然変異検査の記述。
4.エストロゲン受容体(ER)−ネガティブ、プロゲステロン受容体−ネガティブ、及びヒト上皮成長因子(HER2)−ネガティブ(トリプル−ネガティブ)乳癌。
5.ECOGパフォーマンスステータス0−1。
6.登録の1カ月以内でのECG及び心臓エコー(LVEFまたは左室内径短縮率)により確認された正常な心機能。
7.CBC及びHgbレベルにより反映される十分な骨髄機能。
8.無作為化の前に、妊娠の可能性がないまたは陰性血清妊娠反応。
除外基準
1.現在の乳癌に対する治療目的を有する治験剤を含む、以前の全身または局所領域的抗癌治療。
2.この治験に含まれる薬剤のいずれかを用いた以前の処置。
3.転移性乳癌
4.無作為化の時点で卵巣補充療法もしくはホルモン剤を用いるまたは任意のエストロゲン受容体調節因子を用いる同時処置。
5.試験登録の12カ月以内のてんかん発作の病歴。
6.グレード1を超える任意の原因からの既存神経障害。
7.既存する異常に低い値の白血球(好中球)、血小板、赤血球またはヘモグロビン。
8.In situでの子宮頸癌または皮膚の基底細胞癌以外の癌の5年以内の病歴。
9.ネオアジュバント療法に対する不耐性を示す医学的状態(未制御肺疾患、糖尿病、重度汗腺、活動性消化性潰瘍、凝固障害、結合組織疾患、骨髄抑制性疾患)。
10.不十分な肝臓または腎臓機能。
11.デキサメタゾンまたは高用量のコルチコステロイドの使用に対する禁忌。
12.うっ血性心不全またはコントロール不良の高血圧を含む他の重篤な心臓状態の病歴。
13.妊娠または授乳。
14.本試験処置を開始する30日以内のいずれかの治験薬物を用いた処置。
60歳の男性を非小細胞肺癌と診断している。その後、患者は、6.5×4cmと測定される左縦隔腫瘤及び胸水を示す。インフォームドコンセントにサインした後に、患者に、IMMU−132を18mg/kgの用量で、隔週で投与する。最初の2回の注射の間に、短期間の好中球減少症及び下痢が経験され、4時間以内に4回の腸運動を伴うが、これらは、2日以内に解消するか、対症薬物療法に応答する。合計6回のIMMU−132の注入の後に、インデックス病変のCT評価は、22%の減少を示し、これは部分奏効に少し満たないが、明確な腫瘍縮小である。患者は、この治療をさらに2カ月継続し、この時、インデックス病変の直径の合計の45%腫瘍縮小の部分奏効がCTによって認められ、RECIST判定基準による部分奏効を成している。
この44歳の患者は、転移性膵臓癌腫の病歴を有し、膵頭部に膵管腺癌を伴い、左右の肝葉への転移を示し、前者の測定値は3×4cmであり、後者の測定値は2×3cmである。患者は、1コースのゲムシタビンを与えられたが、客観的な奏効を示さない。4週後に、男性は、hPAM4−CL2A−SN−38を静脈内に8mg/kgの用量で週2回2週間とその後1週間の休薬を、その後、さらに2サイクルにわたって反復して与えられる。CT試験が1週間後に行われ、転移の除去及び原発腫瘍量における32%の減少(部分奏功)を示すとともに、男性の血中CA19−9力価がベースラインの220からX線診断評価の時点で75まで低下する。患者は、抗体−薬物コンジュゲートを用いた各処置の後にグレード1の悪心及び嘔吐のみを、ならびに、最後の処置サイクルの終了時に、グレード2の好中球減少症を示すが、これは4週後に解消する。転移性病変の除去及び原発腫瘍のサイズ減少により、以前には手術不可能であった腫瘍量の外科的除去が可能になる。外科処置の6カ月後、患者は、膵臓癌腫の再発の兆候を示さない。
