JP2019519481A - チェックポイント阻害薬に再発/耐性を示す腫瘍を治療するための抗Trop−2−SN−38抗体薬物複合体の効果 - Google Patents
チェックポイント阻害薬に再発/耐性を示す腫瘍を治療するための抗Trop−2−SN−38抗体薬物複合体の効果 Download PDFInfo
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Abstract
【選択図】図3
Description
本出願は、2016年4月27日出願の米国仮特許出願62/328,289に対する米国特許法119(e)条の利益を主張するものであり、その全文は参照として本明細書に組み込まれる。
本出願は、EFS−Webを経由してASCII形式で提出された配列表を含み、その全体は参照として本明細書に組み込まれる。上記ASCIIのコピー(2017年4月5日に作成)の名称は、IMM366WO2_SL.txt.であり、そのサイズは13,002バイトである。
本明細書で使用する場合、略語「CPT」とは、特に明記しない限り、カンプトテシン、またはその誘導体のいずれか、例えば、SN−38などのことを意味し得る。本発明は、CPT−抗体ADCを調製及び投与するための向上した方法及び組成物を提供することにより、当該技術分野において未だ実現されていない要望を解決する。好ましくは、カンプトテシンはSN−38であり、抗体は抗Trop−2抗体(例えば、サシツズマブゴビテカン)である。開示する方法及び組成物は、その他の治療形態に耐性を示す、またはその他の治療形態にほとんど反応を示さない疾患、例えば、チェックポイント阻害抗体を用いた治療に耐性を示す、またはチェックポイント阻害抗体を用いた治療から再発したTrop−2+がんなどを治療するために用いられる。
以下に続く記載において、多数の用語を用い、本願請求項に記載の主題への理解を促進するため、以下の定義を提供する。本明細書で特に定義しない用語は、その明白かつ一般的な意味に従い用いられる。
様々な実施形態は、Trop−2に結合する抗体またはそのフラグメントの使用に関する。特定の好ましい実施形態では、抗Trop−2抗体は、軽鎖CDR配列CDR1(KASQDVSIAVA、配列番号:1)、CDR2(SASYRYT、配列番号:2)及びCDR3(QQHYITPLT、配列番号:3)、ならびに、重鎖CDR配列CDR1(NYGMN、配列番号:4)、CDR2(WINTYTGEPTYTDDFKG、配列番号:5)及びCDR3(GGFGSSYWYFDV、配列番号:6)を含む、ヒト化RS7抗体であってもよい(例えば、米国特許番号7,238,785を参照のこと(その全体は本明細書に参照として組み込まれる))。
抗体または抗原結合抗体フラグメントに結合したカンプトテシン治療薬を含むADCを調製するための限定されない方法及び組成物について、以下で説明する。好ましい実施形態では、所定のポリエチレングリコール(PEG)部分(すなわち、所定数のモノマー単位を含有するPEG)(所定のPEGは低分子量PEGであり、好ましくは1〜30モノマー単位を含有し、より好ましくは1〜12モノマー単位含有する)を、薬物と抗体の間に配置することにより、薬物の溶解性が向上する。
MAb−[L2]−[L1]−[AA]m−[A’]−薬物(2)
の、薬物誘導体と抗体の複合体に関し、
式中、MAbは疾患標的化抗体であり、L2は、抗体結合部分及び1個または複数個のアセチレン(またはアジド)基を含むクロスリンカーの構成要素であり、L1は、一方の端にアジド(またはアセチレン)を有する所定のPEG(L2のアセチレン(またはアジド)部分に対して相補的)、及びもう一方の端にカルボン酸基またはヒドロキシル基などの反応性基を含み、AAはL−アミノ酸であり、mは0、1、2、3または4の値の整数であり、A’は、エタノールアミン、4−ヒドロキシベンジルアルコール、4−アミノベンジルアルコール、または置換または非置換エチレンジアミンの群から選択される追加のスペーサーである。「AA」のL−アミノ酸は、アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン及びバリンから選択される。A’基がヒドロキシルを含む場合、A’基は、それぞれカーボネートまたはカルバメートの形態で薬物のヒドロキシル基またはアミノ基に結合する。
がん治療にチェックポイント阻害抗体を用いた試験が、以前からがん治療に耐性を示すと考えられてきたがんにおいて、前例のない奏効率を示している(例えば、Ott & Bhardwaj,2013,Frontiers in Immunology 4:346;Menzies & Long,2013,Ther Adv Med Oncol 5:278−85;Pardoll,2012,Nature Reviews 12:252−264;Mavilio & Lugliを参照のこと)。CTLA−4、PD−1及びPD−L1に対する拮抗的なチェックポイント阻害抗体を用いた治療は、がん及びその他の疾患に対する免疫療法における最も有望な新規方法の1つである。大部分の抗がん剤とは対照的に、チェックポイント阻害薬は、腫瘍細胞を直接の標的とはせずに、逆に、免疫機構の内因性抗腫瘍活性を高めるために、リンパ球受容体またはそのリガンドを標的としている(Pardoll,2012,Nature Reviews 12:252−264)。このような抗体が主に、疾患細胞、組織または病原体に対する免疫応答を調節する働きを有していることから、これらの抗体を抗体薬物複合体(ADC)などその他治療様式と組み合わせて使用して、ADCの抗腫瘍効果を高めてもよい。
事実上のあらゆる標的抗原に対するモノクローナル抗体を作製するための技術は、当該技術分野において周知である。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。簡潔に説明すると、モノクローナル抗体は、抗原を含む組成物をマウスに注入し、脾臓を取り出しBリンパ球を採取して、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作製し、そのハイブリドーマをクローニングし、抗原に対する抗体を産生する陽性クローンを選抜し、抗原に対する抗体を産生するクローンを培養してから、ハイブリドーマ培養液から抗体を単離することによって得ることができる。当業者は、ヒト対象のどこに抗体を投与するか、抗体がヒト抗原のどこに結合するかを理解するであろう。
キメラ抗体とは、ヒト抗体の可変領域が、例えば、マウス抗体の可変領域(マウス抗体の相補性決定領域(CDR)を含む)で置換された組換えタンパク質のことである。キメラ抗体は、対象に投与する際、低い免疫原性及び高い安定性を示す。キメラ抗体の構築方法は当該技術分野において周知である(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で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作製するための方法は、当技術分野において周知である(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)。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と比較して更に副作用が少なく、事実上の内因性ヒト抗体としてインビボで機能すると予想されている。特定の実施形態では、本願請求項に記載の方法及び手順を、このような技術により作製されたヒト抗体に利用してもよい。
本願請求項に記載の方法及び/または組成物の一部の実施形態は、抗体フラグメントに関係していてもよい。このような抗体フラグメントは、例えば、通常の方法で完全抗体をペプシン消化またはパパイン消化することにより得ることができる。例えば、抗体をペプシンで酵素開裂させて抗体フラグメントを作製し、5Sフラグメント(F(ab’)2と表記する)を得てもよい。チオール還元剤、及び任意選択的に、ジスルフィド結合の開裂により生じたスルフヒドリル基用のブロック基を用いて、このフラグメントを更に開裂させて、3.5S Fab’一価フラグメントを作製してもよい。あるいは、ペプシンを用いた酵素開裂により、2つの一価Fabフラグメント、及び1つのFcフラグメントを作製する。抗体フラグメントの例示的な作製方法は、米国特許番号4,036,945、米国特許番号4,331,647、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)に開示されている。
特定の実施形態では、抗体の配列、例えば、抗体のFc部分は、複合体の生理学的特性、例えば、血清中半減期などを最適化するために、変化させることができる。タンパク質のアミノ酸配列を置換するための方法、例えば、部位特異的突然変異誘発などは、当該技術分野において広く知られている(例えば、Sambrook et al.,Molecular Cloning,A laboratory manual,2nd Ed,1989)。好ましい実施形態では、バリエーションは、Fc配列内における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伴っていてもよい(例えば、米国特許番号6,254,868(その実施例セクションは参照として本明細書に組み込まれる))。その他の好ましい実施形態では、Fc配列内における特定のアミノ酸を置換してもよい(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、米国特許番号7,217,797(それぞれは参照として本明細書に組み込まれる))。
