JP7273858B2 - 癌を治療するための方法と材料 - Google Patents
癌を治療するための方法と材料 Download PDFInfo
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- JP7273858B2 JP7273858B2 JP2020569132A JP2020569132A JP7273858B2 JP 7273858 B2 JP7273858 B2 JP 7273858B2 JP 2020569132 A JP2020569132 A JP 2020569132A JP 2020569132 A JP2020569132 A JP 2020569132A JP 7273858 B2 JP7273858 B2 JP 7273858B2
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Description
本明細書は、腫瘍関連抗原(例えばHER2ポリペプチド)を標的とする抗体と、該抗原を発現している癌をもつ哺乳動物(例えばヒト)に投与して該哺乳動物を治療することができる抗癌薬とを含有するADCを提供する。例えば、抗体薬物複合体(ADC)は、抗HER2抗体(例えばMAB802)と、該抗体に結合された抗癌薬(例えばモノメチルアウリスタチンE(MMAE)などのアウリスタチン誘導体)少なくとも1分子とを含みうる。ADCは、抗体1分子当たり複数の(2以上の)分子を含むことができる。場合によっては、本明細書に記載のADCは、増加したレベルのフコシル化(例えば別の抗HER2抗体に比較して)を有する抗HER2抗体を含み得る。幾つかの場合には、本明細書に記載のADCは、増加した薬物/抗体比(DAR;例えば抗HER2抗体を含む別のADCに比較して)を含むことができる。本明細書は、抗HER2抗体(例えばMAB802)と1種以上の抗癌薬(例えばMMAE)とを含むADCを作製して使用するための方法と材料も提供する。例えば、抗HER2抗体と複数の抗癌薬とを含むADCは、HER2陽性癌を有する哺乳動物に該哺乳動物を治療するために投与することができる。
本明細書は、癌の治療に有用な方法と材料を提供する。幾つかの場合、本明細書中に提供されるADCは、腫瘍関連抗原(例えばHER2ポリペプチド)を標的とする抗体と、前記抗原を発現する癌を有する哺乳動物(例えばヒト)に投与することができる抗癌薬とを含むことができる。例えば、ADCは、抗HER2抗体(例えばMAB802)と、1種以上の抗癌薬(例えばMMAEなどのアウリスタチン誘導体)少なくとも1(例えば2、3、4、5以上)分子とを含むことができる。幾つかの場合、本明細書に提供されるADCは、抗原を発現する癌(例えばHER2陽性癌)を有する哺乳動物(例えばヒト)に、該哺乳動物を治療するために投与することができる。例えば、抗HER2抗体と抗癌薬とを含む1種以上のADCは、癌の重症度を低くするため、癌の症状を軽減するため、および/または哺乳動物の中に存在する癌細胞の数を減少させるために、HER2陽性癌を有する哺乳動物に投与することができる。
抗体薬物複合体(コンジュゲート)
抗体
ASQDVNTAVA (配列番号1);
SASFLYS (配列番号2);および
QQHYTTPPT (配列番号3)。
GFNIKDTYIH (配列番号5);
IYPTNGYTRYADSVK (配列番号6);および
WGGDGFYAMDY (配列番号7)。
本明細書に記載のADC(例えば抗HER2抗体と1種以上の抗癌薬とを含むADC)は、任意の適当な抗癌薬を含むことができる。幾つかの場合には、1種以上の抗癌薬は、単一の抗癌薬を1分子以上(例えば抗HER2抗体あたり)含むことができる。幾つかの場合、1種以上の抗癌薬は、2種以上の異なる抗癌薬を1分子以上(例えば抗HER2抗体あたり)含むことができる。抗癌薬は、細胞毒性薬であり得る。抗癌薬は抗微小管作用薬でありうる。抗癌薬は微小管形成阻害剤であり得る。抗癌薬は抗新生物薬であり得る。抗癌薬は、天然化合物または合成薬であることができる。本明細書に記載のADCに使用できる抗癌薬の例としては、限定されないが、アウリスタチン(例えばモノメチルアウリスタチンE(MMAE)およびモノメチルアウリスタチンF(MMAF))、メイタンシン(例えばメルタンシン(DM1)、マイタンシン(INN)およびメイタンシン(USAN))、ピロロベンゾジアゼピン(PBD)、デュオカルマイシン、カリケアミシン、SN-38、アマニチンおよびエリブリン、またはそれらの誘導体が挙げられる。
