JP2019535731A - コンジュゲートさせた生物学的分子、医薬組成物及び方法 - Google Patents
コンジュゲートさせた生物学的分子、医薬組成物及び方法 Download PDFInfo
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Abstract
Description
したがって、本開示は、グロボ系列の抗原が、広範ながんにおいて、異常に発現するが、正常細胞において発現しないという発見に基づく。グロボ系列の抗原を発現させるがんは、肉腫、皮膚がん、白血病、リンパ腫、脳腫瘍、神経膠芽腫、肺がん、乳がん、口腔がん(oral cancer)、頭頸部がん、鼻咽頭がん、食道がん、胃がん、肝臓がん、胆管がん、胆嚢がん、膀胱がん、膵臓がん、腸がん、結腸直腸がん、腎臓がん、子宮頸がん、子宮内膜がん、卵巣がん、睾丸がん、口腔がん(buccal cancer)、口腔咽頭がん、喉頭がん及び前立腺がんを含むがこれらに限定されない。
本発明の実施において、そうでないことが指し示されない限り、当分野の範囲内にある、分子生物学、微生物学、組換えDNA及び免疫学についての従来の技術を援用する。そのような技術は、文献において、完全に説明されている。例えば、「Molecular Cloning:A Laboratory Manual」、2版、Sambrook、Fritsch及びManiatis編(Cold Spring Harbor Laboratory Press、1989);「DNA Cloning」、I及びII巻(D.N.Glover編、1985);「Culture Of Animal Cells」(R.I.Freshney,Alan R.Liss,Inc.、1987);「Immobilized Cells And Enzymes」(IRL Press、1986);B.Perbal、「A Practical Guide To Molecular Cloning」(1984);論文集「Methods In Enzymology」(Academic Press,Inc.、N.Y.)、「Gene Transfer Vectors For Mammalian Cells」(J.H.Miller及びM.P.Calos編、1987、Cold Spring Harbor Laboratory);「Methods In Enzymology」、154及び155巻(Wuら編)、「Immunochemical Methods In Cell And Molecular Biology」(Mayer及びWalker編、Academic Press、London、1987);「Antibodies:A Laboratory Manual」、Harlow及びLane著(Cold Spring Harbor Laboratory Press、1988)及び「Handbook Of Experimental Immunology」、I〜IV巻(D.M.Weir及びC.C.Blackwell編、1986)を参照されたい。
本発明の化合物は、抗がん活性のための有用性を伴う化合物を含む。特に、化合物は、リンカーを介して、薬物部分へとコンジュゲートさせた、すなわち、共有結合的に付着させた抗体を含み、この場合、薬物は、抗体へとコンジュゲートさせなければ、細胞傷害効果又は細胞増殖抑制効果を有する。したがって、薬物部分の生物学的活性は、抗体へのコンジュゲーションによりモジュレートされる。本発明の抗体−薬物コンジュゲート(ADC)は、有効用量の細胞傷害剤を、腫瘍組織へと選択的に送達することが可能であり、これにより、選択性の増大、すなわち、有効用量の低減が達成されうる。
Ab−(L−D)n (I)
若しくは薬学的に許容されるその塩又はこれらの溶媒和物
[式中、Abは、グロボ系列の抗原に結合する、又は1つ以上の腫瘍関連抗原若しくは細胞表面受容体に結合する抗体であり、nは、薬物対抗体比(DAR)であり、1〜8の範囲である]
により表されうる。
Ab−(L−D)n (I)
[式中、1つ以上のMMAEによる薬物部分(D)は、リンカー(L)により、抗体(Ab)へと共有結合的に連結される。Abは、グロボ系列の抗原をターゲティングする、又は1つ以上の腫瘍関連抗原若しくは細胞表面受容体に結合する抗体である。リンカーであるLは、細胞の外部において安定でありうる、すなわち、細胞外リンカーでありうる]
により表されうる。
式Iの抗体単位(Ab−)は、その範囲内に、受容体、抗原又は所与の標的細胞集団と関連する他の受容性部分に結合する、又はこれらと反応して会合する、又はこれらと複合体化する、抗体の任意の単位を含む。抗体は、治療的に又は他の形で、生物学的に改変されることが求められる細胞集団の部分に、結合するか、これらと複合体化するか、又はこれらと反応する、任意のタンパク質又はタンパク質様分子でありうる。一態様において、抗体単位は、メイタンシノイド薬物部分を、抗体単位が反応する、特定の標的細胞集団へと送達するように作用する。このような抗体は、全長抗体及び抗体断片のような高分子量タンパク質を含むがこれらに限定されない。
本開示の1つの態様は、グロボHに特異的な、新たなADC(OBI−999)を特色とする。ADCの抗グロボH抗体は、Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcに結合する。
モノクローナル抗体(MAb)を作製するのに、多様な方法が援用されている。単一種類の抗体を産生するクローニングされた細胞株を指す、ハイブリドーマ技術は、マウス(mice(murine))、ハムスター、ラット及びヒトを含む多様な種の細胞を使用する。キメラ抗体及びヒト化抗体を含むMAbを調製する他の方法は、遺伝子操作、すなわち、組換えDNA技術を使用する。
例示的なADCリンカー
