JP6625690B2 - Psma結合性リガンド−リンカー結合体及び使用方法 - Google Patents
Psma結合性リガンド−リンカー結合体及び使用方法 Download PDFInfo
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- JP6625690B2 JP6625690B2 JP2018100343A JP2018100343A JP6625690B2 JP 6625690 B2 JP6625690 B2 JP 6625690B2 JP 2018100343 A JP2018100343 A JP 2018100343A JP 2018100343 A JP2018100343 A JP 2018100343A JP 6625690 B2 JP6625690 B2 JP 6625690B2
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- Prior art keywords
- linker
- psma
- pharmaceutically acceptable
- acid
- acceptable salt
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical group C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
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- 239000007790 solid phase Substances 0.000 description 1
- GUCKKCMJTSNWCU-BQBZGAKWSA-N spaglumic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(=O)N[C@H](C(O)=O)CCC(O)=O GUCKKCMJTSNWCU-BQBZGAKWSA-N 0.000 description 1
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- 230000006641 stabilisation Effects 0.000 description 1
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- 229930002534 steroid glycoside Natural products 0.000 description 1
- 150000008143 steroidal glycosides Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000626 sulfinic acid group Chemical group 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 101150072109 trr1 gene Proteins 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
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- 238000012447 xenograft mouse model Methods 0.000 description 1
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Description
B−L−D
を有する結合体が記載され、ここで、Bは、前立腺特異的膜抗原(PSMA)に結合する又はそれを標的化するリガンドであり、Lはリンカーであり、そしてDは薬剤である。本明細書で使用されるとき、薬剤Dという用語は、別段の指示のない限り又は文脈にない限り、治療剤、細胞毒性剤、画像化剤、診断剤などを集合的に含む。例えば、一つの例示的な構成において、本明細書に記載される結合体は、病原性細胞集団を除去するために使用され、したがって薬剤Dは、治療剤、細胞毒性剤などである。別の例示的な構成において、本明細書に記載される結合体は、疾患又は疾患状態を画像化及び/又は診断するために使用され、したがって薬剤Dは、画像化剤、診断剤などである。他の構成も本明細書において考慮及び記載される。前述のB、L及びDのそれぞれの類似体及び誘導体も本明細書において考慮及び記載され、本明細書に使用されるとき、B、L及びDという用語は、そのような類似体及び誘導体を集合的に意味することが理解されるべきである。