好ましい実施形態では、標的細胞上に高レベルで発現する抗原、及び、正常組織と比較して疾患細胞上で圧倒的にまたは排他的に発現する抗原を認識する及び/またはそれら抗原に結合する抗体を使用する。より好ましくは、抗体は、結合後速やかに内部移行する。速やかに内部移行する例示的な抗体は、LL1(抗CD74)抗体であり、その内在化速度は、約8 x 106個の抗体分子/細胞/日である(例えば、Hansen et al.,1996,Biochem J.320:293−300)。それゆえ、「速やかに内部移行する」抗体は、約1 x 106〜約1 x 107個の抗体分子/細胞/日の内在化速度を有する抗体であってもよい。本願請求項に記載の組成物及び方法に使用する抗体としては、上で列挙した特性を有するMAbを挙げてもよい。例えば、がんの治療に使用する例示的な抗体としては、LL1(抗CD74)、LL2またはRFB4(抗CD22)、ベルツズマブ(hA20、抗CD20)、リツキシマブ(抗CD20)、オビヌツズマブ(GA101、抗CD20)、ランブロリズマブ(抗PD−1受容体)、ニボルマブ(抗PD−1受容体)、イピリムマブ(抗CTLA−4)、RS7(抗上皮糖タンパク質−1(EGP−1、Trop−2としても周知))、PAM4またはKC4(両方とも抗ムチン)、MN−14(抗がん胎児性抗原(CEA、CD66eまたはCEACAM5としても周知))、MN−15またはMN−3(抗CEACAM6)、Mu−9(抗結腸特異的抗原p)、Immu 31(抗α−フェトプロテイン)、R1(抗IGF−1R)、A19(抗CD19)、TAG−72(例えば、CC49)、Tn、J591またはHuJ591(抗PSMA(前立腺特異的膜抗原))、AB−PG1−XG1−026(抗PSMA二量体)、D2/B(抗PSMA)、G250(抗炭酸脱水酵素IX MAb)、L243(抗HLA−DR)、アレムツズマブ(抗CD52)、ベバシズマブ(抗VEGF)、セツキシマブ(抗EGFR)、ゲムツズマブ(抗CD33)、イブリツモマブチウキセタン(抗CD20)、パニツムマブ(抗EGFR)、トシツモマブ(抗CD20)、PAM4(別名クリバツズマブ、抗ムチン)、及びトラスツズマブ(抗ErbB2)が挙げられるがこれらに限定されない。このような抗体は当技術分野において周知である(例えば、米国特許番号5,686,072、5,874,540、6,107,090、6,183,744、6,306,393、6,653,104、6,730.300、6,899,864、6,926,893、6,962,702、7,074,403、7,230,084、7,238,785、7,238,786、7,256,004、7,282,567、7,300,655、7,312,318、7,585,491、7,612,180、7,642,239、及び、米国特許出願公開番号20050271671、20060193865、20060210475、20070087001(それぞれの実施例セクションは参照として本明細書に組み込まれる))。使用される特に周知の抗体としては、hPAM4(米国特許番号7,282,567)、hA20(米国特許番号7,251,164)、hA19(米国特許番号7,109,304)、hIMMU−31(米国特許番号7,300,655)、hLL1(米国特許番号7,312,318)、hLL2(米国特許番号7,074,403)、hMu−9(米国特許番号7,387,773)、hL243(米国特許番号7,612,180)、hMN−14(米国特許番号6,676,924)、hMN−15(米国特許番号7,541,440)、hR1(米国特許出願12/772,645)、hRS7(米国特許番号7,238,785)、hMN−3(米国特許番号7,541,440)、AB−PG1−XG1−026(米国特許出願11/983,372、ATCC PTA−4405及びPTA−4406として寄託)、及びD2/B(WO2009/130575)が挙げられる(列挙した特許または特許出願におけるそれぞれの本文(図面セクション及び実施例セクションに対応)は、参照として本明細書に組み込まれる)。特に好ましい実施形態では、抗体はhRS7である。当業者であれば、特定の実施形態において、その他TAAに対する抗体(Trop−2を除く)を抗Trop−2抗体と組み合わせて使用してもよいということを理解するであろう。
二重特異性抗体は、多数の生物医学用途において有用である。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細胞による特定腫瘍細胞の溶解を誘導することができる。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、ヒト患者における脳腫瘍の治療に成功裏に用いられている(Nitta,et al.Lancet.1990;355:368−371)。好ましい二重特異性抗体は、抗CD3 X 抗CD19抗体である。代替実施形態では、抗CD3抗体またはそのフラグメントを、別のB細胞関連抗原に対する抗体またはフラグメント、例えば、抗CD3 X 抗Trop−2、抗CD3 X 抗CD20、抗CD3 X 抗CD22、抗CD3 X 抗HLA−DR、または抗CD3 X 抗CD74などに結合してもよい。特定の実施形態では、本明細書で開示するADC治療のための技術及び組成物を、二重特異性抗体または多重特異性抗体と組み合わせて使用してもよい。例えば、抗Trop−2 x 抗CD3 bsAbを、抗Trop−2 ADCの投与前に、それと同時に、またはその投与後に投与してもよい。
好ましい実施形態では、二価抗体または多価抗体は、DOCK−AND−LOCK(登録商標)(DNL(登録商標))複合体として形成される(例えば、米国特許番号7,521,056、7,527,787、7,534,866、7,550,143、7,666,400、7,858,070、7,871,622、7,906,121、7,906,118、8,163,291、7,901,680、7,981,398、8,003,111及び8,034,352を参照のこと(それぞれの特許の実施例セクションは参照として本明細書に組み込まれる))。一般的に、この技術は、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)配列の間に生じる特異的かつ高親和性の結合相互作用を利用している(Baillie et al.,FEBS Letters.2005;579:3264.Wong and Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。DDDペプチド及びADペプチドを、任意のタンパク質、ペプチドまたはその他の分子に結合させてもよい。DDD配列が自発的に二量化してAD配列に結合するため、この技術は、DDD配列またはAD配列に結合し得る任意の選択分子間の複合体形成を可能とする。
異なるタイプのDNL(商標)構築物には、異なるAD配列またはDDD配列を利用してもよい。例示的なDDD配列及びAD配列を以下に示す。
DDD1
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(配列番号:7)
DDD2
CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(配列番号:8)
AD1
QIEYLAKQIVDNAIQQA(配列番号:9)
AD2
CGQIEYLAKQIVDNAIQQAGC(配列番号:10)
DDD3
SLRECELYVQKHNIQALLKDSIVQLCTARPERPMAFLREYFERLEKEEAK(配列番号:11)
DDD3C
MSCGGSLRECELYVQKHNIQALLKDSIVQLCTARPERPMAFLREYFERLEKEEAK(配列番号:12)
AD3
CGFEELAWKIAKMIWSDVFQQGC(配列番号:13)
PKA RIα
SLRECELYVQKHNIQALLKDVSIVQLCTARPERPMAFLREYFEKLEKEEAK(配列番号:14)
PKA RIβ
SLKGCELYVQLHGIQQVLKDCIVHLCISKPERPMKFLREHFEKLEKEENRQILA(配列番号:15)
PKA RIIα
SHIQIPPGLTELLQGYTVEVGQQPPDLVDFAVEYFTRLREARRQ(配列番号:16)
PKA RIIβ
SIEIPAGLTELLQGFTVEVLRHQPADLLEFALQHFTRLQQENER(配列番号:17)
治療抗体の免疫原性は、インフュージョンリアクションリスクの増加、及び治療効果期間の短縮に関係している(Baert et al.,2003,N Engl J Med 348:602−08)。治療抗体が宿主内の免疫応答を誘導する程度は、抗体のアロタイプにより部分的に測定することができる(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の特定位置におけるアミノ酸配列バリエーションに関係している。重鎖γ型定常領域を含むIgG抗体のアロタイプは、Gmアロタイプとして設計された(1976,J Immunol 117:1056−59)。
リツキシマブ重鎖可変領域配列(配列番号:18)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
ベルツズマブ重鎖可変領域(配列番号:19)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
特定の実施形態では、本明細書に記載の結合部分は、1つまたは複数のアビマー配列を含んでいてもよい。アビマーとは、様々な標的分子に対するその親和性及び特異性がある程度抗体と類似している結合タンパク質の部類のことである。アビマーは、インビトロエキソンシャッフリング及びファージディスプレイを用いてヒト細胞外受容体ドメインから開発された(Silverman et al.,2005,Nat. Biotechnol.23:1493−94;Silverman et al.,2006,Nat.Biotechnol.24:220)。得られたマルチドメインタンパク質は複数の独立した結合ドメインを含んでいてもよく、それら結合ドメインは、単一エピトープ結合タンパク質と比較して、優れた親和性(場合によってはサブナノモル)及び特異性を示していてもよい(Id.)。様々な実施形態では、本願請求項に記載の方法及び組成物に使用するために、アビマーを、例えば、DDD配列及び/またはAD配列に結合させてもよい。アビマーの構築方法及び使用方法に関係する更なる詳細については、例えば、米国特許出願公開番号20040175756、20050048512、20050053973、20050089932及び20050221384に開示されている(それぞれの特許の実施例セクションは参照として本明細書に組み込まれる)。