ADCに適する例示的リンカーについては、例えば、米国特許第7595292号(WO2005/007197)において記載されている。リンカーへと方向付けられた全ての内容は、参照により本明細書に組み込まれている。リンカーであるLは、共有結合を介して、抗体を薬物部分へと付着させ、ジスルフィド基を含まない。リンカーは、1つ以上の薬物部分(D)と抗体単位(Ab)とを連結して、式Iの抗体−薬物コンジュゲート(ADC)を形成するのに使用されうる、二官能性又は多官能性部分である。抗体−薬物コンジュゲート(ADC)は、薬物及び抗体への結合のための反応性の官能基を有するリンカーを使用して、簡便に調製されうる。抗体(Ab)のシステインのチオール又はアミン、例えば、N末端又はリシンのようなアミノ酸側鎖は、リンカー試薬、薬物部分又は薬物−リンカー試薬の官能基と共に、結合を形成しうる。
本発明のADC(OBI−999)は、当分野で公知の多様なアッセイにより、それらの物理的/化学的特性及び生物学的機能について特徴付けられうる。
本発明は、ヒト化抗体を包摂する。当分野において、非ヒト抗体をヒト化するための多様な方法が公知である。例えば、ヒト化抗体は、非ヒト供給源から導入された、1つ以上のアミノ酸残基を有しうる。これらの非ヒトアミノ酸残基は、「移入」残基と称することが多く、「移入」残基は、「移入」可変ドメインから採取されることが典型的である。ヒト化は、Winterらによる方法(Jonesら(1986、Nature、321:522〜525頁;Riechmannら(1988)、Nature、332:323〜327頁;Verhoeyenら(1988)、Science、239:1534〜1536頁)に従い、超可変領域配列によってヒト抗体の対応する配列を置換することにより、本質的に実施されうる。したがって、このような「ヒト化」抗体とは、実質的に無傷に満たないヒト可変ドメインが、非ヒト種に由来する対応する配列により置換されているキメラ抗体(米国特許第4,816,567号)である。実際は、ヒト化抗体は、一部の超可変領域残基及び、おそらく、一部のFR残基が、齧歯動物抗体における類似の部位に由来する残基で置換されているヒト抗体であることが典型的である。
本発明のADC(OBI−999)は、例えば、インビトロ、エクスビボ及びインビボの治療法において使用されうる。本発明のADC(OBI−999)は、インビトロ、エクスビボ及び/又はインビボにおいて、特異的抗原活性を、部分的又は完全に遮断するアンタゴニストとして使用されうる。したがって、本発明のADC(OBI−999)は、例えば、抗原を含有する細胞培養物、本発明のADC(OBI−999)が交差反応する抗原を有する、ヒト対象又は他の哺乳動物対象(例えば、チンパンジー、ヒヒ、マーモセット、カニクイザル及びアカゲザル、ブタ又はマウス)における特異的抗原活性を阻害するのに使用されうる。一実施形態において、本発明のADC(OBI−999)は、抗原活性が、阻害されるように、ADC(OBI−999)を、抗原と接触させることにより、抗原活性を阻害するために使用されうる。一実施形態において、抗原は、ヒトタンパク質分子である。
本明細書において、治療有効量の、本明細書において記載された、1つ以上のADC(OBI−999)を含む組成物をこのような処置を必要とする対象に投与するステップを含む治療方法について記載される。
治療用の抗体−薬物コンジュゲート(ADC)は、処置される状態に適切な任意経路により投与されうる。ADCは、非経口投与、すなわち、注入、皮下注入、筋内注入、静脈内注入、皮内注入、髄腔内注入、ボーラス注射、腫瘍内注射又は硬膜外注射されることが典型的である(Shireら(2004)J.Pharm.Sciences、93(6):1390〜1402頁)。治療用の抗体−薬物コンジュゲート(ADC)の医薬製剤は、非経口投与のために、薬学的に許容される非経口媒体と共に、かつ、注射用単位剤形において調製されることが典型的である。所望の純度を有する抗体−薬物コンジュゲート(ADC)は、任意選択的に、薬学的に許容される希釈剤、担体、賦形剤又は安定化剤と、凍結乾燥製剤又は水溶液の形態において混合される(「Remington’s Pharmaceutical Sciences」(1980)、16版、Osol,A.編)。
抗体−薬物コンジュゲート(ADC)は、組合せ医薬製剤又は組合せ療法としての投与レジメンにおいて、抗がん特性を有する第2の化合物と組み合わされうる。組合せ医薬製剤又は投与レジメンの第2の化合物は、互いに、有害な影響を及ぼし合わないように、組合せのうちのADCと、相補的な活性を有することが好ましい。
別の実施形態において、ADC及び上記において障害の処置に有用な材料を含有する製品又は「キット」が提供される。製品は、容器及び容器上のラベル若しくはパッケージ添付文書又は容器と関連する表示若しくはパッケージ添付文書を含む。適切な容器は、例えば、ボトル、バイアル、シリンジ又はブリスターパックを含む。容器は、ガラス又はプラスチックのような様々な材料から形成されうる。容器は、状態を処置するのに有効な、抗体−薬物コンジュゲート(ADC)組成物を保持し、滅菌アクセスポートを有しうる(例えば、容器は、静脈内注射用溶液バッグの場合もあり、皮下注射用注射針で穿刺可能な止栓を有するバイアルの場合もある)。組成物中の少なくとも1つの活性薬剤は、ADCである。ラベル又はパッケージ添付文書は、組成物が、がんのような、えり抜きの状態を処置するために使用されることを指し示す。
PolyThericsが、抗体薬物コンジュゲート(ADC;OBI−999)を調製するのに、MMAE試薬の、OBI−888モノクローナル抗体へのコンジュゲーションを実施した。ジスルフィドコンジュゲーションリンカーは、PCT出願番号:米国特許第7595292号(WO2005/007197)に開示されている通りであり;OBI−888は、抗グロボHモノクローナル抗体であり、US20170101462(WO2017/062792)に開示されている通りであり;モノメチルアウリスタチンE(MMAE)は、市販の抗新生物剤である。パイロット規模の反応及び精製を実行して、適切な状態を同定した。還元抗体には、凝集への傾向がないことが見出された。還元状態及びコンジュゲーション状態についての、後続のスクリーニングは、コンジュゲーション収量の著明な改善を結果としてもたらした。OBI−999(DAR=4)の化学的構造の全体は、以下:
2.1 外観
生成物溶液の外観を、色及び透明度について視覚的に検討した。
Dionex Ultimate 3000RS HPLCシステムへと接続されたTOSOH、TSKgel Butyl−NPRカラム(3.5cm×4.6mm)を使用して、分析的HIC(疎水性相互作用クロマトグラフィー)を実行した。移動相は、緩衝液A(50mMのリン酸ナトリウム、pH7.0中、1.5Mの硫酸アンモニウム)であった。20%〜86%の緩衝液B(50mMのリン酸ナトリウム、pH7.0中、20%のイソプロパノール(v/v))を使用して、勾配を適用した(1.2mL/分の流量で、18.4分間にわたる)。カラム温度は、分析を通して、30℃に維持し、UVの検出は、280nmにおいて実行した。各分析のために、10μgの天然OBI−888又はコンジュゲート生成物を注入した。
Agilent Infinity 1260 Bioinertシステムへと接続されたTOSOH Bioscience TSKgel Super SW 3000カラム(4.6mm×30cm、4μm)及びガードカラム(4.6mm×4cm)を使用して、SEC(サイズ排除クロマトグラフィー)を実行した。移動相は、0.2Mのリン酸カリウム緩衝液、pH6.8(0.2Mの塩化カリウム、15%イソプロパノール)であった。流量は、0.35mL/分において、一定に保った。カラムは、分析を通して、周囲温度に維持した。280nmにおけるUV検出を伴う、20分間にわたる定組成溶離により、分析を実行した。各分析のために、10μgのコンジュゲート生成物を注入した。純度百分率及び存在する凝集百分率は、主要ピーク及び早期溶離ピークそれぞれのピーク面積を、全ピーク面積と比較することにより計算した。
MES緩衝液を伴う還元条件下において、NuPAGE 4−12% Bis−Trisゲル(Invitrogen、型番NP0321BOX)を使用して、SDS−PAGE分析を実行した。分析のために、1μgの試料(タンパク質に基づく)を、レーンごとに、ゲルへとロードした。電気泳動は、200Vにおいて、35分間にわたり実行した。タンパク質検出のために、ゲルを、InstantBlue(Expedeon、型番ISB1LUK)により染色し、ImageQuantイメージング装置(GE Healthcare)を使用して分析した。
コンジュゲートの濃度は、ブラッドフォードマイクロプレートアッセイにより、天然OBI−888についての検量線(0〜100μg/mL)に照らして決定した。アッセイは、平底96ウェルプレートにおいて、100μLの各較正標準物質及び試料を、200μLのブラッドフォード試薬(Expedeon、BFU1L)と、三連において混合することにより実施した。595nmにおける光学密度を読み取り、天然OBI−888についての検量線に照らして、試料濃度を決定した。コンジュゲートの濃度(タンパク質に基づく)もまた、Nanodrop分光光度計を使用するUV吸光度(A280)により決定した。三連において採取した測定値及び平均値を使用して、抗体濃度:
c=Abs/ε×l
[式中、c=濃度(mg/mL);Abs=280nmにおける吸光度;ε=吸光係数(mL/mg・cm);l=長さ(cm)]
を決定した。
ヒト乳腺腺癌についての異種移植腫瘍モデルにおいて、MCF−7(ATCC HTB−22)細胞を、雌無胸腺(nu/nu)ヌードマウスの右脇腹へと、皮下(SC)に移植した(マウス1匹当たり、1:1のマトリゲル/培地混合物0.2mL中の細胞2.0×107個)。エストラジオールプロピオン酸シクロペンチル(マウス1匹当たり100μg)の補充の注射を、細胞移植の1週間前〜研究の完了において、毎週2回ずつ、肩甲骨の間に皮下投与した。腫瘍を移植されたマウスを、各群が6匹ずつの動物を含有する、11の処置群へと分け、被験薬剤の投与を、細胞移植の1日後(1日目と表示される)に開始した。
原液を、25mMのクエン酸ナトリウム、100mMのNaCl緩衝液(pH6.5)により、毎日希釈することにより、被験物質である、ADC(OBI−999)、OBI−888及びMMAEを製剤化し、毎週1回ずつ2又は6週間にわたり、静脈内(IV)投与した。2つの対照群に、媒体(25mMのクエン酸ナトリウム、pH6.5+100mMのNaCl)の静脈内注射を、毎週1回ずつ6週間(群1)又は2週間(群2)にわたり施した。被験物質である、ADC(OBI−999)は、10mg/kgにおいて、毎週1回ずつ2週間にわたり、並びに0.3、1及び3mg/kgにおいて、毎週1回ずつ6週間にわたり投与した。被験物質である、OBI−888は、10mg/kgにおいて、毎週1回ずつ2週間にわたり、並びに0.3、1及び3mg/kgにおいて、毎週1回ずつ6週間にわたり投与した。被験物質である、MMAEは、0.057mg/kgにおいて、毎週1回ずつ6週間にわたり投与した。全ての被験物質は、ADC(OBI−999)を、12.5mL/kgの投与容量により、10mg/kgにおいて投与したことを除き、10mL/kgの投与容量において投与した。
ヒト乳腺腺癌の腫瘍細胞株である、MCF−7(ATCC HTB−22、乳腺腺癌)は、治験依頼者により提供された。腫瘍細胞は、治験依頼者により、調製及び培養され(1mL当たりの細胞1×108個)、細胞2×107個を含有する、0.2mLのMCF−7腫瘍細胞接種物(マトリゲル及び培地の混合物;1:1)が、各マウスの右脇腹の皮下に移植された。