本明細書に記載のADC(例えば抗HER2抗体と1つ以上の抗癌薬とを含むADC)は、前記HER2抗体と前記1つ以上の抗癌薬とを連結する1つ以上のリンカーを含むことができる。リンカーは任意の適当なリンカーであってよい。
-L1 x-Ay-L2 z-
上式中
L1は第一の二価化学基であり;
xは0または1であり;
Ayはアミノ酸またはペプチド基であり;
各Aは独立に選択されたアミノ酸基であり;
yは0、1、2、3、4、5、6、7、8、9、10、11または12であり;
L2は第二の二価化学基であり;そして
zは0または1である。
存在する場合、L1は、式-Ay-のアミノ酸またはペプチド成分に抗体を連結する。抗体は、適当な共有結合、例えばメルカプト(SH)、アミノ、ヒドロキシル、カルボキシまたはカルボキシルを形成することができる官能基を介してL1に結合される。官能基は、最初に得られるかまたは化学修飾により導入された抗体上に存在することができる。例えば、メルカプト基は、分子内ジスルフィド結合の還元によって生成することができる。適当なアミノ基には、抗体のリシン成分のアミノ基が含まれる。
-NH-CH(A1)-C(O)-
の基である。
-NH-CH(A11)-C(O)-NH-CH(A12)-C(O)-
ここで、A11とA12 は独立に上記に定義した式A1の基から選択される。幾つかの実施形態では、A11 はメチルであり、そしてA12 は (CH2)4NH2でありうる。幾つかの実施形態では、A11はイソプロピルであり、そしてA12 は(CH2)4NH2でありうる。幾つかの実施形態では、A11 がベンジルでありそしてA12 が(CH2)4NH2でありうる。幾つかの実施形態では、A11 がインドール-3-イルメチルであり、そしてA12 が(CH2)4NH2でありうる。幾つかの実施形態では、A11 がメチルであり、そしてA12 が(CH2)3NHCONH2でありうる。幾つかの実施形態では、A11 がイソプロプルであり、そしてA12 が(CH2)3NHCONH2でありうる。幾つかの実施形態では、A11 がベンジルであり、そしてA12 が(CH2)3NHCONH2でありうる。幾つかの実施形態では、A11 がインドール-3-イルメチルであり、そしてA12 が(CH2)3NHCONH2でありうる。
例えば: -O-、-S-、-S(O)-、-S(O)2-、-C(O)-、-NH-、-N(C1~C6)アルキル、-NHC(O)-、-C(O)NH-、-O(CO)-、-C(O)O-、-O(CO)NH-、-NHC(O)O-、-O(CO)O-、-NHC(O)NH-、-O(C1~C6)アルキレン-、-S(C1~C6)アルキレン-、 -S(O)(C1~C6)アルキレン-、-S(O)2(C1~C6)アルキレン-、-C(O)(C1~C6)アルキレン-、-NH((C1~C6)アルキレン)C(O)-、-C(O)((C1~C6)アルキレン)C(O)-、-C(O)((C1~C6)アルキレン)NH-、-O(CO)-、-C(O)O-、-O(CO)NH-、-NHC(O)O-、-O(CO)O-、-NHC(O)NH-、非置換(C1~C10)アルキレン-、非置換(C1~C10)ヘテロアルキレン、または、次の基:(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、ハロゲン、(C1~C6)ハロアルキル、-CN、-NO2、-C(=O)R、-OC(=O)Ar、-C(=O)OR、-C(=O)NR2、-C(=NR)NR2、-OR、-Ar、-OAr、-((C1~C6)アルキレン)Ar、-O((C1~C6)アルキレン)Ar、-OC(=O)(C1~C6)アルキル、-OC(=O)O(C1~C6)アルキル、-OC(=O)NR2、-NR2、-NRAr、-NR((C1~C6)アルキレン)Ar、-NRC(=O)R、-NRC(=O)Ar、-NRC(=O)O(C1~C6)アルキル、-NRC(=O)NR2、-NRSO2R、-SR、-S(O)R、-SO2R、-OSO2(C1~C6)アルキル、-SO2NR2、(C1~C8)ペルフルオロアルキル、-(C2~C6)アルキレン-OR、-O(C2~C6)アルキレン-N((C1~C6)アルキル)2、-P(=O)(OR)2、-OP(=O)(OR)2、オキソおよびスルフィドから成る群より選択された1つ以上の置換基(例えば1,2,3,4または5個の置換基)で置換された-(C1~C10)アルキレンまたは-(C1~C10)ヘテロアルキレンであり、ここで各R基は水素または(C1~C6 