本出願は、米国仮出願第60/956,489号(2007年8月17日出願)及び米国仮出願第61/074,358号(2008年6月20日出願)の優先権を請求する。なおこの開示は全て参照により本明細書に組み込まれる。
B−L−TA
B−L−IA
B−L−DA
〔式中、Bは、PSMA結合性部分であってその類似体又は誘導体を含み、Lは、リンカーであり、TAは、治療剤であってその類似体又は誘導体を含み、IAは、画像化剤であってその類似体又は誘導体を含み、そしてDAは、診断剤であってその類似体又は誘導体を含む〕で示されるPSMA結合性薬剤結合体、PSMA結合性画像化剤結合体及びPSMA結合性診断剤結合体を調製するのに使用されるリンカーに含まれていてもよい。リンカーLは、本明細書に記載されている二価リンカーを含む複数の二価リンカーを含むことができる。本明細書に使用されるとき、TAは、治療剤及びその類似体と誘導体を集合的に意味し、IAは、画像化剤及びその類似体と誘導体を集合的に意味し、そしてDAは、診断剤及びその類似体と誘導体を集合的に意味することも、理解されるべきである。
により定義される。
る。
様に交換しうることが理解されるべきである。
、下記式:
の量、又は例えば、多回用量1日レジメンにおける約0.1MIU/m2/用量/日から7.5MIU/m2/用量/日の範囲の量を、結合リガンド薬剤送達結合体と共に使用して、病原性細胞を有する宿主動物において病原性細胞を排除、低減又は中和することができる(MIU=ミリ国際単位;m2=平均的なヒトの体表面積の概算)。
物に投与することができ、治療因子を、結合リガンド薬剤送達結合体を含有する同じ組成物の一部として、又は結合リガンド薬剤送達結合体と異なる組成物の一部として、投与することができる。治療因子を治療的に有効な用量で含有する任意のそのような治療組成物を、本発明に使用することができる。
数Kdを有する。
−OtBu(291.4mg、0.774mmol)及びトリエチルアミン(30μL、240mmol)の混合物を加えた。反応混合物を1時間かけて室温にして、室温で一晩撹拌を続けた。反応混合物を1N HClとブラインで洗浄し、Na2SO4で乾燥した。粗生成物を、フラッシュクロマトグラフィー(ヘキサン:EtOAc=50:50、Rt=0.6)を使用して精製して、SK15(374mg、86.4%)を得た。C35H48N2O7S;MW=640.83g/mol;淡黄色の油状物;1H NMR(CDCl3)δ1.45(s,27H,CH3−tBu);1.88(m,1H,Glu−H);2.10(m,1H,Glu−H);2.32(m,2H,Glu−H);2.97(m,2H,Fm−CH2);3.13(m,2H,Cys−H);4.09(t,1H,Fm−H);4.38(m,1H,αH);4.66(m,1H,α−H);5.55(d,1H,尿素−H);5.67(d,1H,尿素−H);7.30(q,2H,Ar−H);7.36(q,2H,Ar−H);7.73(m,4H,Ar−H)。13C NMR (CDCl3)δ28.05;28.14;28.42;31.64;36.27;37.25;53.07;53.73;80.51;81.98;82.42;119.85;124.95;125.09;127.09;127.51;141.09;145.99;156.76;170.80;172.15;172.43;CI−MS=641(M+H)+,ESI−MS=641(M+H)+。
(M+H)+。
022(M+H)+;1020(M−H)-。
nが0〜約12の整数である関連する類似体も、本明細書に記載されている方法に従って調製することができる。
nが0〜約12の整数である関連する類似体も、本明細書に記載されている方法に従って調製することができる。
nが0〜約12の整数である関連する類似体も、本明細書に記載されている方法に従って調製することができる。
SK51:MW約2360.13g/mol;青色の固体,Rt=6.7分間;(AlexaFluor 647の構造は未知);
SK45:C67H87BF2N13O20S;MW=1475.35g/mol;橙色の固体,Rt=7.6分間;LC−MS=1475.3(M+H)+;