BioLasco Taiwan(Charles River Laboratoriesから実施権を許可されている)から得た、6〜7週齢の雌(nu/nu)ヌードマウスを使用した。動物は、個別換気型ケージ(IVC;36 Mini Isolator System)において飼育した。3〜5匹の動物の割当ては、cm単位で27×20×14であった。全ての動物は、明暗周期を12時間として、温度(20〜24℃)及び湿度(30〜70%)を制御した、衛生的な環境下において維持した。標準実験飼料(オリエンタル酵母工業株式会社、日本)及びオートクレーブ処理された水道水に自由にアクセスさせた。本作業の全ての側面であって、飼育、実験及び動物の処分を含む側面は、一般に、AAALACにより正式に認可された、本発明者らの実験動物施設において、「Guide for Care and Use of Laboratory Animals」、8版(National Academies Press、Washington、D.C.、2011)に従い実施した。加えて、動物のケア及び使用されるプロトコールは、Eurofins Panlabs Taiwan,LtdにおけるIACUCにより再検討され、承認された。
この実験において、Estol−Depot Inj.(エストラジオールプロピオン酸シクロペンチル)(Astar、Taiwan)及びBD Matrigel Matrix(BD Biosciences、US)が使用された。
キャリパー(株式会社ミツトヨ、日本)、遠心分離機5810R(Eppendorf、Germmany)、CO2インキュベーター(Forma Scientific Inc.、USA)、血球計算盤(Hausser Scientific Horsham、USA)、個別換気型ケージ(36 Mini Isolator system、Tecniplast、Italy)、倒立顕微鏡CK−40(オリンパス株式会社、日本)、システム顕微鏡E−400(株式会社ニコン、日本)及び垂直層流型クリーンルーム(Tsao−Hsin、Taiwan)である。
腫瘍体積、体重、死亡及び明らかな毒性の徴候を、毎週2回ずつ77日間にわたり、モニタリングし、記録した。腫瘍体積(mm3)は、扁長楕円体についての式:長さ(mm)×[幅(mm)]2×0.5に従い計算した。腫瘍増殖の阻害は、T/C(処置/対照)×100%として計算した。≦42%のT/C値が、有意な抗腫瘍活性であると考えられた。二元ANOVAに続いて、ボンフェローニ検定を使用して、群の、それぞれの媒体対照と比較した統計学的有意性を確認した(*p<0.05)。
ヒト胃癌についての異種移植腫瘍モデルにおいて、NCI−N87(ATCC CRL−5822)生細胞を、雌nu/nuマウスの右脇腹へと、皮下(SC)に移植した(マウス1匹当たり0.2mLのマトリゲル(1:1)を伴う、1mL当たりの細胞2.5×106個)。腫瘍を移植されたマウスを、各群が8匹ずつの動物を含有し、1つの群が、5匹の動物を含有する、7つの処置群へと分け、投与を、細胞移植の1日後(1日目と表示される)に開始した。
原液を、25mMのクエン酸ナトリウム、100mMのNaCl緩衝液(pH6.5)により、毎日希釈することにより、被験物質である、ADC(OBI−999)、OBI−888及び対応する媒体を製剤化し、毎週1回ずつ4週間にわたり、静脈内(IV)投与した。0.191mg/kgの、標準薬剤である、MMAE抗体及び対応する媒体(PBS pH7.4)は、毎週1回ずつ4週間にわたり、腹腔内(IP)投与した。1つの処置群に、被験物質である、10mg/kgのOBI−888の、0.191mg/kgのMMAEとの組合せ療法を施した。
ヒト胃癌NCI−N87(ATCC CRL−5822)生細胞株は、Eurofins Panlabs Taiwan,Ltdにおいて購入及び培養された。細胞は、5%CO2インキュベーター内、10%のウシ胎仔血清(FBS)を含有するRPMI−1640培地中、37℃において培養され、各マウスの右脇腹の皮下に移植された。
BioLasco Taiwan(Charles River Laboratoriesから実施権を許可されている)から得た、5〜6週齢の雌(nu/nu)ヌードマウスを使用した。動物は、個別換気型ケージ(IVC;36 Mini Isolatorシステム)において飼育した。3匹の動物の割当ては、cm単位で27×20×14であった。全ての動物は、明暗周期を12時間として、温度(20〜24℃)及び湿度(30%〜70%)を制御した、衛生的な環境下において維持した。標準実験飼料[MFG(オリエンタル酵母工業株式会社、日本)]及びオートクレーブ処理された、ボトル内の水道水に自由にアクセスさせた。本作業の全ての側面であって、飼育、実験及び動物の処分を含む側面は、一般に、AAALACにより正式に認可された、本発明者らの実験動物施設において、「Guide for Care and Use of Laboratory Animals」、8版(National Academies Press、Washington、D.C.、2011)に従い実施した。加えて、動物のケア及び使用されるプロトコールは、Eurofins Panlabs Taiwan,LtdにおけるIACUCにより再検討され、承認された。
0.9%のNaCl(Sin−Tong、Taiwan)、ウシ胎仔血清(HyClone、USA)、Matrigel(BD、USA)及びRPMI−1640(HyClone、USA)である。
動物用ケージ(Tecniplast、Italy)、1000mLビーカー(Kimax、USA)、キャリパー(株式会社ミツトヨ、日本)、クラスII生物学的安全キャビネット(NuAire、USA)、個別換気型ケージ(IVC;36 Mini Isolatorシステム)(Tecniplast、Italy)、マウス体重計Z−40型(Taconic、USA)、ステンレス製鉗子(Klappenecker、Germany)及び垂直層流型クリーンルーム(Tsao−Hsin、Taiwan)である。
腫瘍体積、体重、死亡及び明らかな毒性の徴候を、毎週2回ずつ100日間にわたり、モニタリングし、記録した。腫瘍増殖の阻害は、T/C(処置/対照)×100%として計算した。媒体対照群のT/C値と比較して、≦42%のT/C値が、有意な抗腫瘍活性であると考えられた。二元ANOVAに続いて、ボンフェローニ検定を使用して、群の、それぞれの媒体対照と比較した統計学的有意性を確認した(*p<0.05)。