アルキル)、例えばメチルであり、そして各Arは独立に、非置換アリールもしくはヘテロアリールであるかまたは1つ以上の(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、ハロゲン、(C1~C6)ハロアルキル、-CN、-NO2、-C(=O)R、-C(=O)OR、-C(=O)NR2、-C(=NR)NR2、-OR、-OC(=O)(C1~C6)アルキル、-OC(=O)O(C1~C6)アルキル、-OC(=O)NR2、-NR2、-NRC(=O)R、-NRC(=O)O(C1~C6)アルキル、-NRC(=O)NR2、-NRSO2R、-SR、-S(O)R、-SO2R、-OSO2(C1~C6)アルキル、-SO2NR2、(C1~C8)ペルフルオロアルキル、-(C2~C6)アルキレン-OR、-O(C2~C6)アルキレン-N((C1~C6)アルキル)2、-P(=O)(OR)2、-OP(=O)(OR)2 であり、ここで各R基は水素または (C1~C6アルキル)である。加えて、-(C1~C10)アルキレンと-(C1~C10)ヘテロアルキレンは、1つ以上のオキソ基(C=O)により置換されてよく、そしてヘテロアルキレン基の窒素原子と硫黄原子は場合により酸化され得る(例えばS(O)、-S(O)2-またはN-オキシドを形成する)。適当なヘテロアルキレン基は、1つ以上の1,2-ジオキシエチレン単位-(O-CH2CH2)nO-を含むことができる(ここでnは整数、例えば1、2、3、4 または5である)。前記-(C1~C10)アルキレン-および-(C1~C10)ヘテロアルキレンは-(C1~C6)アルキレン-および-(C1~C6)ヘテロアルキレン並びに-(C1~C3)アルキレンおよび-(C1~C3)ヘテロアルキレンも包含する。
ADC
方法
組成物と投与
本明細書に記載の1以上のADC(例えばHER2抗体(例えばMAB802)と1種以上の抗癌薬とを含むADC)は、HER2陽性癌を有する哺乳動物への投与のために組成物(例えば薬学上許容可能な組成物)に製剤化することができる。例えば、本明細書に記載の1以上のADCの治療上有効な量を、組成物へと製剤化し、そしてHER2発現癌を有する哺乳動物に投与して該哺乳動物を治療することができる。組成物は無菌組成物であることができる。組成物は任意の適当な剤形、例えば限定されないが、液剤、懸濁液剤、徐放性製剤、錠剤、カプセル剤、ピル、粉剤、および粒剤の形で投与用に製剤化することができる。
MAB802の調製
MRG002は3成分:抗HER2モノクローナル抗体(MAB802)、vcLinker、およびアウリスタチン誘導体MMAEから構成される、抗体薬物複合体(ADC)である(図1)。各MRG002分子は、平均で3.8分子のMMAEを担持している。
調製したMRG002バッチの薬物/抗体比(DAR)を、HIC-HPLCプロファイル(図3)により測定した。HIC-HPLCはいずれかに記載の通りに実施した(例えば、Ouyang, “Chapter 17: Drug-to-Antibody Ratio (DAR) and Drug Load Distribution by Hydrophobic Interaction Chromatography and Reversed Phase High-Performance Liquid Chromatography” 2013; Laurent Ducry (編), Antibody-Drug Conjugates, Methods in Molecular Biology, 第1045巻; Springer Science+Business Media参照)。