SK49:C71H76F2N10O24S;MW=1523.48g/mol;橙色の固体,Rt=6.7分間;LC−MS=1524(M+H)+。
に調製した。
SK125(FITC結合体)
== 実施例1A ==
LNCaP細胞及びSK28(原子14個のリンカー)を使用したインビトロ結合研究。LNCaP細胞(PSMAを過剰発現しているヒト前立腺癌細胞株、American Type Culture Collection(ATCC)から購入)を、2つの24ウエルファルコンプレートに接種し(120,000細胞/ウエル)、グルタミン(2mM)を有するRPMI(Gibco RPMI培地1640、カタログ番号22400)+10%FBS(ウシ胎児血清)、1%ピルビン酸ナトリウム(100mM)及び1%PS(ペニシリンストレプトマイシン)中で、5%のCO2雰囲気下、37℃で48時間増殖させて、接着単層にした。1つ目の24ウエルプレートの細胞を、0nMから450nMまで濃度を増加させたK28−99mTcと共に(それぞれの濃度で3通り)、5%のCO2雰囲気下、37℃で1時間インキュベートした。2つ目の24ウエルプレートの細胞を、50uMのPMPAと共に5%のCO2雰囲気下、37℃で30分間インキュベートし、次に、0nMから450nMまで濃度を増加させたK28−99mTcと共に(それぞれの濃度で3通り)、5%のCO2雰囲気下、37℃で1時間インキュベートした(競合研究)。細胞を1.0mLのRPMIで3回すすいだ。細胞をトリス緩衝剤で溶解し、個別のガンマシンチグラフィーバイアルに移し、放射能をカウントした。放射標識化合物に対する細胞結合放射能のプロットを使用して、Kd値を計算した。競合研究を使用して、PSMAに対するリガンド(DUPA)の結合特異性を決定した(図1A)。
LNCaP細胞及びSK33(原子14個のスペーサー)を使用したインビトロ結合研究。LNCaP細胞を24ウエルファルコンプレートに接種し(150,000細胞/ウエル)、48時間かけてコンフルエント単層を形成させた。それぞれのウエルの消費培地を、過剰PMPAの(▲)存在下又は(■)不在下で、濃度を増加させたDUPA−99mTcを含有する新たな培地(0.5mL)に代えた。37℃で1時間インキュベートした後、細胞を培養培地(2×1.0mL)及びトリス緩衝液(1×1.0mL)ですすいで、あらゆる非結合放射能を除去した。トリス緩衝剤(0.5mL)に懸濁させた後、細胞結合放射能を、γ−カウンター(Packard, Packard Instrument Company)を使用してカウントした。解離定数(KD)は、GraphPad Prism 4による非線形回帰を使用し、放射性トレーサーの濃度に対する細胞結合放射能のプロットを使用して計算した。エラーバーは、1標準偏差を表す(n=3)。実験を3回実施して、同様の結果を得た(図1B)。
LNCaP細胞に対するPSMMA分子の定量化。LNCaP細胞を24ウエルファルコンプレートに接種し、RPMI(Gibco RPMI培地1640、カタログ番号22400)+10%FBS(ウシ胎児血清)、1%グルタル酸及び1%PS(ペニシリンストレプトマイシン)中で、5%のCO2雰囲気下、37℃で48時間増殖させて、接着単層にした。次に細胞を、0nMから450nMまで濃度を増加させたSK28−99mTcと共に(それぞれの濃度で3通り)、5%のCO2雰囲気下、4℃又は37℃で1時間インキュベートした。細胞を1.0mLのRPMIで3回すすいだ。細胞をトリス緩衝剤で溶解し、個別のガンマシンチレーションバイアルに移し、放射能をカウントした。放射標識化合物に対する細胞結合放射能のプロットを使用して、PSMA/LNCaP細胞の数を計算した。SK28−99mTc(20uL)の30nMの試料の放射能をカウントした。4℃で(PSMAのエンドサイトーシスを防止するため)、30nMの試料のモル数は、30nM×20uL=(30×10-9mol/L)×(20×10-6L)=6×10-13mol。30nMの試料の原子の数は、(6×10-13mol)×(6.023×1023原子/mol)=3.6×1011原子。30nMの試料の20uLの放射能カウントは、20477cpm(cpm/原子=3.6×1011/20477=1.76×107)であった。4℃での飽和点の細胞結合放射能は、12000cpm。飽和点の原子の数は、(1.76×107原子)×(12,000cpm)。細胞/ウエルの数は、245,000個。4℃でのPSMA/細胞の数は、(2.12×1011)/2.45×105=864,396.4=約0.9×106個のPSMA/LNCaP細胞。