本願請求項に記載の組成物及び/または方法の特定の実施形態は、様々な標的分子、細胞または組織の結合ペプチド及び/またはペプチド模倣薬に関係していてもよい。ファージディスプレイ技術を含むがこれらに限定されない当該技術分野において周知の任意の方法を用いて、結合ペプチドを同定してもよい。ファージディスプレイの様々な方法、及び多種多様なペプチド群を作製するための技術は、当技術分野において周知である。例えば、米国特許番号5,223,409、5,622,699及び6,068,829は、ファージライブラリを作製するための方法について開示している。ファージディスプレイ技術は、その表面上に低分子ペプチドを発現できるように遺伝子操作したバクテリオファージを含む(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、より大きなタンパク質ドメイン、例えば、一本鎖抗体などもまた、ファージ粒子の表面上に提示することができる(Arap et al.,1998,Science 279:377−380)。
特定の実施形態では、使用する標的化部分はアプタマーであってもよい。アプタマーの合成方法、及びアプタマーの結合特性を測定するための方法については、当該技術分野において周知である。例えば、このような技術については、米国特許番号5,582,981、5,595,877及び5,637,459に記載されている(それぞれの実施例セクションは参照として本明細書に組み込まれる)。特定の目的標的に結合するアプタマーを作製及びスクリーニングするための方法は周知であり、例えば、米国特許番号5,475,096及び米国特許番号5,270,163に記載されている(それぞれの実施例セクションは参照として本明細書に組み込まれる)。
特定の代替実施形態では、抗体の代わりにアフィボディを利用してもよい。アフィボディは、Affibody AB(Solna,Sweden)から市販されている。アフィボディは、抗体模倣薬として機能し、標的分子への結合に使用される低分子タンパク質である。アフィボディは、αヘリックスタンパク質スキャフォールドのコンビナトリアルエンジニアリングによって開発された(Nord et al.,1995,Protein Eng 8:601−8;Nord et al.,1997,Nat Biotechnol 15:772−77)。アフィボディの設計は、タンパク質AのIgG結合ドメインを含む3ヘリックスバンドル構造をベースとしている(Nord et al.,1995;1997)。細菌タンパク質AのFc結合活性に関与する13種類のアミノ酸を無作為化することにより、幅広い結合親和性を有するアフィボディを作製してもよい(Nord et al.,1995;1997)。無作為化後、変異体タンパク質のファージディスプレイによるスクリーニング用に、PCR増幅ライブラリをファージミドベクターにクローニングした。標的抗原に対する1つまたは複数のアフィボディを同定するために、標準的なファージディスプレイスクリーニング技術(例えば、Pasqualini and Ruoslahti,1996,Nature 380:364−366;Pasqualini,1999,Quart.J.Nucl.Med.43:159−162)を使用し、任意の周知の抗原に対してファージディスプレイライブラリをスクリーニングしてもよい。
特定の実施形態では、細胞傷害性薬物、またはその他の治療薬もしくは診断薬を、抗体または抗体フラグメントに共有結合で結合させて、イムノコンジュゲートを形成してもよい。一部の実施形態では、薬物またはその他の薬剤を、担体部分を介して抗体またはそのフラグメントに結合させてもよい。担体部分を、例えば、還元SH基及び/または炭水化物側鎖に結合させてもよい。還元抗体構成要素のヒンジ領域において、ジスルフィド結合形成を介し担体部分を結合させることができる。あるいは、ヘテロ二官能性クロスリンカー、例えば、N−サクシニル 3−(2−ピリジルジチオ)プロピオネート(SPDP)などを使用して、このような薬剤を結合させることができる(Yu et al.,Int.J.Cancer 56:244(1994))。このような結合を実施するための一般的な技術は、当該技術分野において周知である。例えば、Wong,CHEMISTRY OF PROTEIN CONJUGATION AND CROSS−LINKING(CRC Press 1991);Upeslacis et al.,「Modification of Antibodies by Chemical Methods」in MONOCLONAL ANTIBODIES:PRINCIPLES AND APPLICATIONS,Birch et al.(eds.),pages 187−230(Wiley−Liss,Inc.1995);Price,「Production and Characterization of Synthetic Peptide−Derived Antibodies」in MONOCLONAL ANTIBODIES:PRODUCTION,ENGINEERING AND CLINICAL APPLICATION,Ritter et al.(eds.),pages 60−84(Cambridge University Press 1995)を参照されたい。あるいは、抗体のFc領域中の炭水化物部分を介して、担体部分を結合することができる。
別の態様では、本発明は、対象に、治療有効量の本明細書に記載の抗体薬物複合体(ADC)、例えば、IMMU−132などを投与することを含む、対象を治療するための方法に関する。対象は、チェックポイント阻害抗体を用いた治療に耐性を示すTrop−2陽性がんを有していることが好ましい。疾患状態及び複合体の忍容性に応じて、ADCを一度または繰り返し投与してもよく、また任意選択的に、その他の治療様式、例えば、外科手術、外部放射線、放射免疫治療、免疫療法、化学療法、アンチセンス療法、干渉RNA療法、遺伝子治療などと組み合わせてADCを使用してもよい。それぞれの組み合わせは、腫瘍タイプ、ステージ、患者の状態、及び前治療、ならびに、管理医師が検討するその他の因子に合わせられる。
複合体の好適な投与経路としては、経口投与、非経口投与、皮下投与、直腸投与、経粘膜投与、腸内投与、筋肉内注射、髄内注射、硬膜内注射、直接心室内注射、静脈内注射、硝子体内注射、腹腔内注射、鼻腔内注射、または眼内注射が挙げられるがこれらに限定されない。好ましい投与経路は非経口である。あるいは、例えば、固形腫瘍に直接化合物を注入することにより、全身ではなく局所に化合物を投与してもよい。
様々な実施形態は、患者の疾患組織を治療するのに好適な構成要素を含有するキットに関係していてもよい。例示的なキットは、本明細書に記載の少なくとも1種のADCまたはその他標的化部分を含有していてもよい。投与用の構成要素を含有する組成物が、経口送達などによる消化管を介した送達用に製剤化されていない場合、一部の別の経路でキット構成要素を送達可能なデバイスが含まれていてもよい。非経口送達などの用途に用いる1種のデバイスは、対象の体内に組成物を注射するのに用いる注射器である。吸入用デバイスを使用してもよい。
米国特許番号7,238,785に記載のとおり、ヒト化RS7(hRS7)抗Trop−2抗体を作製した(その図面セクション及び実施例セクションは参照として本明細書に組み込まれる)。米国特許7,999,083に従い、CL2Aリンカーに結合したSN−38を調製してから、hRS7(抗Trop−2)抗体、hPAM4(MUC5ac)抗体、hA20(抗CD20)抗体またはhMN−14(抗CEACAM5)抗体にコンジュゲートした(その実施例10及び実施例12は参照として本明細書に組み込まれる)。コンジュゲーションプロトコルにより、抗体分子1つあたり結合したSN−38分子が約6つという比率となった。
要約
IMMU−132(サシツズマブゴビテカン、別名、hRS7−CL2A−SN−38)は、転移性トリプルネガティブ乳癌及びその他のがんを有する患者(多数の前治療暦があり(ClinicalTrials.gov,NCT01631552)、高レベルのTrop−2を発現)の第II相試験において、有望な治療結果を示した。この新規のTrop−2標的化ヒト化抗体は、上述したCL2Aリンカーで7.6モルのSN−38(イリノテカンの活性化形態)とコンジュゲートされており、イリノテカンと比較して、インビボでより少なくグルクロン酸抱合され、この薬剤で治療した患者における極めて低い下痢発症率に対する説明となる。
がん:TNBC(PD−L1治療後の患者において進行)
最良効果:部分寛解が確認された(54%縮小)
IMMU−132開始用量:10mg/kg
IMMU−132による治療回数:40+
無増悪期間:12.4+ヶ月間(到達せず)
試験の終了:治療継続
患者には当初、直径の合計が60mmに及ぶ3つの標的病変(肺に1つ、胸部リンパ節が2つ)、及び別の非標的病変(胸部の別のリンパ節)が認められた(図2)。最初の評価時(2015年4月7日)において、患者の標的病変直径の合計は33%減少しており、RECIST 1.1における部分寛解と評価された。約5週間後(2015年5月18日)に実施した確認用の追跡CTでは、48%の全体縮小を伴う効果改善が認められた(図3、図4)。2015年7月19日時点におけるCTでは、患者の継続的な部分寛解(50%の縮小を伴う)が認められた。2015年9月13日時点におけるCTでは、52%の縮小を伴う継続的なPRが認められ、また2015年11月15日時点におけるCTでは、54%の縮小が認められた。2016年2月25日に実施した最新のCTでは、46%の縮小を伴う継続的なPRが認められた。
hRS7 IgGとの比較で、様々なhRS7−ADC複合体のADCC活性を測定した(データは省略)。Blood Center of New Jerseyから購入した血液からPBMCを精製した。Trop−2陽性ヒト膵腺癌細胞株(BxPC−3)を標的細胞株として使用した(エフェクター:標的の比率、100:1)。hRS7 IgGが関与するADCCを、hRS7−Pro−2−PDox、hRS7−CL2A−SN−38、及び還元して末端保護したhRS7−NEMと比較した。全て33.3nMで用いた。
抄録