材料と方法
固定化したHER2-Fc、ヒトCD16a(176Val、Hisタグ)およびヒトCD16a(176Phe、Hisタグ)に対するMRG002、MAB802およびハーセプチン(Herceptin;登録商標)の結合速度論を、Biacore T200を使った表面プラズモン共鳴(SPR)により分析した。抗体his IgGとHER2-hFcを、酢酸ナトリウム(pH 4.5)中それぞれ20μg/mLと2μg/mLに希釈し、Series S Sensor Chip CM5(GE Healthcare社製)上で、それぞれ約6000および300共鳴単位の量にアミンカップリングすることにより固定化し;次いで固定化した抗his IgG、0.5μg/mLのヒトCD16a(176Val、Hisタグ)またはヒトCD16a(176Phe、Hisタグ)を有するフローセルを、10μL/分の流速で注入して前記固定化抗his IgGに結合させた。最後に、HBS-EP緩衝液(10 mM HEPES、150 mM NaCl、3.0 mM EDTA、0.05%界面活性剤P20、pH 7.4)中のMRG002、MAB802またはハーセプチン(登録商標)の連続希釈液を、30μL/分の流速でそれらの対応するフローセルに注入した。会合速度(Ka)、解離速度(Kd)および解離平衡定数(KD)は、データを二価結合モデルと適合させることにより、BIA評価ソフトウェア(BIAcore、登録商標)を使って算出した。
in vitro結合親和性(以下、親和性と称する)研究は、ヒトHER2に対するものに加えてヒトCD16a(176Val; 176Phe)に対するMRG002、MAB802および比較参照薬物ハーセプチン(Herceptin;登録商標)の親和性を含んだ。
材料と方法
MRG002は、組み換えヒト化抗HER2 IgG1モノクローナル抗体MAB802をリンカー-薬物vcMMAEにコンジュゲートすることにより調製した。MRG002がMAB802(IgG1型のモノクローナル抗体である)からのADCC活性とCDC活性を保持しているかどうかを評価するため、3バッチのMRG002とそれらの対応するMAB802バッチを、それらの活性について試験した。
エフェクター細胞としての遺伝子操作されたNK細胞系、標的細胞としてのHER2の過剰発現を有するSKBR3細胞系、および陽性参照薬物としてのハーセプチン(登録商標)を使用し、標的された細胞溶解の量(最大標的細胞溶解%)を算出しそして比較することにより、ADCC活性を評価した。 実験結果は図4に示される。
材料と方法
MRG002とT-DM1の平均IC50が表5に示され、一方で代表的なin vitro細胞増殖阻害曲線が図5に示される。
材料と方法
MRG002の抗腫瘍活性を2つのCDX(Cell line-Derived Xenograft;細胞系由来異種移植片)および多数のPDX(Patient-Derived Xenograft;患者由来異種移植片)モデルにおいて評価した。2つのCDXモデルを乳癌細胞系BT-474と胃癌細胞系NCI-N87を用いて確立した。その両細胞系は高レベルのHER2発現を有し、一方でPDXモデルは変動するレベルのHER2発現を示す。
腫瘍体積(TV)=腫瘍の長さ(l)×腫瘍の幅(w)2/2、ここで「l」と「w」はそれぞれ腫瘍の長さと幅を表す;
相対腫瘍体積(RTV)=Vf/V0、ここでV0はグループ分け前(即ち0日目)に測定した腫瘍体積であり、そしてVfは実験の最終日に測定した腫瘍体積である;
T/C(%)=(被験薬群のRTV/ビヒクル群のRTV)×100%;
TGI%=(ビヒクル群の平均TV-被験薬群の平均TV)/被験薬群の平均TV×100%。
全ての動物実験は、承認された実験動物の管理と飼育プロトコルを用いて実施した。
乳癌および胃癌CDXモデルにおけるin vivo有効性
BT-474乳癌CDXモデルにおけるMRG002の抗腫瘍活性。図6は、MRG002 (3 mg/kg、iv、q7d×2) およびハーセプチン-ADC (3 mg/kg、iv、q7d×2) の両方が6匹中6匹(6/6)のマウスにおいてD21(21日目)に完全な腫瘍退縮を引き起こした。また、T-DM1(3 mg/kg、iv、q7d×2) およびmAb-2 (3 mg/kg、iv、q7d×2)は、それぞれD21に64%および57%の腫瘍阻害率を有した。全ての試験は腫瘍担持マウスにより十分に忍容された。