スペーサー依存結合研究。LNCaP細胞を24ウエルファルコンプレート(プレート10枚)に接種し(120,000細胞/ウエル)、RPMI(Gibco RPMI培地1640、カタログ番号22400)+10%FBS(ウシ胎児血清)、1%ピルビン酸ナトリウム及び1%PS(ペニシリンストレプトマイシン)中で、5%のCO2雰囲気下、37℃で48時間増殖させて、接着単層にした。次に細胞を、それぞれ0nMから1280nMまで濃度を増加させたSK60−99mTc(原子0個のスペーサー)、SK62-99mTc(原子7個のスペーサー)、SK28-99mTc(原子14個のスペーサー)、SK38-99mTc(原子16個のスペーサー)及びSK57−99mTc(原子24個のスペーサー)と共に(それぞれの濃度で3通り)、5%のCO2雰囲気下、37℃で1時間インキュベートした。また、別のプレートでは、50uMのPMPAを5%のCO2雰囲気下、37℃で30分間インキュベートし、次に、それぞれ0nMから1280nMまで濃度を増加させたSK60−99mTc(原子0個のスペーサー)、SK62-99mTc(原子7個のスペーサー)、SK28-99mTc(原子14個のスペーサー)、SK38-99mTc(原子16個のスペーサー)及びSK57−99mTc(原子24個のスペーサー)と共に(それぞれの濃度で3通り)、5%のCO2雰囲気下、37℃で1時間インキュベートした(競合研究、データ示さず)。細胞を1.0mLのRPMIで3回すすいだ。細胞をトリス緩衝剤で溶解し、個別のガンマシンチグラフィーバイアルに移し、放射能をカウントした。放射標識化合物の濃度に対する細胞結合放射能のプロットを使用して、Kd値を計算した。放射標識化合物の濃度に対する飽和率のプロット、また、スペーサー長さに対するKdのプロットを示す(図3A及びB)。
ヌードマウスにおけるヒトLNCaP腫瘍細胞のインビボ増殖。LNCaP細胞を、グルタミン(2mM)を有するRPMI1640(Gibco RPMI培地1640、カタログ番号22400)、10%FBS(ウシ胎児血清)、1%ピルビン酸ナトリウム(100mM)及び1%PS(ペニシリンストレプトマイシン)中で、5%のCO2雰囲気下、37℃で維持した。4〜5週齢の胸腺欠損雄ヌードマウス(nu/nu)を、NCI Charles Riverから得て、滅菌環境中で維持した。マウスを、ワイヤー上蓋を有するポリカーボネートの靴箱型ケージに収容し、通常の食餌で維持した。マウスを、LNCaP細胞を接種する1週間前に順化させた。マトリゲル及び高濃度(HC)マトリゲルをBD Biosciencesから購入した。ヌードマウスには、50%マトリゲル(100uLのPPMI培地+100uLのマトリゲル)又は50%高濃度マトリゲル(100uLのPPMI培地+100uLのHCマトリゲル)中のインビトロ繁殖LNCaP細胞を2.5×106個又は5.0×106個接種して、細胞の数、ビヒクルなどを含む最適条件を決定した。細胞を、ヌードマウスのそれぞれの体幹及びそれぞれの側腹部に皮下注射して、最適部位を決定した。それぞれの腫瘍の体積を、カリパスを使用して一週間に2回、垂直方向で測定し、体重を一週間に1回測定した(データ示さず)。
マウスにおけるLNCaP、KB及びA549細胞の腫瘍増殖の比較。LNCaP、KB及びA549細胞を、グルタミン(2mM)を有するRPMI1640(Gibco RPMI培地1640、カタログ番号22400)、10%FBS(ウシ胎児血清)、1%ピルビン酸ナトリウム(100mM)及び1%PS(ペニシリンストレプトマイシン)中で、5%のCO2雰囲気下、37℃で維持した。4〜5週齢の雄ヌードマウス(nu/nu)を、NCI Charles Riverから得て、滅菌環境中で維持した。マウスを、ワイヤー上蓋を有するポリカーボネートの靴箱型ケージに収容し、通常の食餌で維持した。マウスを、細胞を接種する1週間前に順化させた。