合成−P2PDoxの合成経路における中間体の構造、ならびに抗体もしくは他のタンパク質もしくはスルフヒドリル含有ペプチドへのコンジュゲーションに好適なP2PDoxのマレイミド誘導体を本明細書に開示する。例示的なP2PDoxを産生するための一般的なスキームを以下のスキーム1に示す。本発明者らは、1g規模の反応を実施して、約40%の収率で1g超の4,4−ジアセトキシブチルアルデヒドを生成している。シアン化物で生成物を汚染し得る可能性があるシアノ水素化ホウ素ナトリウムの使用を回避するため、還元剤を還元アルキル化においてナトリウムトリアセトキシボロヒドリドに変更した。探索スケールでは、ドキソルビシンのP2PDoxへの80%を超える変換が記録された。これを2g規模まで増加させて、1g超のP2PDoxを生成した(スキーム1)。4,4−ジアセトキシブチルアルデヒドを、報告されている方法(Nagy et al.,1998,Proc Natl Acad Sci USA 95:1794−9)を改変して調製したが、これは、危険なオゾン分解ステップを避けるために必要であった。無水酢酸及び塩化インジウム触媒を用いる市販の4−ペンテン−1−アールのジアセトキシ化、それに続く、塩化ルテニウム及び過ヨウ素酸ナトリウム組み合わせ(Yang&Zhang,2001,66:4814−8)によるオレフィンの酸化切断により、4,4−ジアセトキシブチルアルデヒドを得て、これをドキソルビシンに還元的にカップリングして、P2PDoxを得た。
In vitro細胞結合性試験−抗体結合の保持は、非コンジュゲート抗体に対するコンジュゲートの結合を比較する細胞結合性アッセイによって確認された(Chari,2008,Acc Chem Res 41:98−107)。コンジュゲートの作用強度は、適切な標的細胞を使用して4日間のMTSアッセイにおいて検査された。hRS7−P2PDoxコンジュゲートは、胃(NCI−N87)、膵臓(Capan−1)、及び乳房(MDA−MB−468)ヒト癌細胞株において0.35〜1.09nMのIC50値を呈し、遊離薬物は、同じ細胞株において0.02〜0.07nM作用強度を呈した。
一般−腫瘍サイズを長さ(L)及び幅(W)のキャリパー測定で、腫瘍体積を(L×W2)/2として算出することにより決定した。週2回、腫瘍を測定し、マウスの体重を測定した。マウスは、その腫瘍が1cm3を超えるサイズに達した、その開始時体重の15%超が低下した場合、またあるいは瀕死になった場合に安楽死させた。腫瘍増殖データについての統計学的分析は、曲線下面積(AUC)及び生存時間に基づいた。個別の腫瘍増殖のプロファイルは、線形曲線モデリングを通して得た。f検定を採用して、群間の等分散性を決定してから増殖曲線の統計学的分析をおこなった。両側t検定を使用して、全ての様々な処置群と非特異的対照の間の統計学的有意性を評価した。食塩水対照の分析については、片側t検定を使用して有意性を評価した。生存試験を、カプランマイヤープロット(ログランク分析)を使用して分析し、これには、Prism GraphPadソフトウェア(v4.03)ソフトウェアパッケージ(Advanced Graphics Software,Inc.;カリフォルニア州エンシニータス)を使用した。前臨床実験における全ての用量は、抗体量で表した。薬物に関しては、20gのマウスにおける100μgの抗体(5mg/kg)は、例えば、3〜6薬物/IgGでADCを使用するとき、1.4μg〜2.8μg(0.14〜0.17mg/kg)のP2PDox当量用量を有する。
マウスにおいて、原型抗体であるhLL1の2−PDox及びP2PDoxコンジュゲートを比較するMTD試験は、P2PDoxコンジュゲートが遥かに強力であることを実証した(図示せず)。単回静脈内注射のMTDは、100から300μgの間であった。その後、4日間毎に合計4回(q4d×4)のスケジュールでの複数回注射のMTDを、注射毎に25μgから150μgの間のタンパク質用量を使用して、決定した。これらの用量で、100から600μgの間の累積用量が動物に与えられた。以下の表5は、様々な群の概要である。
NCI−N87胃癌腫細胞に対する抗体部分の結合において、未コンジュゲートhRS7と抗体あたり6分子のP2PDoxにコンジュゲートしたP2PDox−hRS7との間に有意差は観察されなかった(図示せず)。標的抗原に対する抗体結合に与えるコンジュゲーションの影響の欠如がP2PDox−hMN−15(抗CEACAM6)、P2PDox−hLL2(抗CD22)及びP2PDox−hMN−24(抗CEACAM5)コンジュゲートについて実証された。抗体へのP2PDoxのコンジュゲーションは、抗体−抗原結合活性に影響しないと結論付けられた。