この試験の目的は、いくつかのヒト固形腫瘍タイプに対するSN−38抗Trop−2(hRS7)ADCの効果を評価すること、及び、マウス及びサルにおけるSN−38抗Trop−2(hRS7)ADCの忍容性(後者においては、ヒトに類似のhRS7に対する組織交差反応性が認められた)を評価することであった。2種のSN−38誘導体、CL2−SN−38及びCL2A−SN−38を、抗Trop−2ヒト化抗体、hRS7にコンジュゲートさせた。それらADCを、安定性、結合性及び細胞傷害性について、インビトロでキャラクタライズした。Trop−2抗原を発現した5種の異なるヒト固形腫瘍異種移植モデルを用いて、効果を試験した。マウス及びカニクイザルを用いて毒性を評価した。
固形腫瘍を有する患者において奏効するイリノテカン治療は、大部分において、活性なSN−38代謝物へのCPT−11プロドラッグの低変換率により、限定的なものであった。この変換の必要性をバイパスしてSN−38を受動的に腫瘍へと送達するための方法として、非標的化形態のSN−38が試験されている。本発明者らは、SN−38を、ヒト化抗Trop−2抗体、hRS7に共有結合でコンジュゲートさせた。この抗体薬物複合体は、ある種のs.c.ヒトがん異種移植モデル(非小細胞肺癌、膵臓癌、結腸癌及び扁平上皮細胞肺癌を含む)に特異的な抗腫瘍効果(全て非毒性用量(例えば、≦3.2mg/kgの累積SN−38等用量)で)を有している。Trop−2は多くの上皮癌において広く発現しているが、一部の正常組織においても発現しているため、カニクイザルにおける用量漸増試験を実施してこの複合体の臨床的安全性を評価した。サルは、軽微で可逆的な毒性を示すだけで、24mg SN−38当量/kgに耐性を示した。その腫瘍標的化プロファイル及び安全性プロファイルにより、サシツズマブゴビテカンは、イリノテカンに反応を示す固形腫瘍の管理において著しい改善をもたらしている。
細胞株、抗体及び化学療法剤−この試験に使用した全てのヒトがん細胞株は、American Type Culture Collectionから購入した。これらには、Calu−3(非小細胞肺癌)、SK−MES−1(扁平上皮細胞肺癌)、COLO 205(結腸腺癌)、Capan−1及びBxPC−3(膵腺癌)、ならびにPC−3(前立腺癌)が含まれる。Immunomedics,Inc.において、ヒト化RS7 IgG抗体、ならびに、対照のヒト化抗CD20(hA20 IgG、ベルツズマブ)抗体及び抗CD22(hLL2 IgG、エプラツズマブ)抗体を作製した。イリノテカン(20mg/mL)は、Hospira,Inc.から入手した。
異なるヒトがん細胞株を動物に皮下移植した。キャリパーを使用した2寸法測定法により、腫瘍容積(TV)を測定した(容積はL x w2/2と定義され、式中、Lは腫瘍の最長寸法であり、wは腫瘍の最短寸法である)。治療開始時の腫瘍サイズは、0.10〜0.47cm3であった。それぞれの実験における治療レジメン、用量、及び、動物の数については、結果に記載している。凍結乾燥させたサシツズマブゴビテカン及び対照ADCを、必要に応じ、滅菌生理食塩水で戻して希釈した。イリノテカンを除く全ての試薬を腹腔内投与(0.1mL)した(イリノテカンは静脈内投与した)。投与レジメンは、本発明者らの先行研究(様々な期間長にわたり、3日おきまたは週に2回、ADCを投与)(Moon et al.,2008,J Med Chem 51:6916−26;Govindan et al.,2009,Clin Chem Res 15:6052−61)の影響を受けた。この投与頻度は複合体のインビトロ血清中半減期への配慮を反映しており、ADCへのより持続的な曝露を可能とした。
hRS7−SN−38の安定性及び力価−2種類の異なる結合部を用いて、SN−38をhRS7 IgGにコンジュゲートさせた(図示せず)。第1の結合部はCL2−SN−38と呼ばれ、上に記載している(Moon et al.,2008,J Med Chem 51:6916−26;Govindan et al.,2009,Clin Chem Res 15:6052−61)。リンカー内部のフェニルアラニン部分を除去するCL2合成の変化を利用して、CL2Aリンカーを調製した。この変化により合成が簡略化されるが、コンジュゲート結果には影響を与えなかった(例えば、CL2−SN−38とCL2A−SN−38の両方には、IgG分子毎に約6つのSN−38が導入された)。並列比較において、血清中安定性、抗原結合性またはインビトロ細胞傷害性に有意差は認められなかった。CL2内のフェニルアラニン残基が、リソソームプロテアーゼ用のカテプシンBの設計開裂部位の一部であるため、この結果は驚くべきものであった。
Trop−2とは、肺癌、乳癌、結腸直腸癌、膵臓癌、前立腺癌及び卵巣癌を含むほとんどの上皮性腫瘍上で発現するタンパク質のことであり、それゆえ、細胞傷害薬を送達するための潜在的に重要な標的とされている(Ohmachi et al.,2006,Clin Cancer Res 12:3057−63;Fong et al.,2008,Br J Cancer 99:1290−95;Cubas et al.,2009,Biochim Biophys Acta 1796:309−14)。RS7抗体はTrop−2に結合すると内部移行する(Shih et al.,1995,Cancer Res 55:5857s−63s)ため、細胞傷害性物質の直接細胞内送達が可能となる。
hRS7−SN−38(CL2−SN−38またはCL2A−SN−38のいずれか)を用いて腫瘍を有するマウスを治療することにより、5つの異なる腫瘍モデルにおいて腫瘍増殖が有意に阻害された。それら腫瘍モデルのうちの4つにおいては腫瘍退縮が認められ、Calu−3について言えば、最高用量のhRS7−SN−38を投与された全てのマウスは、試験の判定時において腫瘍フリーとなった。ヒトの場合とは異なり、マウスにおけるイリノテカンは、血漿エステラーゼによって極めて効率的にSN−38へと変換された(50%超の変換率、ヒトよりもマウスにおいてより効果的に生成)(Morton et al.,2000,Cancer Res 60:4206−10;Furman et al.,1999,J Clin Oncol 17:1815−24)。イリノテカンを10倍超のSN−38濃度または10倍当量のSN−38濃度で投与する場合、hRS7−SN−38は腫瘍増殖を制御する上で有意に優れていた。イリノテカンをそのMTDの24mg/kg q2dx5(37.5倍超のSN−38)で投与する場合のみ、hRS7−SN−38の効果と同等となった。患者において、イリノテカンの生物学的変換が実質的に低いことから、本発明者らは、この利点がサシツズマブゴビテカンに更により有利であると期待した。
ヒトTrop−2に対する2種類の異なるマウスモノクローナル抗体を、ADCコンジュゲート用に得た。第1の162−46.2を、ローラーボトル内で増殖させたハイブリドーマ(ATCC、HB−187)から精製した。第2の抗体であるMAB650は、R&D Systems(Minneapolis,MN)から購入した。結合性を比較するために、Trop−2陽性ヒト胃癌であるNCI−N87を標的として使用した。結合アッセイの前日に、細胞(1.5 x 105/ウェル)を96ウェルプレートに播種した。翌朝、162−46.2、MAB650及びマウスRS7(0.03〜66nM)を用いて、用量/反応曲線を作成した。これらの一次抗体を細胞と、4℃で1.5時間インキュベートした。ウェルを洗浄してから、抗マウスHRP二次抗体を全てのウェルに加え、4℃で1時間放置した。再度ウェルを洗浄してから、蛍光基質を加えた。Envisionプレートリーダを用いてプレートを読み、相対蛍光単位の数値を記録した。
SN−38及びMAB650を使用して、6.89の平均置換比率(薬物/抗体)を有する新規抗Trop−2 ADCを調製した。2種類の異なるヒト膵腺癌細胞株(BxPC−3及びCapan−1)及びヒトトリプルネガティブ乳癌細胞株(MDA−MB−468)を標的として用いて細胞傷害性アッセイを実施し、MAB650−SN−38とサシツズマブゴビテカンADCを比較した。
SN−38及び162−46.2を使用して、6.14の置換比率(薬物/抗体)を有する新規抗Trop−2 ADCを調製した。2種類の異なるTrop−2陽性細胞株(BxPC−3ヒト膵腺癌及びMDA−MB−468ヒトトリプルネガティブ乳癌)を標的として用いて細胞傷害性アッセイを実施し、162−46.2−SN−38とhRS7−SN−38 ADCを比較した。
要約
本実施例では、第I相臨床試験、及び、IMMU−132(pH感受性リンカーでSN−38にコンジュゲートした内部移行、ヒト化、hRS7抗Trop−2抗体のADC)(平均薬物−抗体比 = 7.6)を用いた進行中の第II相継続試験の結果について報告する。Trop−2とは、多くのヒトがんが高密度(約1 x 105)で頻繁に特異的に発現する、カルシウムを変換するI型膜貫通タンパク質(正常組織における発現は限定的)のことである。Capan−1ヒト膵臓腫瘍異種移植片を有するヌードマウスでの前臨床試験では、IMMU−132が最大耐量のイリノテカン治療薬に由来する量と比較して120倍超ものSN−38を腫瘍に送達可能であること、が明らかとなった。
2つのELISA法を用いて、IgGのクリアランス(抗hRS7イディオタイプ抗体による補足)及びインタクト複合体のクリアランス(抗hRS7イディオタイプ抗体を有する抗SN−38 IgG/プローブによる補足)を測定した。HPLCを用いてSN−38を測定した。全IMMU−132部分(インタクト複合体)はIgGよりも急速に消失した(データは省略)。このことは、周知である、複合体からのSN−38の徐放を反映している。SN−38のHPLC測定(非結合性及び全体)により、血清中における>95%のSN−38がIgGに結合していることが示された。低濃度のSN−38Gは、IgGに結合したSN−38がグルクロン酸抱合から保護されていることを示唆している。複合体のELISAとSN−38のHPLCを比較することにより、双方のオーバーラップが明らかとなった。このことは、ELISAが、SN−38のクリアランスをモニターするための代用法であることを示唆している。
平均3種類の前治療暦があり多種多様な転移性がんを有する合計69名の患者(第I相の25名の患者を含む)について記録した。8名の患者に臨床増悪が認められ、CT評価前に中止した。13名のCTで評価可能な膵臓癌患者については、個々に記録した。PDC患者の平均TTP(無増悪期間)は、最後の前治療による平均8週間のTTPと比較して、11.9週間(2〜21.4週間の範囲)であった。