ヒト小細胞肺がんについての異種移植腫瘍モデルにおいて、生存するNCI−H526病期E癌;変異体の小細胞肺がん細胞(ATCC CRL−5811)を、雌nu/nuマウスの右脇腹へと、皮下(SC)に移植した(マウス1匹当たり0.2mLのマトリゲル(1:0.8)を伴う、1mL当たりの細胞1×106個)。腫瘍を移植されたマウスを、各群が8匹ずつの動物を含有する、5つの処置群へと分け、被験薬剤の投与を、細胞移植の1日後(1日目と表示される)に開始した。
原液を、25mMのクエン酸ナトリウム、100mMのNaCl緩衝液(pH6.5)により、毎日希釈することにより、被験物質である、ADC(OBI−999)、OBI−888及び対応する媒体を製剤化し、毎週1回ずつ4週間にわたり、静脈内(IV)投与した。0.191mg/kgの、標準薬剤である、MMAE抗体及び対応する媒体(PBS pH7.4)は、毎週1回ずつ4週間にわたり、腹腔内(IP)投与した。1つの処置群に、被験物質である、10mg/kgのOBI−888の、0.191mg/kgのMMAEとの組合せ療法を施した。
NCI−H526腫瘍細胞株は、American Type Culture Collectionから購入され(ATCC CRL−5811、変異体小細胞肺癌)、Eurofins Panlabs Taiwan,Ltdにおいて培養された。細胞は、5%CO2インキュベーター内、10%のウシ胎仔血清(FBS)を含有するRPMI−1640培地中、37℃において培養され、各マウスの右脇腹の皮下に移植された。
6〜7週齢の雌(nu/nu)ヌードマウスを、BioLasco Taiwan(Charles River Laboratoriesから実施権を許可されている)から得、使用した。動物は、個別換気型ケージ(IVC;36 Mini Isolatorシステム)において飼育した。5匹の動物の割当ては、cm単位で27×20×14であった。全ての動物は、明暗周期を12時間として、温度(20〜24℃)及び湿度(30〜70%)を制御した、衛生的な環境下において維持した。標準実験飼料[MFG(オリエンタル酵母工業株式会社、日本)]及びオートクレーブ処理された水道水に自由にアクセスさせた。本作業の全ての側面であって、飼育、実験及び動物の処分を含む側面は、一般に、AAALACにより正式に認可された、本発明者らの実験動物施設において、「Guide for Care and Use of Laboratory Animals」、8版(National Academies Press、Washington、D.C.、2011)に従い実施した。加えて、動物のケア及び使用されるプロトコールは、Eurofins Panlabs Taiwan,LtdにおけるIACUCにより再検討され、承認された。
この実験において、ウシ胎仔血清(Hyclone、USA)、RPMI−1640培地(ThermoFisher、USA)及びMatrigel(Corning、USA)が使用された。
キャリパー(株式会社ミツトヨ、日本)、遠心分離機5810R(Eppendorf、Germmany)、CO2インキュベーター(Forma Scientific Inc.、USA)、血球計算盤(Hausser Scientific Horsham、USA)、個別換気型ケージラック(36 Mini Isolator system、Tecniplast、Italy)、倒立顕微鏡CK−40(オリンパス株式会社、日本)、システム顕微鏡E−400(株式会社ニコン、日本)及び垂直層流型クリーンルーム(Tsao−Hsin、Taiwan)である。
腫瘍体積、体重、死亡及び明らかな毒性の徴候を、毎週2回ずつ45日間にわたり、モニタリングし、記録した。腫瘍増殖の阻害は、T/C(処置/対照)×100%として計算した。媒体対照群のT/C値と比較して、≦42%のT/C値が、有意な抗腫瘍活性であると考えられた。二元ANOVAに続いて、ボンフェローニ検定を使用して、群の、それぞれの媒体対照と比較した統計学的有意性を確認した(*p<0.05)。
この研究の目的は、雄BALB/cヌードマウスによる、HPACヒト膵臓がん異種移植モデルにおいて、OBI−888、ADC(OBI−999)、MMAE及びMMAEと組み合わせたOBI−888の、インビボにおける抗腫瘍有効性を査定することであった。
原液を、25mMのクエン酸ナトリウム、100mMのNaCl緩衝液(pH6.5)により、毎日希釈することにより、被験物質である、ADC(OBI−999)、OBI−888及び対応する媒体を製剤化し、毎週1回ずつ4週間にわたり、静脈内(IV)投与した。0.191mg/kgの、標準薬剤である、MMAE抗体及び対応する媒体(PBS pH7.4)は、毎週1回ずつ4週間にわたり、腹腔内(IP)投与した。1つの処置群に、被験物質である、10mg/kgのOBI−888の、0.191mg/kgのMMAEとの組合せ療法を施した。
HPAC腫瘍細胞(ATCC CRL−2119)は、0.002mg/mLのインスリン、0.005mg/mLのトランスフェリン、40ng/mLのヒドロコルチゾン、10ng/mLの表皮増殖因子並びに5%のウシ胎仔血清、100U/mLのペニシリン及び100μg/mLのストレプトマイシンを補充された1.2g/Lの炭酸水素ナトリウム、2.5mMのL−グルタミン、15mMのHEPES及び0.5mMのピルビン酸ナトリウムを含有するダルベッコ改変イーグル培地及びハムF12培地の1:1混合物における単層培養物として、インビトロの、37℃、空気中に5%のCO2による雰囲気において維持した。腫瘍細胞は、トリプシン−EDTA処理により、毎週2回ずつ、規定通りに継代培養した。指数関数的増殖相において増殖する細胞を採取し、腫瘍接種のためにカウントした。
6〜8週齢の雄nu/nuヌードマウスを、Shanghai Lingchangから得、使用した。マウスは、個別換気型ケージにおいて、各ケージの動物を4匹ずつ、温度及び湿度を一定として保持した(温度:20〜26℃及び湿度:40〜70%)。ケージは、ポリカーボネート製であり、サイズは、300mm×200mm×180mmであった。寝床材料は、毎週2回交換される、トウモロコシの軸であった。動物は、全研究期間において、照射滅菌された乾燥顆粒飼料及び飲用水に自由にアクセスした。各ケージの識別ラベルは、以下の情報:動物数、性別、株、受領日、処置、研究番号、群番号及び処置の開始日を含有した。