P2PDox−hRS7 ADCは、上記実施例に記載のように調製される。少なくとも2つの標準療法に失敗したトリプルネガティブ乳癌を有する患者は、3サイクルの70mg P2PDox−hRS7を3週間毎に静脈内注射された。客観的奏効が、この用量レベルのP2PDox−hRS7で観察され、2サイクルの治療後、平均で腫瘍体積において35%低減した。ヒト抗hRS7抗体(HAHA)について評価した全ての血清試料は陰性であった。腫瘍量の減少のあと、腫瘍を外科的に除去した。
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Claims (34)
- 癌のネオアジュバント処置のための方法であって、
a)抗体−薬物コンジュゲート(ADC)を、癌を有する対象に投与すること、ここで前記薬物は、アントラサイクリン及びカンプトテシンからなる群より選択される;及び
b)外科手術、放射線療法、化学療法、及び免疫療法からなる群より選択される標準的な抗癌治療で前記対象を処置することを含み、前記ADCが、前記標準的な抗癌治療の前に投与される、前記方法。 - 前記カンプトテシンが、SN−38である、請求項1に記載の方法。
- 前記アントラサイクリンが、プロ−2−ピロリノドキソルビシン(P2PDox)である、請求項1に記載の方法。
- 前記ADCが、抗体、抗原結合性抗体断片、及び標的化ペプチドからなる群より選択される抗体部分を含む、請求項1に記載の方法。
- 前記抗体部分が、炭酸脱水酵素IX、CCCL19、CCCL21、CSAp、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、IGF−1R、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD45、CD46、CD47、CD52、CD54、CD55、CD59、CD64、CD66a−e、CD67、CD70、CD70L、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、AFP、PSMA、CEACAM5、CEACAM−6、c−MET、B7、フィブロネクチンのED−B、H因子、FHL−1、Flt−3、葉酸受容体、GRO−β、ヒストンH2B、ヒストンH3、ヒストンH4、HMGB−1、低酸素誘導因子(HIF)、HM1.24、インスリン様成長因子−1(ILGF−1)、IFN−γ、IFN−α、IFN−β、IL−2、IL−4R、IL−6R、IL−13R、IL−15R、IL−17R、IL−18R、IL−6、IL−8、IL−12、IL−15、IL−17、IL−18、IL−23、IL−25、IP−10、LIV−1、MAGE、mCRP、MCP−1、MIP−1A、MIP−1B、MIF、D−DT(D−ドパクロムトートメラーゼ)、MUC1、MUC2、MUC3、MUC4、MUC5ac、MUC16、PAM4抗原、NCA−95、NCA−90、Ia、HM1.24、EGP−1(TROP−2)、EGP−2、HLA−DR、テネイシン、Le(y)、RANTES、T101、TAC、Tn抗原、トムソン−フリーデンライヒ抗原、腫瘍壊死抗原、TNF−α、TRAIL受容体(R1及びR2)、VEGFR、EGFR、PlGF、補体因子C3、C3a、C3b、C5a、C5、及び発がん遺伝子産物からなる群より選択される腫瘍関連抗原に結合する、請求項4に記載の方法。
- 前記抗体部分が、hR1(抗IGF−1R)、hPAM4(抗MUC5ac)、hA20(抗CD20)、GA101(抗CD20)、hA19(抗CD19)、hIMMU−31(抗AFP)、hLL1(抗CD74)、hLL2(エプラツズマブ、抗CD22)、hRFB4(抗CD22)、hMu−9(抗CSAp)、hL243(抗HLA−DR)、hL243 IgG4P(抗HLA−DR)、hMN−14(抗CEACAM5)、hMN−15(抗CEACAM6)、hRS7(抗TROP−2)、hMN−3(抗CEACAM6)、Ab124(抗CXCR4)及びAb125(抗CXCR4)からなる群より選択される、請求項4に記載の方法。