ヒト胃癌異種移植片(NCI−N87)を有するマウスを用いて、SN−38をコンジュゲートさせたマウス抗Trop−2モノクローナル抗体(162−46.2)の治療効果を、サシツズマブゴビテカン抗体薬物複合体(ADC)と比較した。組織培養液中でNCI−N87細胞を増殖させてから、トリプシン/EDTAで回収した。1 x 107個の細胞がそれぞれのマウスに投与されるように、マトリゲルと1:1で混合した200μLのNCI−N87細胞懸濁液を雌無胸腺ヌードマウスにs.c.注射した。腫瘍サイズが約0.25cm3に達した時点(6日後)で、動物を7つの異なる治療群(それぞれ9匹のマウス)へと分割した。2週間にわたり週に1回、500μgのSN−38 ADCをi.v.注射でマウスに投与した。対照マウスには、同一の用量/スケジュールで、非腫瘍標的化hA20−SN−38 ADCを投与した。最後の群のマウスには生理食塩水だけを投与して未治療対照とした。週に2回、腫瘍を測定してマウスの体重を測った。マウスの腫瘍容積が1.0cm3のサイズを超えた場合、増悪によりマウスを安楽死させた。
要約
IMMU−132(サシツズマブゴビテカン)は、pH感受性リンカーでSN−38(イリノテカンの活性代謝物)にコンジュゲートした、がん細胞に内部移行する、ヒト化抗Trop−2 hRS7抗体を含む、抗Trop−2 ADC(平均薬物−抗体比 7.6)である。Trop−2とは、膵管腺癌を含む多くの上皮癌が高密度で頻繁に特異的に発現する、カルシウムを変換するI型膜貫通タンパク質(正常組織における発現は限定的)のことである。試験した全29の膵臓腫瘍マイクロアレイ標本は、免疫組織化学試験によればTrop−2陽性であり、またヒト膵臓癌細胞株が115k〜891kのTrop−2複製を細胞膜上に発現することが見出された。
Trop−2発現−QUANTBRITE(登録商標)PEビーズを用いたフローサイトメトリーで、様々ながん細胞株表面上におけるTrop−2発現を測定した。異なる細胞株中に検出されたTrop−2分子の数の結果は、BxPC−3膵臓癌(891,000)、NCI−N87胃癌(383,000)、MDA−MB−468乳癌(341,000)、SK−MES−1扁平細胞肺癌(27,000)、Capan−1膵臓癌(115,000)、AGS胃癌(78,000)、COLO 205結腸癌(52,000)であった。Trop−2発現はまた、29の膵腺癌組織マイクロアレイのうち29(100%)で認められた(データは省略)。
前臨床試験は、イリノテカン投与時と比較して、IMMU−132が、120倍の量のSN−38をヒト膵臓腫瘍異種移植片へと送達することを示した。多種多様な転移性固形がんを有する患者を登録する大規模試験の一部では、第II相のIMMU−132用量を、主な副作用である管理可能な好中球減少症及び下痢を基準として、8〜10mg/kgと決定した。治療サイクルを繰り返しているにもかかわらず、抗抗体または抗SN−38抗体は今日まで検出されていない。
本発明者らは以前、ゲムシタビン(GEM)と組み合わせると効果が高まる90Y−ヒト化PAM4 IgG(hPAM4;90Y−クリバツズマブテトラキセタン)を投与したヒト膵臓腫瘍を有するヌードマウスにおける有効な抗腫瘍活性について報告した(Gold et al.,Int J.Cancer 109:618−26,2004;Clin Cancer Res 9:3929S−37S,2003)。これらの試験は、有望な客観的効果を示す、GEMと組み合わせた分割用量90Y−hPAM4 IgGの臨床試験につながった。GEMはその放射線増感能で知られているが、単剤ではあまり有効な膵臓癌治療薬ではなく、その用量は血液毒性により制限される。90Y−hPAM4 IgGもまた血液毒性により制限される。
SN−38をコンジュゲートさせたhRS7抗体を、上記のとおりに、また上記のプロトコル(Moon et al.J Med Chem 2008,51:6916−6926;Govindan et al.,Clin Cancer Res 2009.15:6052−6061)に従って調製した。SN−38の反応性二官能性誘導体(CL2A−SN−38)を調製した。CL2A−SN−38の式は、マレイミド−[x]−Lys−PABOCO−20−O−SN−38(式中、PABはp−アミノベンジルであり、「x」は短いPEGを含む)である。TCEPで抗体中のジスルフィド結合を還元した後、CL2A−SN−38を還元抗体と反応させて、SN−38をコンジュゲートさせたRS7を調製した。
Trop−2抗原は、ほとんどの上皮癌(肺、乳房、前立腺、卵巣、結腸直腸、膵臓)で発現しており、サシツズマブゴビテカン複合体は、様々なヒトがんマウス異種移植モデルで試験されている。90Y−hPAM4 IgGに加えて放射線を増感する量のGEMを用いた初期の臨床試験は有望であり、腫瘍縮小または安定のエビデンスがある。しかしながら、膵臓癌の治療は非常に難易度が高い。それゆえ、併用療法が優れた効果を誘導するかどうかを明らかにするために、併用療法に関する試験を行った。具体的には、有効でその上非毒性用量のサシツズマブゴビテカンの投与を、90Y−hPAM4 IgGを用いたRAITと組み合わせた。
患者は、2005年に初めて診断され、ステージIVのトリプルネガティブ乳癌(ER/PR陰性、HER−neu陰性)を有する57歳の女性であった。彼女は、2005年に自身の左乳房の乳腺腫瘍摘出術を受けた後、2005年9月に、アジュバント設定Dose−Dense ACTを受けた。その後、彼女は放射線治療を受け始め、11月に終了した。2012年の初期に患者が対側(右)乳房のしこりを触診した際、病変の局所再発が確認され、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)化学療法による治療を受けた。同年、彼女の疾患は、胸壁皮膚における転移性病変を伴って再発した。その後彼女は、カルボプラチン + TAXOL(登録商標)の化学療法レジメンを受け、その間、血小板減少症を発症した。彼女の病変は増悪し、彼女は週に1回のドキソルビシンを開始して、6回の投薬まで継続した。皮膚の病変もまた増悪していた。2012年9月26日のFDG−PETスキャンでは、胸壁及び肥大した固形の腋窩リンパ節における病変の増悪が認められた。患者は、疼痛コントロールのためオキシコドンを投与された。
この実施例は、左肺の縦隔リンパ節、及び、MRIによる左頭頂部脳葉への転移の形跡が認められる、小細胞肺癌と診断された65歳女性に関する。前化学療法にはカルボプラチン、エトポシド及びトポテカンが含まれていたが、効果は認められなかった。放射線治療もまた、彼女の病変の制御に失敗している。その後、彼女は、18mg/kgのIMMU−132を2週間おきに1回、合計5回の注入で投与された。2回目の投薬後、彼女は低血圧症及びグレード2の好中球減少症を起こしたが、次回の注入前に改善した。5回目の注入後のCT検査では、彼女の標的左肺腫瘤に13%の縮小が認められた。脳のMRIでもまた、この転移部に10%の縮小が認められた。彼女は、2週間おきのIMMU−132投薬を更に3ヶ月間継続し、彼女の病状に客観的かつ主観的な改善(左肺腫瘤の25%の縮小、及び脳転移部の21%の縮小)が認められるまで継続した。
この患者は、喫煙履歴、及び40年間にわたる過度のアルコール摂取期間を有する60歳男性であった。彼は、体重減少、制酸薬では軽減しない摂食不快感及び疼痛、頻繁な腹痛、腰部痛、ならびに、直近では、両腋窩の触知可能なリンパ節を発症した。彼は医学的助言を求め、精密検査後、胃内視鏡による生検に基づいて、胃−食道接合部に若干の扁平部を含む腺癌の存在が認められた。放射線学的検査(CT及びFDG−PET)により、右腋窩及び左腋窩、縦隔領域、腰椎、ならびに肝臓(右葉に2つの腫瘍、左葉に1つの腫瘍、全て直径2〜4cmの大きさ)における転移性病変もまた明らかとなった。彼は、胃腫瘍の切除後、エピルビシン、シスプラチン及び5−フルオロウラシルによる化学療法のクールに入った。4ヶ月間、及び6週間の休薬期間の後、彼は、ドセタキセル化学療法に切り替えたが、転移性腫瘍のCT測定で確認された増悪、及び一部の全身的な悪化に基づくと、この療法もまた彼の病変の制御に失敗した。
抄録
サシツズマブゴビテカン(IMMU−132、hRS7−CL2A−SN−38としても周知)とは、SN−38(イリノテカンの活性代謝物)を送達するための、Trop−2(ほとんどの上皮性腫瘍上で発現している表面糖タンパク質)を標的とする抗体薬物複合体(ADC)のことである。超毒性薬物及び安定したリンカーを使用するほとんどのADCとは異なり、IMMU−132は、SN−38とリンカーの間の適度に安定したカーボネート結合を有する適度な毒性薬物を使用する。フローサイトメトリー及び免疫組織化学試験により、胃、膵臓、トリプルネガティブ乳癌(TNBC)、結腸、前立腺及び肺を含む広範囲の腫瘍タイプでTrop−2が発現していることが明らかとなった。細胞結合試験では、IMMU−132と親hRS7抗体の間に有意差は認められなかったが、Trop−2 CM5チップを使用した表面プラズモン共鳴解析では、hRS7と比較して、IMMU−132に有意な結合優位性が認められた。複合体は新生児受容体への結合を維持したが、hRS7と比較して、抗体依存性細胞媒介性細胞傷害活性の60%超を失った。
異なる超毒性(ピコモル力価)薬物を導入した2種類の新規抗体薬物複合体(ADC)が承認されており、超毒性薬物の使用を含む同様の原理に基づいたその他ADCの更なる開発につながっている(Younes et al.,2011,Nat Rev Drug Discov 11:19−20;Sievers & Senter,2013,Ann Rev Med 64:15−29;Krop & Winer,2014,Clin Cancer Res 20:15−20)。あるいは、Moon et al.(2008,J Med Chem 51:6916−26)及びGovindan et al.(2009,Clin Cancer Res 15:6052−61)は、SN−38(イリノテカンの活性代謝物であるトポイソメラーゼI阻害剤、周知だが複雑な薬物動態を有する承認薬)を選択した(Mathijssen et al.,2001,Clin Cancer Res 7:2182−94)。SN−38をコンジュゲートするためのいくつかのリンカーについて、様々な速度(数時間から数日間)の、IgGからの遊離を評価した(Moon et al.,2008,J Med Chem 51:6916−26;Govindan et al.,2009,Clin Cancer Res 15:6052−61;Cardillo et al.,2011,Clin Cancer Res 17:3157−69)。血清中において中間的なコンジュゲート安定性を示す選択された最適なリンカー(CL2Aと呼ばれる)を、SN−38のラクトン環上のヒドロキシル基に結合させることにより、この環をリンカーに結合させつつも、この環が毒性の少ないカルボキシレート形態へと開環することから保護し、溶解性を高めるための短いポリエチレングリコール部分を導入した(Cardillo et al.,2011,Clin Cancer Res 17:3157−69)。リンカーとSN−38の間のカーボネート結合が開裂する際に活性化形態のSN−38が遊離するが、このことは、リソソームに加え腫瘍微小環境でみられるように、あるいは、酵素分解を介してみられるように、低pHで起こる。