予備試験におけるMRG002の抗腫瘍活性が図7に示される。MRG002 (3 mg/kg、iv、q7d×3) は、HER2を過剰発現しているNCI-N87異種移植片の増殖を、T/C (%)=10.00%およびTGI%=90.07%で有意に阻害した。T-DM1 (3 mg/kg、iv、q7d×3) のT/C(%)とTGI%はそれぞれ31.72%と67.52%であった。ハーセプチン-ADC (3 mg/kg、iv、q7d×3) のT/C(%)とTGI%はそれぞれ8.28%と91.86%であった。mAb-2(3 mg/kg、iv、q7d×3)のT/C (%)とTGI%はそれぞれ74.83%と26.28%であった。全ての被験薬は腫瘍担持マウスにより忍容された。
乳癌PDXモデルBC#046におけるMRG002の抗腫瘍活性
BC#046 はハーセプチン(登録商標)耐性ヒト乳癌PDXモデルである。結果(図8)は、63日目に、MRG002投与群のT/C(%)が1 mg/kgでは45.07%であり(P<0.001)そして3 mg/kgでは0.45%(P<0.001)であり、一方でそれらの対応するTGI%は54.93%と99.55%であり、3 mg/kgでのT-DM1のT/C(%)とTGI%は、それぞれ6.56%(P<0.001)と93.44%であることを示した。
BC#197 はハーセプチン(登録商標)耐性ヒト乳癌PDXモデルである。結果(図9)は、69日目に、MRG002群のT/C(%)が3 mg/kgで14.11%(P<0.001)でありそして10 mg/kg では2.26%(P<0.001)であり、一方でそれらの対応するTGI%はそれぞれ85.89%と97.74%であり、それぞれ1/8および5/8の完全腫瘍退縮、並びに1/8 および3/8の部分腫瘍退縮を有した;10 mg/kgでのT-DM1のT/C (%)とTGI%はぞれぞれ63.31%(P<0.001)と36.69%であることを示した。
STO#041はハーセプチン(登録商標)耐性ヒト胃癌PDXモデルである。結果(図10)は、46日目に、MRG002投与群のT/C (%)が1 mg/kgで61.46% (P<0.001)であり、3 mg/kg では32.47%(P<0.001)であり、一方でそれらの対応するTGI%はそれぞれ38.54%と67.53%であった;3 mg/kgでのT-DM1のT/C (%)とTGI%はそれぞれ83.66%(P>0.05) と16.34%であったことを示す。
結果(図11)は、45日目に、MRG002投与群のT/C(%)は3 mg/kgで47.75%(P<0.01)であり、そして10 mg/kgでは0.65%(P<0.001)であり、一方でそれらの対応するTGI%はそれぞれ52.25%と99.35%であった;10 mg/kgでのT-DM1のT/C(%)とTGI%はそれぞれ19.43%(P>0.05)と80.57%であったことを示す。
結果(図12)は、40日目に、MRG002投与群のT/C (%)が1 mg/kgでは70.78% (P>0.05)であり3 mg/kgでは6.02%(P<0.001) であり、一方でそれらの対応するTGI%はそれぞれ29.22%と93.98%であった;3 mg/kgでのT-DM1のT/C (%)とTGI%はそれぞれ90.03% (P>0.05)と9.97%であったことを示す。
STO#179はハーセプチン(登録商標)耐性ヒト胃癌PDXモデルである。結果(図13)は、59日目に、MRG002投与群のT/C (%)が1 mg/kgでは35.20% (P<0.001)であり3 mg/kgでは4.14% (P<0.001)であり、一方でそれらの対応するTGI%はそれぞれ64.80%と95.86%であった;3 mg/kgのT-DM1のT/C (%) とTGI%はそれぞれ92.56% (P>0.05) と7.44%であったことを示す。