- 前記抗体断片が、F(ab’)2、F(ab)2、Fab、Fab’及びscFv断片からなる群より選択される、請求項4に記載の方法。
- 前記抗体または抗原結合性抗体断片が、IgG1、IgG2、IgG3及びIgG4からなる群より選択されるヒト定常領域を含む、請求項4に記載の方法。
- 前記抗体が、非G1m1(nG1m1)抗体である、請求項4に記載の方法。
- 前記抗体が、G1m3重鎖アロタイプを有する、請求項4に記載の方法。
- 前記抗体が、nG1m1、2重鎖ヌルアロタイプを有する、請求項4に記載の方法。
- 前記抗体が、Km3軽鎖アロタイプを有する、請求項4に記載の方法。
- 前記P2PDoxが、SMCCヒドラジド、アミノキシ、フェニルヒドラジド及び4−(ヒドラジノスルホニル)安息香酸からなる群より選択される架橋剤により前記抗体、抗体断片またはペプチドに付着する、請求項3に記載の方法。
- 前記P2PDoxが、マレイミド部分を含み、前記マレイミドとシステイン残基の反応により前記抗体、抗体断片またはペプチドに付着する、請求項3に記載の方法。
- 前記P2PDoxが、前記抗体または抗原結合性抗体断片と分子内架橋を形成する、請求項3に記載の方法。
- 前記分子内架橋が、in vivoで前記コンジュゲートを安定化し、循環中への遊離薬物の放出を防止する、請求項15に記載の方法。
- 前記ADCが、前記薬物を前記抗体に付着させるリンカーを含む、請求項1に記載の方法。
- 前記薬物がSN−38であり、前記リンカーがCL2Aである、請求項17に記載の方法。
- 少なくとも1つの治療剤を前記対象に投与することをさらに含む、請求項1に記載の方法。
- 前記治療剤が、薬物、プロドラッグ、毒素、酵素、チロシンキナーゼ阻害剤、スフィンゴシン阻害剤、免疫調節剤、サイトカイン、ホルモン、二次抗体、二次抗体断片、イムノコンジュゲート、放射性核種、アンチセンスオリゴヌクレオチド、RNAi、抗血管新生剤、アポトーシス促進剤及び細胞毒性薬剤からなる群より選択される、請求項19に記載の方法。
- 前記薬物が、5−フルオロウラシル、アファチニブ、アプリジン、アザリビン、アナストロゾール、アントラサイクリン、アキシチニブ、AVL−101、AVL−291、ベンダムスチン、ブレオマイシン、ボルテゾミブ、ボスチニブ、ブリオスタチン−1、ブスルファン、カリケアマイシン、カンプトテシン、カルボプラチン、10−ヒドロキシカンプトテシン、カルムスチン、セレブレックス、クロラムブシル、シスプラチン(CDDP)、Cox−2阻害薬、イリノテカン(CPT−11)、SN−38、カルボプラチン、クラドリビン、カンプトテカン、クリゾチニブ、シクロホスファミド、シタラビン、ダカルバジン、ダサチニブ、ジナシクリブ、ドセタキセル、ダクチノマイシン、ダウノルビシン、ドキソルビシン、2−ピロリノドキソルビシン(2P−DOX)、シアノ−モルフォリノドキソルビシン、ドキソルビシングルクロニド、エピルビシングルクロニド、エルロチニブ、エストラムスチン、エピドフィロトキシン、エルロチニブ、エンチノスタット、エストロゲン受容体結合剤、エトポシド(VP16)、エトポシドグルクロニド、エトポシドホスフェート、エキセメスタン、フィンゴリモド、フロクスウリジン(FUdR)、3’,5’−O−ジオレイル−FudR(FUdR−dO)、フルダラビン、フルタミド、ファルネシル−タンパク質トランスフェラーゼ阻害剤、フラボピリドール、フォスタマチニブ、ガネテスピブ、GDC−0834、GS−1101、ゲフィチニブ、ゲムシタビン、ヒドロキシウレア、イブルチニブ、イダルビシン、イデラリシブ、イホスファミド、イマチニブ、L−アスパラギナーゼ、ラパチニブ、