終点は、被験化合物の抗腫瘍効果を決定することであった。腫瘍サイズは、キャリパーを使用して、毎週2回ずつ、2つの寸法により測定し、体積は、式:V=0.5a×b2[式中、a及びbは、それぞれ、腫瘍の長径及び短径である]を使用して、mm3単位で表した。次いで、腫瘍サイズを、T/C値を計算するために使用した。T/C値(パーセント単位)は、抗腫瘍有効性の指標であり、T及びCは、それぞれ、所与の日における、処置群及び対照群の平均値体積である。TGIは、式:TGI(%)=[1−(Ti−T0)/(Vi−V0)]×100[式中、Tiは、所与の日における、処置群の平均腫瘍体積であり、T0は、0日目における、処置群の平均腫瘍体積であり、Viは、Tiと同じ日における、媒体対照群の平均腫瘍体積であり、V0は、0日目における、媒体群の平均腫瘍体積である]を使用して、各群について計算した。
Claims (47)
- がん細胞の固有の標的である、1つ以上の抗原を含む炭水化物分子。
- 抗原が、抗原特異的抗体に、治療剤を、標的がん細胞へと、効果的にもたらすことを可能とする、請求項1に記載の炭水化物分子。
- 抗原が、グロボ系列の抗原である、請求項1に記載の炭水化物分子。
- グロボ系列の抗原が、ステージ特異的胚性抗原4(SSEA−4;Neu5Acα2→3Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1)、ステージ特異的胚性抗原3(SSEA−3;Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1)又はグロボH(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glc)である、請求項3に記載の炭水化物分子。
- 治療剤が、抗がん毒素、化学療法剤、光力学療法剤又は生物学的薬剤である、請求項2に記載の炭水化物分子。
- がんが、グロボ系列の抗原を発現しているがんである、請求項1に記載の炭水化物分子。
- 治療剤及びグロボ系列の抗原に結合する抗体又は抗原結合性断片を含む抗体−薬物コンジュゲート(ADC)であって、
治療剤が、リンカーにより、抗体又は抗原結合性断片へと、共有結合的にコンジュゲートされた
ADC。 - 式:
Ab−(L−D)n (I)
[式中、1つ以上の治療用薬物部分(D)は、リンカー(L)により、グロボ系列の抗原をターゲティングする抗体である抗体(Ab)へと共有結合的に連結され、nは、1〜8の整数である]
を有する、請求項7に記載のADC化合物の混合物を含む組成物。 - 抗体が、モノクローナル抗体、抗原結合性断片、キメラ抗体及びヒト化抗体から選択される、請求項7に記載のADC。
- 抗原結合性断片が、Fab断片、F(ab’)2断片、Fv断片又はscFv断片である、請求項9に記載のADC。
- 抗体が、がん細胞において発現した、グロボ系列の抗原SSEA−4(Neu5Acα2→3Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1)、SSEA−3(Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1)及び/又はグロボH(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glc)のうちの1つ以上をターゲティングする、請求項7に記載のADC。
- 抗体が、抗グロボH抗体、抗SSEA3抗体又は抗SSEA4抗体である、請求項7に記載のADC。
- 抗グロボH抗体が、OBI−888である、請求項12に記載のADC。
- 抗SSEA4抗体が、OBI−898である、請求項12に記載のADC。
- 治療剤が、モノメチルアウリスタチンE(MMAE)である、請求項7に記載のADC。
- 請求項7に記載のADC化合物又は薬学的に許容されるその塩;及び薬学的に許容される希釈剤、担体又は賦形剤を含む医薬組成物。
- グロボ系列の抗原をターゲティングする、他のADCの組合せを含む、請求項16に記載の医薬組成物。
- 請求項8に記載の組成物を作製する方法であって、
Abを、式Iのリンカー試薬と反応させて、抗体−リンカー中間体であるAb−Lを形成し、次いで、Ab−Lを、薬物部分と反応させて、抗体−薬物コンジュゲート化合物の混合物を形成するステップ;又は
薬物部分であるDを、リンカー試薬と反応させて、薬物−リンカー中間体であるD−Lを形成し、次いで、D−Lを、Abと反応させて、抗体−薬物コンジュゲート化合物の混合物を形成するステップ
を含む方法。 - リンカーであるLが、チオ基を含む、請求項8に記載の組成物。
- チオ基が、ジスルフィド架橋の還元により発生する、請求項19に記載の組成物。
- 薬物部分であるDが、化学療法剤、光力学療法剤又は生物学的薬剤である、請求項8に記載の組成物。
- 光力学療法剤が、フォトフリン、レザフィリン、アミノレブリン酸(ALA)、シリコンフタロシアニンPc4、m−テトラヒドロキシフェニルクロリン(mTHPC)、クロリンe6(Ce6)、アルメラ、レブラン、フォスカン、メトビックス、ヘクスビックス、フォトクロール、フォトセンス、フォトレックス、ルマカン、ビソナック、アムフィネックス、ベルテポルフィン、プルリチン、ATMPn、アエンフタロシアニン(ZnPc)、プロトポルフィリンIX(PpIX)、ピロフェオフォルバイドa(PPa)又はフェオフォルバイド(PhA)から選択される、請求項21に記載の組成物。
- 薬物部分であるDが、抗増殖剤である、請求項8に記載の組成物。