STO#240は、ハーセプチン(登録商標)耐性ヒト胃癌PDXモデルである。結果(図14)は、83日目に、MRG002投与群のT/C (%)が3 mg/kgで20.70%(P<0.001)であり10 mg/kgで18.78% (P<0.001)であり、それらの対応するTGI%はそれぞれ79.30%と81.22%であった;10 mg/kgの T/C (%) とTGI%はそれぞれ40.96% (P<0.01) と59.04%であったことを示す。
STO#410はハーセプチン(登録商標)耐性ヒト胃癌PDXモデルである。結果(図15)は、38日目に、MRG002投与群のT/C (%)が3 mg/kgでは39.94% (P<0.001) であり10 mg/kgでは0% (P<0.001)であり、それらの対応するTGI%はそれぞれ60.06%と100%であった;10 mg/kgでのT-DM1のT/C (%) とTGI%はそれぞれ108.79% (P>0.05) と-8.79%であったことを示す。
要約
他の実施形態
Claims (17)
- 抗体薬物複合体であって、
90%超のフコシル化を有する1つの抗HER2抗体であって、前記抗HER2抗体が、配列番号4に記載のアミノ酸配列を含む軽鎖および配列番号8に記載のアミノ酸配列を含む重鎖を含む、抗HER2抗体、
抗癌薬少なくとも1分子、ここで、前記抗癌薬はモノメチルアウリスタチンEである、および、
前記抗HER2抗体と前記抗癌薬少なくとも1分子とを連結するリンカー
を含み、
フコシル化率は、フコシル化グリカンと非フコシル化グリカンの両方の総モル量に対するフコシル化グリカンのモル量の比率を意味する、抗体薬物複合体。 - 前記抗HER2抗体がIgG抗体である、請求項1に記載の抗体薬物複合体。
- 前記抗HER2抗体がヒト化抗体である、請求項1~2のいずれか一項に記載の抗体薬物複合体。
- 前記抗HER2抗体が、配列番号9に記載のアミノ酸配列を含む重鎖を含む、請求項1~2のいずれか一項に記載の抗体薬物複合体。
- 前記抗HER2抗体が、2.5×10-08Mより大きい平衡解離定数(KD)値をもつ、CD16に対する結合親和性を有する、請求項1~2のいずれか一項に記載の抗体薬物複合体。
- (i)前記抗HER2抗体が8%未満の非フコシル化を有する、ここで、非フコシル化率は、フコシル化グリカンと非フコシル化グリカンの両方の総モル量に対する非フコシル化グリカンのモル量の比率を意味する;
(ii)前記ADCが抗体1分子あたり前記抗癌薬少なくとも3分子を含む;
(iii)前記リンカーが開裂可能リンカーである、
のうちの1つ以上により特徴づけられる、請求項1~2のいずれか一項に記載の抗体薬物複合体。 - 前記リンカーがバリン・シトルリン・ジペプチドリンカーを含む、請求項6に記載の抗体薬物複合体。
- 複数の抗体薬物複合体を含む組成物であって、前記抗体薬物複合体が請求項1~7のいずれか一項に定義されるものである組成物。
- 前記組成物が抗HER2抗体あたり前記抗癌薬3.5分子より大きい薬物/抗体比を含む、請求項8に記載の組成物。
- 抗体薬物複合体(ADC)または組成物を哺乳動物に投与することを含む、HER2発現癌を有する哺乳動物の治療用の医薬品の製造のための、請求項1~7のいずれか一項に記載の抗体薬物複合体または請求項8~9のいずれか一項に記載の組成物の使用。
- 前記哺乳動物がヒトである、請求項10に記載の使用。
- 前記HER2発現癌が乳癌、胃癌または難治性癌である、請求項10に記載の使用。
- 前記難治性癌がトラスツズマブ耐性癌またはT-DM1耐性癌である、請求項12に記載の使用。
- 前記ADCが、0%~30%細胞溶解をもたらす抗体依存性細胞傷害(ADCC)活性を有する、請求項10~13のいずれか一項に記載の使用。
- 前記投与が、前記哺乳動物の体重1kgあたり前記ADCを0.6mg~4mgを投与することを含む、請求項10~13のいずれか一項に記載の使用。
- 1以上の追加の抗癌薬の投与を更に含む、請求項10~13のいずれか一項に記載の使用。
- 前記1以上の追加の抗癌薬が抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体、および/または抗TIGIT抗体から選択される、請求項16に記載の使用。
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