登録基準−主な目的は、単一薬剤としてのサシツズマブゴビテカン(IMMU−132)の安全性及び忍容性を確認することであった。試験を標準的な3+3第I相デザインとして設計し、注射あたり8mg/kg用量で開始して、3週間の治療サイクルで2週間にわたり週に1回投与した。
患者背景−25名の患者を登録した(表6)。平均年齢は52〜60歳の範囲であり、76%がECOG 1パフォーマンスステータスであり、残りがECOG 0であった。ほとんどの患者は、転移性膵臓癌(PDC)(N=7)、続いて、トリプルネガティブ乳癌(TNBC)(N=4)、結腸直腸癌(CRC)(N=3)、小細胞肺癌(SCLC)(N=2)、及び胃癌(GC)(N=2)を有しており、食道腺癌(EAC)、ホルモン不応性前立腺癌(HRPC)、非小細胞肺癌(NSCLC)、上皮性卵巣癌(EOC)、腎臓癌、扁桃癌、及び膀胱癌(UBC)の症例がそれぞれ1件であった。
Trop−2はほとんどの上皮性腫瘍において大量に発現しており、特に、予後マーカー及びいくつかのがんタイプにおけるがん遺伝子であると考えられている(Cardillo et al.,2011,Clin Cancer Res 17:3157−69;Ambrogi et al.,2014,PLoS One 9:e96993;Cubas et al.,2009,Biochim Biophys Acta 1796:309−14;Trerotola et al.,2013,Oncogene 32:222−33)ため、標的化療法において関心のある抗原となっている(Cubas et al.,2009,Biochim Biophys Acta 1796:309−14)。正常組織におけるTrop−2の発現、及び研究が進んだ別の腫瘍関連抗原であるEpCamとの関係が、Trop−2に対する免疫療法の開発安全性に関する冒頭の一部の注意文言(Trerotola et al.,2009,Biochim Biophys Acta 1805:119−20)をもたらしたが、ヒトとほぼ同等の組織でTrop−2を発現するカニクイザルにおける本発明者らの研究は、ヒト等用量の約40mg/kgのサシツズマブゴビテカンに極めて十分な耐性を示すこと(Cardillo et al.,2011,Clin Cancer Res 17:3157−69)を示した。高用量において、動物は好中球減少症及び下痢(イリノテカン治療に由来するSN−38関連の周知の副作用)を発症したが、Trop−2発現正常組織における有意な組織病理学的変化のエビデンスは未だ欠如していた(Cardillo et al.,2011,Clin Cancer Res 17:3157−69)。その他の前臨床試験所見において、サシツズマブゴビテカンは、低ナノモル濃度で効果があり、また非毒性用量で様々なヒト上皮性腫瘍異種移植片に有効であったため、1つまたは複数の転移性上皮性腫瘍用の標準療法に失敗した患者で第I相試験を実施した。
Trop−2/TACSTD2遺伝子をクローニングすると(Fornaro et al.,1995,Int J Cancer 62:610−18)、細胞遊走及び足場非依存性増殖に機能的に関与し、正常組織と比較して乳癌、肺癌、胃癌、結腸直腸癌、膵臓癌、前立腺癌、頸部癌、頭頸部癌及び卵巣癌を含む様々なヒト上皮癌で高発現する膜貫通Ca++シグナル伝達因子(Basu et al.,1995,Int J Cancer 62:472−72;Ripani et al.,1998,Int J Cancer 76:671−76)をコードすることが明らかとなった(Cardillo et al.,2011,Clin Cancer Res 17:3157−69;Stein et al.,1994;Int J Cancer Suppl 8:98−102;Cubas et al.,2009,Biochim Biophys Acta 196:309−14;Trerotola et al.,2013,Oncogene 32:222−33)。バイシストロニックサイクリンD1−Trop−2 mRNAキメラががん遺伝子である一方で(Guerra et al.,2008,Cancer Res 68:8113−21)、Trop−2の高発現が、がん増殖を促進するために必要かつ十分であると報告されている(Trerotola et al.,2013,Oncogene 32:222−33)。重要なことに、高発現は、乳癌(Ambrogi et al.,2014,PLoS One 9:e96993;Lin et al.,2013,Exp Mol Pathol 94:73−8)を含むいくつかのがんタイプにおいてより活動的な病変及び予後不良と関連付けられている(Cubas et al.,2009,Biochim Biophys Acta 196:309−14;Guerra et al.,2008,Cancer Res 68:8113−21;Bignotti et al.,2010, Eur J Cancer 46:944−53;Fang et al.,2009,Int J Colorectal Dis 24:875−84;Muhlmann et al.,2009,J Clin Pathol 62:152−58)。Trop−2 mRNAの上昇は、浸潤性乳管癌を有する患者における低生存率及びリンパ節転移の有力な予測因子であり、またカプランマイヤー生存曲線は、Trop−2発現が高い乳癌患者の生存率が著しく低いことを示した(Lin et al.,2013,Exp Mol Pathol 94:73−8)。
HICによるDARの算出−ブチル−NPR HPLCカラム(Tosoh Bioscience,King of Prussia,PA)を用いた疎水性相互作用クロマトグラフィー(HIC)により、IMMU−132の臨床ロットを分析した。15分間直線グラジエント(25mM リン酸ナトリウム中2.25〜1.5M NaCl、pH7.4、流速1mL/分、室温)で、IMMU−132導入液(100μg)を分離した。
SN−38の構造及び特性−IMMU−132は、結腸直腸癌、肺癌、頸部癌及び卵巣癌の治療的に有効な、トポイソメラーゼI阻害剤であるSN−38、抗がん剤カンプトテシンの水溶性代謝物であるイリノテカン(7−エチル−10−[4−(1−ピペリジノ)−1−ピペリジノ]カルボニルオキシカンプトテシン)を利用している(Garcia−Carbonero et al.,2002,Clin Cancer Res 8:641061)。SN−38を選択する重要な利点は、薬物のインビボ薬物動態が周知であることである。イリノテカンをエステラーゼで開裂させてSN−38を生成する必要があり、SN−38は、イリノテカンと比較して2〜3桁より強力であり、低ナノモル範囲で活性を有する(Kawato et al.,1991,Cancer Res 51:4187−91)。生理学的pHにおいて、カンプトテシンは、より効果のあるラクトン形態、及びより効果の少ない(10%力価)開環カルボン酸形態を含む平衡状態で存在する(Burke & Mi,1994,J Med Chem 37:40−46)。
本発明者らは、Trop−2を標的とする新規のADC、及び、当該ADCがTNBCに加えその他Trop−2+がんを有する患者に耐性を示し有効であることを示唆する初期の臨床結果について説明する(Bardia et al.,2014,San Antonio Breast Cancer Symposium,P5−19−27)。IMMU−132はその独特な性質により、第2世代ADCの代表例となっている。通常、ADCには、最適な効果を持たせるための4つの広範な特性、(i)選択的な標的化/活性化、(ii)ADCに用いる抗体の結合性、親和性、内部移行性及び免疫原性、(iii)薬物、その力価、代謝及び薬理学的性質、及び(iv)薬物の抗体への結合方式、が求められる。標的選択性は、治療指数(腫瘍対正常細胞の毒性比率)を定義する上で重要な役割を果たすことから、全てのADCにおける最も一般的な必要条件である。Trop−2は、多数の上皮癌において非常に広く存在しているが、いくつかの正常組織においても発現しているため(Cubas et al.,2009,Biochim Biophys Acta 1796:309−14;Trerotola et al.,2013,Oncogene 32:222−33;Stepan et al.,2011,59:701−10)、特異性に影響を及ぼし得ると考えられている。しかしながら、正常組織における発現はがんにおける発現よりも低いと考えられており(Bignotti et al.,2010,Eur J Cancer 46:944−53)、抗体への接近を制限する正常組織構造によりTrop−2が遮蔽される一方で、がんにおいては、浸潤腫瘍がこれらの組織障壁を損傷していると考えられている。上記の証拠はサルにおける初期の毒性学的試験から明白であった。その試験においては、イリノテカン様の好中球減少症及び下痢をまねく濃度にまでIMMU−132の用量を上げたにもかかわらず、Trop−2発現正常組織に対する組織病理学的損傷は生じなかった(Cardillo et al.,2011,Clin Cancer Res 17:3157−69)。これらの結果は臨床的に確認されていると思われ、患者における特異的な器官毒性は、親化合物のイリノテカンによる周知の毒性(IMMU−132を用いれば、より管理可能)を除いて、これまでのところ認められていない(Bardia et al.,2014,San Antonio Breast Cancer Symposium,P5−19−27)。