- 抗増殖剤が、モノメチルアウリスタチンE(MMAE)、モノメチルアウリスタチンF(MMAF)、メルタンシン(DM1)、アントラサイクリン、ピロロベンゾジアゼピン、α−アマニチン、ツブリシン、ベンゾジアゼピン、エルロチニブ、ボルテゾミブ、フルベストラント、スニチニブ、レトロゾール、メシル酸イマチニブ、PTK787/ZK 222584、オキサリプラチン、ロイコボリン、ラパマイシン、ラパチニブ、ロナファルニブ(SARASAR(登録商標)、SCH 66336)、ソラファニブ、ゲフィチニブ、AG1478、AG1571、アルキル化剤;スルホン酸アルキル;アジリジン;エチレンイミン;メチルメラミン;アセトゲニン;カンプトテシン;ブリオスタチン;カリスタチン;CC−1065;クリプトフィシン;ドラスタチン;デュオカルマイシン;エリュテロビン;パンクラチスタチン;サルコチクチイン;スポンジスタチン;クロランブシル;クロルナファジン;シクロホスファミド;エストラムスチン;イホスファミド;メクロレタミン;塩酸メクロレタミンオキシド;メルファラン;ノベムビシン;フェネステリン;プレドニムスチン;トロホスファミド;ウラシルマスタード;カルムスチン;クロロゾトシン;ホテムスチン;ロムスチン;ニムスチン;ラニムスチン;カリケアミシン;ジネミシン;クロドロネート;エスペラミシン;ネオカルチノスタチン発色団;アクラシノマイシン;アクチノマイシン;アントラマイシン;アザセリン;ブレオマイシン;カクチノマイシン;カラビシン;カルミノマイシン;カルジノフィリン;クロモマイシン;ダクチノマイシン;ダウノルビシン;デトルビシン;6−ジアゾ−5−オキソ−L−ノルロイシン;ドキソルビシン;エピルビシン;エソルビシン;イダルビシン;マルセロマイシン;マイトマイシン;ミコフェノール酸;ノガラマイシン;オリボマイシン;ペプロマイシン;ポトフィロマイシン;ピューロマイシン;ケラマイシン;ロドルビシン;ストレプトニグリン;ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン;メトトレキサート;5−フルオロウラシル(5−FU);デノプテリン;プテロプテリン;トリメトレキサート;フルダラビン;6−メルカプトプリン;チアミプリン;チオグアニン;アンシタビン;アザシチジン;6−アザウリジン;カルモフール;シタラビン;ジデオキシウリジン;ドキシフルリジン;エノシタビン;フロクスウリジン;カルステロン;プロピオン酸ドロモスタノロン;エピチオスタノール;メピチオスタン;テストラクトン;アミノグルテチミド;ミトタン;トリロスタン;フォリン酸;アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ベストラブシル;ビサントレン;エダトレキサート;デフォファミン;デメコルシン;ジアジコン;エルフォルミチン;酢酸エリプチニウム;エポチロン;エトグルシド;硝酸ガリウム;ヒドロキシウレア;レンチナン;ロニダイニン;メイタンシン;アンサマイトシン;ミトグアゾン;ミトキサントロン;モピダンモール;ニトラエリン;ペントスタチン;フェナメト;ピラルビシン;ロソキサントロン;ポドフィリン酸;2−エチルヒドラジド;プロカルバジン;ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2’,2’’−トリクロロトリエチルアミン;トリコテセン;ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン;アラビノシド;シクロホスファミド;チオテパ;タキソイド;パクリタキセル;ドセタキセル;クロランブシル;ゲムシタビン;6−チオグアニン;メルカプトプリン;メトトレキサート;シスプラチン;カルボプラチン;ビンブラスチン;白金;エトポシド;イホスファミド;ミトキサントロン;ビンクリスチン;ビノレルビン;ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;ゼローダ;イバンドロネート;トポイソメラーゼ阻害剤;ジフルオロメチルオルニチン(DMFO);レチノイド又はカペシタビンから選択される、請求項23に記載の組成物。
- 対象におけるがんを処置する方法であって、有効量の、請求項7に記載のADCを処置を必要とする対象に投与するステップを含む方法。
- がんが、グロボ系列の抗原を発現しているがんである、請求項25に記載の方法。
- グロボ系列の抗原を発現しているがんが、肉腫、皮膚がん、白血病、リンパ腫、脳腫瘍、神経膠芽腫、肺がん、乳がん、口腔がん、頭頸部がん、鼻咽頭がん、食道がん、胃がん、肝臓がん、胆管がん、胆嚢がん、膀胱がん、膵臓がん、腸がん、結腸直腸がん、腎臓がん、子宮頸がん、子宮内膜がん、卵巣がん、睾丸がん、口腔がん、口腔咽頭がん、喉頭がん及び前立腺がんからなる群から選択される、請求項26に記載の方法。
- 有効量の、グロボ系列の抗原をターゲティングする、他のADCの組合せを、処置を必要とする対象に投与するステップを含む、請求項25に記載の方法。
- 組合せが、がん処置における相乗効果及び治療有効性の増強をもたらす、請求項28に記載の方法。
- 免疫反応の誘導又は増強を必要とする対象における免疫反応を誘導又は増強する方法であって、
免疫学的に有効量の、請求項20に記載の医薬組成物を投与するステップ、及び:
請求項7に記載のADCを、2回以上投与する手順;
2回の逐次的投与の間の時間間隔及び/若しくは用量レジメンを調整する手順;
投与経路を調整する手順及び/若しくは投与の注射部位を変更する手順;又は
グロボ系列の抗原を含む、他のADCを組み合わせる手順
から選択される手順のうちの1つ以上
を含む方法。 - 注射が、免疫応答追加剤の添加により、変更及び/又は補充されうる、請求項30に記載の方法。
- 対象が、ヒトである、請求項25、28又は30に記載の方法。
- 有効量が、0.01μg〜250mgである、請求項25、28又は30に記載の方法。
- 有効量が、0.001μg/kg〜250mg/kgである、請求項25、28又は30に記載の方法。
- 有効量が、配合製剤又は別個の製剤にある、請求項25、28又は30に記載の方法。
- 組合せが、免疫反応の誘導又は増強において、相乗効果をもたらす、請求項30に記載の方法。