レノリダミド(lenolidamide)、ロイコボリン、LFM−A13、ロムスチン、メクロレタミン、メルファラン、メルカプトプリン、6−メルカプトプリン、メトトレキサート、ミトキサントロン、ミトラマイシン、マイトマイシン、ミトタン、ナベルビン、ネラチニブ、ニロチニブ、ニトロソウレア(nitrosurea)、オラパリブ、プリコマイシン(plicomycin)、プロカルバジン、パクリタキセル、PCI−32765、ペントスタチン、PSI−341、ラロキシフェン、セムスチン、ソラフェニブ、ストレプトゾシン、SU11248、スニチニブ、タモキシフェン、テマゾロミド(temazolomide)(DTICの水性形態)、トランスプラチナ、サリドマイド、チオグアニン、チオテパ、テニポシド、トポテカン、ウラシルマスタード、バタラニブ、ビノレルビン、ビンブラスチン、ビンクリスチン、ビンカアルカロイド及びZD1839からなる群より選択される、請求項20に記載の方法。
- 前記毒素が、抗体または抗原結合性抗体断片に付着し、リシン、アブリン、アルファ毒素、サポリン、リボヌクレアーゼ(RNase)、例えば、オンコナーゼ、DNaseI、ブドウ球菌エンテロトキシン−A、ヤマゴボウ抗ウイルスタンパク質、ゲロニン、ジフテリア毒素、シュードモナス外毒素、及びシュードモナス内毒素からなる群より選択される、請求項20に記載の方法。
- 前記放射性核種が、抗体または抗原結合性抗体断片に付着し、111In、111At、177Lu、211Bi、212Bi、213Bi、211At、62Cu、67Cu、90Y、125I、131I、133I、32P、33P、47Sc、111Ag、67Ga、153Sm、161Tb、152Dy、166Dy、161Ho、166Ho、186Re、188Re、189Re、211Pb、212Pb、223Ra、225Ac、77As、89Sr、99Mo、105Rh、149Pm、169Er、194Ir、58Co、80mBr、99mTc、103mRh、109Pt、119Sb、189mOs、192Ir219Rn、215Po、221Fr、255Fm、11C、13N、15O、75Br、198Au、199Au、224Ac、77Br、113mIn、95Ru、97Ru、103Ru、105Ru、107Hg、203Hg、121mTe、122mTe、125mTe、227Th、165Tm、167Tm、168Tm、197Pt、109Pd、142Pr、143Pr、161Tb、57Co、58Co、51Cr、59Fe、75Se、201T1、76Br及び169Ybからなる群より選択される、請求項20に記載の方法。
- 前記免疫調節剤が、サイトカイン、ケモカイン、幹細胞増殖因子、リンホトキシン、造血因子、コロニー刺激因子(CSF)、インターフェロン、エリスロポエチン、トロンボポエチン、腫瘍壊死因子(TNF)、インターロイキン(IL)、顆粒球コロニー刺激因子(G−CSF)、顆粒球マクロファージコロニー刺激因子(GM−CSF)及び「S1因子」と呼ばれる幹細胞増殖因子からなる群より選択される、請求項20に記載の方法。
- 前記サイトカインが、ヒト成長ホルモン、N−メチオニルヒト成長ホルモン、ウシ成長ホルモン、副甲状腺ホルモン、サイロキシン、インスリン、プロインスリン、レラキシン、プロレラキシン、卵胞刺激ホルモン(FSH)、甲状腺刺激ホルモン(TSH)、黄体ホルモン(LH)、肝臓増殖因子、プロスタグランジン、線維芽細胞増殖因子、プロラクチン、胎盤性ラクトゲン、OBタンパク質、腫瘍壊死因子−α、腫瘍壊死因子−β、ミュラー管抑制因子、マウスゴナドトロピン関連ペプチド、インヒビン、アクチビン、血管内皮増殖因子、インテグリン、トロンボポエチン(TPO)、NGF−β、血小板増殖因子、TGF−α、TGF−β、インスリン様成長因子−I、インスリン様増殖因子−II、エリスロポエチン(EPO)、骨誘導性因子、インターフェロン−α、インターフェロン−β、インターフェロン−γ、マクロファージ−CSF(M−CSF)、IL−1、IL−1α、IL−2、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−9、IL−10、IL−11、IL−12、IL−13、IL−14、IL−15、IL−16、IL−17、IL−18、IL−21、IL−25、LIF、FLT−3、アンジオスタチン、トロンボスポンジン、エンドスタチン、腫瘍壊死因子及びリンホトキシンからなる群より選択される、請求項24に記載の方法。