サシツズマブゴビテカン(IMMU−132、hRS7−CL2A−SN−38としても周知)とは、SN−38(イリノテカンの活性代謝物)を送達するための、Trop−2(ほとんどの上皮性腫瘍上で発現している表面糖タンパク質)を標的とする抗体薬物複合体(ADC)のことである。超毒性薬物及び安定したリンカーを使用するほとんどのADCとは異なり、IMMU−132は、SN−38とリンカーの間の適度に安定したカーボネート結合を有する適度な毒性薬物を使用する。フローサイトメトリー及び免疫組織化学試験により、胃、膵臓、トリプルネガティブ乳癌(TNBC)、結腸、前立腺及び肺を含む広範囲の腫瘍タイプでTrop−2が発現していることが明らかとなった。細胞結合試験では、IMMU−132と親hRS7抗体の間に有意差は認められなかったが、Trop−2 CM5チップを使用した表面プラズモン共鳴解析では、hRS7と比較して、IMMU−132に有意な結合優位性が認められた。複合体は新生児受容体への結合を維持したが、hRS7と比較して、抗体依存性細胞媒介性細胞傷害活性の60%超を失った。
米国において今年胃癌と診断された新たな症例は22,220件に上ると推定されており、更に、10,990件の死亡がこの疾患に起因した(Siegel et al.,2014,CA Cancer J Clin 64:9−29)。5年生存率は上昇傾向ではあるが(現時点で29%)、結腸癌、乳癌及び前立腺癌(それぞれ65%、90%及び100%)を含むその他大多数と比較すると、依然としてかなり低いままである。事実、ヒトがん全体でみると、食道癌、肝臓癌、肺癌及び膵臓癌だけが胃癌の5年生存率を下回っている。膵臓癌は依然として米国における全がん死亡原因の第4位であり、その5年生存率はわずか6%である(Siegel et al.,2014,CA Cancer J Clin 64:9−29)。胃癌及び膵臓癌のこのような厳しい統計値から、新しい治療手法が必要とされているのは明らかである。
細胞株及び化学療法剤−使用した全てのヒトがん細胞株は、American Type Culture Collection(ATCC)(Manassas,VA)から購入した。それぞれをATCCの推奨に従い維持し、定期的にマイコプラズマ試験を行い、ATCCによる短鎖縦列反復配列(STR)アッセイを用いて全ての鑑定を行った。IMMU−132(hRS7−SN−38)及び対照ADC(抗CD20 hA20−SN−38及び抗CD22 hLL2−SN−38)を上記のとおりに調製し、−20℃で保管した(Cardillo et al.,2011,Clin Cancer Res 17:3157−69)。SN−38を購入し(Biddle Sawyer Pharma,LLC,New York,NY)、DMSO中1mMのアリコートを−20℃で保管した。
式中、
試験:エフェクター+標的細胞+抗体
エフェクター+標的対照:エフェクター+標的細胞
最大溶解物:標的細胞+Triton−X100
標的対照:標的細胞のみ
複数の固形腫瘍細胞株におけるTrop−2発現レベル−Trop−2の表面発現は、胃癌、膵臓癌、乳癌、結腸癌及び肺癌を含む様々なヒト固形腫瘍株(表10)において明白である。任意のその他の腫瘍タイプを上回って高発現した腫瘍タイプは1つではなく、任意の腫瘍細胞タイプ内においてばらつきが認められた。例えば、胃腺癌全体のTrop−2レベルは、細胞あたりの表面分子で、非常に少ない494 ± 19(Hs 746T)から多い246,857 ± 64,651(NCI−N87)の範囲であった。
細胞あたりの表面Trop−2分子数
細胞株 平均±SD
胃
NCI−N87 246,857 ± 64,651
AGS 53,756 ± 23,527
Hs 746T 494 ± 19
膵臓
BxPC−3 493,773 ± 97,779
CFPAC−1 162,871 ± 28,161
Capan−1 157,376 ± 36,976
HPAF−II 115,533 ± 28,627
乳房(TN)
MDA−MB−468 301,603 ± 29,470
HCC38 181,488 ± 69,351
HCC1806 91,403 ± 20,817
MDA−MB−231 32,380 ± 5,460
乳房
SK−BR−3(HER2+) 328,281 ± 47,996
MCF−7(ER2+) 110,646 ± 17,233
結腸
COLO 205 58,179 ± 6,909
HT−29 68 ± 17
NSCLC
Calu−3 128,201 ± 50,708
扁平上皮細胞肺
SK−MES−1 29,488 ± 5,824
急性T細胞性白血病
ジャーカット 0
a3つの独立したアッセイを実施し、平均及び標準偏差で示した。
処理 平均蛍光強度 パーセント陽性
未処理 2516 ± 191 18.8 ± 6.3
hRS7 2297 ± 18 13.0 ± 0.6
hA20−SN−38 2246 ± 58 12.7 ± 2.4
IMMU−132 5349 ± 234 69.0 ± 4.1
aIMMU−132対全3対照治療、P<0.0002(片側t検定;N=3)。
目下の第I/II相臨床試験(ClinicalTrials.gov,NCT01631552)において、IMMU−132(サシツズマブゴビテカン)は、広範囲の固形腫瘍を発症している患者に対して客観的な効果を示している(Starodub et al.,2015,Clin Cancer Res 21:3870−78)。この第I/II相臨床試験を継続する上で、IMMU−132の効果を更に、拡大リストのTrop−2陽性がんへと広げる必要がある。加えて、超毒性薬物を利用したその他臨床的に意義のあるADCとは対照的に、IMMU−132の独自性を、本発明者らが臨床開発を前進させるにつれて更に明らかにする必要がある。
トリプルネガティブ乳癌(TNBC)
上記実施例で説明した第I/II相臨床試験(NCT01631552)を、10mg/kgで治療した56名のTNBC患者を集めて継続している。患者集団はこれまで、IMMU−132治療を開始する前に、タキサン治療を含む少なくとも2種類の前治療により広く治療を受けてきた。前治療としては、シクロホスファミド、ドキソルビシン、カルボプラチン、ゲムシタビン、カペシタビン、エリブリン、シスプラチン、アナストロゾール、ビノレルビン、ベバシズマブ及びタモキシフェンが挙げられる。この広い治療暦にもかかわらず、TNBC患者は、IMMU−132に対して十分な反応を示し、2名の完全寛解(CR)が確認され、13名が部分寛解(PR)、また25名が安定(SD)となり、客観的奏効率は29%(15/52)であった(データは省略)。CRとPRとSDの症例を足し合わせると、TNBCの治療は、IMMU−132治療患者において71%の好ましい奏効率となった(データは省略)。多数の前治療暦を有するこのTNBC患者集団の平均無増悪期間は、これまでのところ9.4ヶ月間(2.9〜14.2ヶ月間の範囲)であった。しかしながら、試験における患者の72%はなおも治療継続中であった。
臨床試験はまた、転移性非小細胞肺癌(NSCLC)を有する患者で継続中であり、これまでのところ29名の評価可能な患者を集め、8mg/kgまたは10mg/kgのIMMU−132で治療を行った。RESIST 1.1基準による最良効果を判定した(データは省略)。29名の患者のうち、8名がPRで13名がSDであった。NSCLC患者の無増悪期間は、NSCLC患者の21/33(64%)がPRまたはSDであることを示した(データは省略)。平均無増悪期間は9/4ヶ月間(1.8〜15.5+ヶ月間の範囲)であり、患者の47%はなおも治療を受けている。8mg/kgまたは10mg/kgのIMMU−132で治療したNSCLC患者の無増悪生存期間を測定した(データは省略)。平均PFSは、8mg/kgで3.4ヶ月間であり、10mg/kgで3.8ヶ月間であった。しかしながら、試験はなおも継続中であり、平均無増悪生存期間の数字は改善する可能性がある。
転移性SCLC患者において同等の結果が認められた(データは省略)。無増悪期間(データは省略)は、平均4.9ヶ月間(1.8〜15.7+ヶ月間の範囲)を示し、7名の患者はなおもIMMU−132による治療を受けている。無増悪生存期間(データは省略)は、8mg/kgで2.0ヶ月間の平均PFS、10mg/kgで3.6ヶ月間の平均PFSを示した。平均OSは、8mg/kgで8.1ヶ月間であり、これまでのところ10mg/kgでは測定できていない。
8mg/kgまたは10mg/kgのIMMU−132で治療した尿路上皮癌患者で同様の結果が得られた。11名の評価可能な患者の最良効果データは、6名のPR及び2名のSDを示した(データは省略)。無増悪期間(データは省略)は、平均8.1ヶ月間(3.6〜9.7+ヶ月間の範囲)を示した。
Claims (28)
- Trop−2陽性がんを有するヒト患者に、抗Trop−2抗体またはその抗原結合フラグメントに結合したリンカー部分にコンジュゲートしたSN−38を含むADCを投与することを含む、Trop−2陽性がんを治療するための方法であって、前記患者は、チェックポイント阻害薬を用いた治療から再発した、または前記チェックポイント阻害薬を用いた前記治療に耐性を示す、前記方法。
- 前記チェックポイント阻害薬は、PD−1、PD−L1またはCTLA−4の阻害薬である、請求項1に記載の方法。
- 前記チェックポイント阻害薬は、MPDL3280A、ペンブロリズマブ、ニボルマブ、イピリムマブ、ピディリズマブ、MDX−1105、デュルバルマブ、BMS−936559及びトレメリムマブからなる群から選択される、請求項1に記載の方法。
- 前記チェックポイント阻害薬はMPDL3280Aである、請求項1に記載の方法。
- 前記抗Trop−2抗体は、軽鎖CDR配列CDR1(KASQDVSIAVA、配列番号:1)、CDR2(SASYRYT、配列番号:2)及びCDR3(QQHYITPLT、配列番号:3)、ならびに、重鎖CDR配列CDR1(NYGMN、配列番号:4)、CDR2(WINTYTGEPTYTDDFKG、配列番号:5)及びCDR3(GGFGSSYWYFDV、配列番号:6)を含むhRS7抗体である、請求項1に記載の方法。