- 肉腫、皮膚がん、白血病、リンパ腫、脳腫瘍、神経膠芽腫、肺がん、乳がん、口腔がん、頭頸部がん、鼻咽頭がん、食道がん、胃がん、肝臓がん、胆管がん、胆嚢がん、膀胱がん、膵臓がん、腸がん、結腸直腸がん、腎臓がん、子宮頸がん、子宮内膜がん、卵巣がん、睾丸がん、口腔がん、口腔咽頭がん、喉頭がん及び前立腺がんからなる群から選択されるがんの処置における使用のための、抗がん剤、免疫抑制剤及び抗感染剤からなる群から選択される、有効量の、さらなる薬剤と組み合わせた使用のための、請求項7に記載の抗体−薬物コンジュゲート化合物。
- 肉腫、皮膚がん、白血病、リンパ腫、脳腫瘍、神経膠芽腫、肺がん、乳がん、口腔がん、頭頸部がん、鼻咽頭がん、食道がん、胃がん、肝臓がん、胆管がん、胆嚢がん、膀胱がん、膵臓がん、腸がん、結腸直腸がん、腎臓がん、子宮頸がん、子宮内膜がん、卵巣がん、睾丸がん、口腔がん、口腔咽頭がん、喉頭がん又は前立腺がんの処置のための医薬の製造における、請求項7に記載の抗体−薬物コンジュゲート化合物の使用。
- 肉腫、皮膚がん、白血病、リンパ腫、脳腫瘍、神経膠芽腫、肺がん、乳がん、口腔がん、頭頸部がん、鼻咽頭がん、食道がん、胃がん、肝臓がん、胆管がん、胆嚢がん、膀胱がん、膵臓がん、腸がん、結腸直腸がん、腎臓がん、子宮頸がん、子宮内膜がん、卵巣がん、睾丸がん、口腔がん、口腔咽頭がん、喉頭がん又は前立腺がんの処置のための、抗がん剤、免疫抑制剤及び抗感染剤からなる群から選択される、有効量の、さらなる薬剤と組み合わせた使用のための医薬の製造における、請求項7に記載の抗体−薬物コンジュゲート化合物の使用。
- がん細胞の、ADCへの治療有効性を決定するための方法であって、
細胞を、請求項7に記載のADCへと接触させるステップ;
結合したADCの量に基づき、ADCの、がん細胞への結合の程度を測定するステップ;及び
がん細胞の、ADCへの結合有効性を決定するステップ
を含む方法。 - イメージング剤及びグロボ系列の抗原に結合する抗体又は抗原結合性断片を含む、有効量の、抗体−薬物コンジュゲート(ADC)を投与するステップであって;
イメージング剤が、リンカーにより、抗体又は抗原結合性断片へと、共有結合的にコンジュゲートされているステップ;並びに
対象において、イメージング剤を検出するステップ
を含む、対象をイメージングする方法。 - イメージング剤が、フルオロフォア、色素、MRI造影剤又は放射性核種である、請求項41に記載の方法。
- 対象が、がんを有し、がんの転移を検出する方法としてさらに規定される、請求項41に記載の方法。
- 対象が、ヒトである、請求項41に記載の方法。
- ADCが、グロボ系列の抗原SSEA−4(Neu5Acα2→3Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1)、SSEA−3(Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glcβ1)及び/又はグロボH(Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Glc)をターゲティングする、請求項41に記載の方法。
- グロボHに結合する抗体−薬物コンジュゲート(ADC)であって、
重鎖可変ドメインが、
配列番号1のアミノ酸配列を有する、第1の重鎖相補性決定領域(HCDR1);
配列番号2のアミノ酸配列を有する、第2の重鎖相補性決定領域(HCDR2);
配列番号3のアミノ酸配列を有する、第3の重鎖相補性決定領域(HCDR3)
を含み、軽鎖可変ドメインが、
配列番号7のアミノ酸配列を有する、第1の軽鎖相補性決定領域(LCDR1);
配列番号8のアミノ酸配列を有する、第2の軽鎖相補性決定領域(LCDR2);
配列番号9のアミノ酸配列を有する、第3の軽鎖相補性決定領域(LCDR3)
を含む抗体を含むADC。 - SSEA−4に結合する抗体−薬物コンジュゲート(ADC)であって、
重鎖可変ドメインが、
配列番号29のアミノ酸配列を有する、第1の重鎖相補性決定領域(HCDR1);
配列番号31のアミノ酸配列を有する、第2の重鎖相補性決定領域(HCDR2);
配列番号33のアミノ酸配列を有する、第3の重鎖相補性決定領域(HCDR3)
を含み、軽鎖可変ドメインが、
配列番号22のアミノ酸配列を有する、第1の軽鎖相補性決定領域(LCDR1);
配列番号24のアミノ酸配列を有する、第2の軽鎖相補性決定領域(LCDR2);
配列番号26のアミノ酸配列を有する、第3の軽鎖相補性決定領域(LCDR3)
を含む抗体を含むADC。
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AU2017361549B2 (en) | 2023-12-21 |
CN110290800A (zh) | 2019-09-27 |
BR112019010356A2 (pt) | 2019-08-27 |
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EP3541414A1 (en) | 2019-09-25 |
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WO2018094414A1 (en) | 2018-05-24 |
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AU2017361549A1 (en) | 2019-06-06 |
US20180193481A1 (en) | 2018-07-12 |
IL266693A (en) | 2019-07-31 |
TW201834695A (zh) | 2018-10-01 |
TWI822055B (zh) | 2023-11-11 |
US11000601B2 (en) | 2021-05-11 |
CA3044274A1 (en) | 2018-05-24 |
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