- 前記ケモカインが、RANTES、MCAF、MIP1−アルファ、MIP1−ベータ及びIP−10からなる群より選択される、請求項24に記載の方法。
- 前記抗血管新生剤が、MIF、D−DT及びHMGB−1からなる群より選択される、請求項20に記載の方法。
- 前記癌が、固形腫瘍または造血性癌である、請求項1に記載の方法。
- 前記癌が、B細胞リンパ腫、B細胞白血病、ホジキン病、T細胞白血病、T細胞リンパ腫、骨髄腫、結腸癌、胃癌、食道癌、甲状腺髄様癌、腎臓癌、乳癌、肺癌、膵臓癌、膀胱癌、卵巣癌、子宮癌、子宮頸癌、精巣癌、前立腺癌、肝臓癌、皮膚癌、骨癌、脳癌、直腸癌、及び黒色腫からなる群より選択される、請求項1に記載の方法。
- 前記B細胞白血病またはB細胞リンパ腫が、B細胞リンパ腫の緩徐進行型形態、B細胞リンパ腫の侵襲性形態、慢性リンパ性白血病、急性リンパ性白血病、毛髪様細胞白血病、非ホジキンリンパ腫、ホジキンリンパ腫、バーキットリンパ腫、濾胞性リンパ腫、びまん性B細胞リンパ腫、マントル細胞リンパ腫及び多発性骨髄腫からなる群より選択される、請求項29に記載の方法。
- 前記癌が、転移性である、請求項1に記載の方法。
- 前記癌が、トリプルネガティブ乳癌(TNBC)、転移性結腸癌、転移性非小細胞肺癌(NSCLC)、転移性膵臓癌、転移性腎細胞癌腫、転移性胃癌、転移性前立腺癌、及び転移性小細胞肺癌からなる群より選択される、請求項1に記載の方法。
- 前記癌が、他の治療法に不応性であるが、ネオアジュバントADCを用いる治療には応答する、請求項1に記載の方法。
- 前記患者が、前記ネオアジュバントADCを用いる処置の前に、少なくとも1つの他の治療への応答に失敗している、請求項1に記載の方法。
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CA2961774C (en) | 2023-05-23 |
CA2961774A1 (en) | 2016-04-14 |
JP7144121B2 (ja) | 2022-09-29 |
JP2020105187A (ja) | 2020-07-09 |
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PT3204018T (pt) | 2021-11-12 |
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AU2021258011A1 (en) | 2021-11-25 |
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US20180296689A1 (en) | 2018-10-18 |
US20160095939A1 (en) | 2016-04-07 |
EP3204018A1 (en) | 2017-08-16 |
SI3204018T1 (sl) | 2021-11-30 |
EP3954373A1 (en) | 2022-02-16 |
CN117138060A (zh) | 2023-12-01 |
WO2016057398A1 (en) | 2016-04-14 |
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AU2015328370A1 (en) | 2017-04-13 |
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