- 前記抗Trop−2抗体は、軽鎖CDR配列CDR1(KASQDVSIAVA、配列番号:1)、CDR2(SASYRYT、配列番号:2)及びCDR3(QQHYITPLT、配列番号:3)、ならびに、重鎖CDR配列CDR1(NYGMN、配列番号:4)、CDR2(WINTYTGEPTYTDDFKG、配列番号:5)及びCDR3(GGFGSSYWYFDV、配列番号:6)を含む抗体と、Trop−2への結合性で競合する、請求項1に記載の方法。
- 前記リンカーはCL2Aであり、前記ADCの構造は、MAb−CL2A−SN−38
である、請求項1に記載の方法。 - 前記抗Trop−2抗体は、軽鎖CDR配列CDR1(KASQDVSIAVA、配列番号:1)、CDR2(SASYRYT、配列番号:2)及びCDR3(QQHYITPLT、配列番号:3)、ならびに、重鎖CDR配列CDR1(NYGMN、配列番号:4)、CDR2(WINTYTGEPTYTDDFKG、配列番号:5)及びCDR3(GGFGSSYWYFDV、配列番号:6)を含むhRS7抗体である、請求項7に記載の方法。
- 前記がんは、結腸直腸癌、肺癌、胃癌、膀胱癌、腎臓癌、膵臓癌、乳癌、卵巣癌、子宮癌、食道癌及び前立腺癌からなる群から選択される、請求項1に記載の方法。
- 前記がんはトリプルネガティブ乳癌である、請求項1に記載の方法。
- 前記がんは、トリプルネガティブ乳癌、HER+、ER+、プロゲステロン+乳癌、転移性非小細胞肺癌、転移性小細胞肺癌、転移性子宮内膜癌、転移性尿路上皮癌及び転移性膵臓癌からなる群から選択される、請求項1に記載の方法。
- 前記ADCは、3mg/kg〜18mg/kgの用量で投与される、請求項1に記載の方法。
- 前記用量は、3mg/kg、4mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、11mg/kg、12mg/kg、16mg/kg及び18mg/kgからなる群から選択される、請求項12に記載の方法。
- 前記ADCは、8mg/kg〜12mg/kgの用量で投与される、請求項1に記載の方法。
- 前記ADCは、8mg/kg〜10mg/kgの用量で投与される、請求項1に記載の方法。
- 前記ADCは、10mg/kgの用量で投与される、請求項1に記載の方法。
- 前記治療は、少なくとも15%、少なくとも20%、少なくとも30%、または少なくとも40%の腫瘍サイズの縮小をもたらす、請求項1に記載の方法。
- 前記ADCは、前記抗体またはその抗原結合フラグメントにコンジュゲートした4分子またはそれ以上の分子のSN−38を含む、請求項1に記載の方法。
- 前記ADCは、前記抗体またはその抗原結合フラグメントにコンジュゲートした6〜8分子のSN−38を含む、請求項1に記載の方法。
- 前記がんは転移性である、請求項1に記載の方法。
- サイズを縮小させること、または転移部を除去することを更に含む、請求項20に記載の方法。
- MAb−CL2A−SN−38におけるSN−38の10−ヒドロキシ位は、「COR」部分を使用した10−O−エステルまたは10−O−カーボネート誘導体であり、式中、「CO」はカルボニルであり、「R」基は、(i)N,N−ジ置換アミノアルキル基「N(CH3)2−(CH2)n−」、式中、nは1〜10であり、式中、末端アミノ基は任意選択的に四級塩の形態である、(ii)アルキル残基「CH3−(CH2)n−」、式中、nは0〜10、(iii)アルコキシ部分「CH3−(CH2)n−O−」、式中、nは0〜10、(iv)「N(CH3)2−(CH2)n−O−」、式中、nは2〜10、または、(v)「R1O−(CH2−CH2−O)n−CH2−CH2−O−」、式中、R1はエチルまたはメチルであり、nは0〜10の値を有する整数、から選択される、請求項7に記載の方法。
- 前記患者に、外科手術、外部放射線、放射免疫治療、免疫療法、化学療法、アンチセンス療法、干渉RNA療法、治療薬を用いた治療、及び遺伝子治療からなる群から選択される少なくとも1つのその他抗がん療法を行うことを更に含む、請求項1に記載の方法。
- 前記治療薬は、薬物、毒素、免疫調節薬、第二抗体、第二抗体の抗原結合フラグメント、プロアポトーシス薬、毒素、RNase、ホルモン、放射性核種、抗血管新生薬、siRNA、RNAi、化学療法剤、サイトカイン、ケモカイン、プロドラッグまたは酵素である、請求項23に記載の方法。
- 前記薬物は、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、Cox−2阻害剤、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−モルホ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、リン酸エトポシド、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−ジオレオイル−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、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、オラパリブ、プリコマイシン、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(DTICの水溶性形態)、トランスプラチン、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からなる群から選択される、請求項24に記載の方法。
- 前記免疫調節薬は、サイトカイン、リンフォカイン、モノカイン、幹細胞増殖因子、リンフォトキシン、造血因子、コロニー刺激因子(CSF)、インターフェロン(IFN)、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、リラキシン、プロリラキシン、卵胞刺激ホルモン(FSH)、甲状腺刺激ホルモン(TSH)、黄体形成ホルモン(LH)、肝増殖因子、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、トランスホーミング増殖因子(TGF)、TGF−α、TGF−β、インスリン様成長因子(IGF)、エリスロポエチン、トロンボポエチン、腫瘍壊死因子(TNF)、TNF−α、TNF−β、ミュラー阻害物質、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、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)、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、S1因子、IL−1、IL−1 cc、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−23、IL−25、LIF、kit−リガンド、FLT−3、アンジオスタチン、トロンボスポンジン及びエンドスタチンからなる群から選択される、請求項24に記載の方法。
- 前記放射性核種は、11C、13N、15O、32P、33P、47Sc、51Cr、57Co、58Co、59Fe、62Cu、67Cu、67Ga、67Ga、75Br、75Se、75Se、76Br、77As、77Br、80mBr、89Sr、90Y、95Ru、97Ru、99Mo、99mTc、103mRh、103Ru、105Rh、105Ru、107Hg、109Pd、109Pt、111Ag、111In、113mIn、119Sb、121mTe、122mTe、125I、125mTe、126I、131I、133I、142Pr、143Pr、149Pm、152Dy、153Sm、161Ho、161Tb、165Tm、166Dy、166Ho、167Tm、168Tm、169Er、169Yb、177Lu、186Re、188Re、189mOs、189Re、192Ir、194Ir、197Pt、198Au、199Au、199Au、201Tl、203Hg、211At、211Bi、211Pb、212Bi、212Pb、213Bi、215Po、217At、219Rn、221Fr、223Ra、225Ac、227Th及び255Fmからなる群から選択される、請求項24に記載の方法。
- 前記毒素は、リシン、アブリン、リボヌクレアーゼ(RNase)、DNase I、Staphylococcalエンテロトキシン−A、アメリカ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、Pseudomonasエキソトキシン、及びPseudomonasエンドトキシンからなる群から選択される、請求項24に記載の方法。
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AU2017257254A1 (en) | 2018-09-20 |
CA3016917A1 (en) | 2017-11-02 |
US20170313781A1 (en) | 2017-11-02 |
JP7379795B2 (ja) | 2023-11-15 |
US10266605B2 (en) | 2019-04-23 |
CN109310385A (zh) | 2019-02-05 |
US11192955B2 (en) | 2021-12-07 |
RU2018139610A3 (ja) | 2020-05-27 |
RU2725292C2 (ru) | 2020-06-30 |
RU2018139610A (ru) | 2020-05-27 |
US20190177427A1 (en) | 2019-06-13 |
AU2017257254B2 (en) | 2022-02-24 |
JP2022046678A (ja) | 2022-03-23 |
EP3448260A4 (en) | 2019-10-09 |
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US20210395385A1 (en) | 2021-12-23 |
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