PSMA−99mTcを使用したマウス中の腫瘍のインビボ画像化。腫瘍が500〜600mm3の体積に達したとき、記載されているように調製した99mTc標識化合物(例えば、SK28−99mTc、SK60−99mTcなど)を、腹腔内(皮下)注射によって投与した。4時間後、動物を安楽死させ、血液を、心臓穿孔により採取し、それぞれの動物について個別のガンマシンチグラフィーバイアルに移した。画像化実験は、Kodak又はガンマシンチグラフカメラ画像装置を使用して実施した(図6A、6B、6C、7A、7B及び7C)。〔注:PMPAは、SK28−99mTc注射の30分前に注射した。癌性塊への取り込み以外では、SK28−99mTcの分布は、腎臓に限定されていた(図6A、6B及び6C)。両方のマウス(図7A、7B及び7C)にSK60−99mTcを注射したが、分布は、ほぼ腎臓に限定されていた(両方の腎臓を遮蔽した後でも腫瘍取り込みはなかった)。〕
DUPA−99mTcを使用したマウス中の腫瘍のインビボ画像化。前立腺癌細胞へのDUPA結合体の特異性を更に確立するために、DUPA−99mTcを、LNCaP腫瘍を肩に有する胸腺欠損ヌードマウスに腹腔内注射した。4時間で結合しなかった結合体のクリアランスをさせた後、保持されたDUPA−99mTcの分布を、ガンマシンチグラフィーにより画像化した。図7D(a)及び7D(c)から分かるように、標的99mTc放射性トレーサーは主にPSMA陽性LNCaP腫瘍に蓄積し、腎臓以外の他の組織にはほとんど又は全く放射能がなかった。重要なことは、腎臓の取り込みがマウスに特有でありうることであり、それは、免疫組織化学的及びRT−PCR分析が、PSMA発現がネズミの腎臓において高く、ヒトの腎臓では最小であると示唆しているからである。PSMA標的画像化剤のインビボ特異性を、DUPA−99mTc投与の前に、全てのPSMA部位をブロックする過剰PMPAを前投与することにより更に試験した。図7D(b)及び7D(d)に示されているように、ブロックされたLNCaP腫瘍は、DUPA−99mTc取り込みを示さず、インビボにおけるPSMAへのDUPA結合体の特異性が確認される。この特異性を更に証明するために、放射性トレーサーも、2つのPSMA陰性マウス異種移植片モデル〔A549(ヒト肺癌細胞株)及びKB(ヒト鼻咽腔癌細胞株)〕に投与し、ここでも全身の画像を撮影した。予測されたように、腎臓の遮蔽を実施して他の組織における低レベルのDUPA−99mTcの検出を可能にした後でも、KB腫瘍にもA549腫瘍にも放射能は観察されなかった(図7D(e)及び7D(f))。したがって、これらの研究では、インビボにおいてPSMAに無関係の部位ではDUPA−99mTc結合はほとんど生じないことが確認される。
生体内分布の研究。画像化した後、全ての動物を、SK28−99mTc又はSK60−99mTc〔又は他の放射標識化合物(データ示さず)〕を投与したおよそ6〜7時間後に解剖し、臓器(血液、腫瘍、心臓、肝臓、腎臓、脾臓、皮膚、筋肉など)を、それぞれの動物について個別のガンマシンチグラフィーバイアルに移し、放射能をカウントした。注:血液試料は、動物を殺処理した直後及び動物を画像化する直前に(心臓穿孔を使用して)収集した。組織に対する腫瘍と組織のcpm/g比率のプロットを使用して、画像化剤の生体内分布を決定した(図8A及び8B)。
LNCaP、A549又はKB腫瘍を有するnu/nuマウスにおけるDUPA−99mTcの生体内分布の研究。腫瘍を有するマウスを、DUPA−99mTc(50μmol/kg、150μCi)の腹腔内注射の4時間後に安楽死させ、組織蓄積放射能をγカウンターを使用してカウントした。湿組織の1グラムあたりの注射用量率を、方法実施例に記載されているとおりに計算した。データは1回の実験から得て、エラーバーは、標準偏差を表す(n=5)。LNCaP腫瘍(中実バー)、100倍のモル過剰PMPAを予め注射したマウスにおけるLNCaP腫瘍(中空バー)、A549腫瘍(斜交線バー)、KB腫瘍(平行線バー)(図8C)。
生存マウスにおける単回用量の毒性。SK71の投与を、示されているように単回用量で行った。データは、結合体のMTDが単回投与では約4.5μmol/kgであることを示す(図9Aを参照すること)。
生存マウスにおける多回用量の毒性。SK71を隔日(M、W、F、M、W)で5用量投与した。データは、SK71のMTDが多回投与では2μmol/kgであり、結合体は、LNCaP腫瘍に有効であることを示す(マウスには、処置を開始する前、LNCaP細胞の移植の2週間前にMTDを使用した)。生理的食塩水対照群における4匹のマウス全てが大きな腫瘍を有した一方、2つの処置群のマウスには、処置の18日後に目に見える腫瘍を有したものはなかった(図9Bを参照すること)。
対照群と競合群を比較した効能研究。動物を、(a)1μmol/kgの結合体SK71を隔日(M、W、F、M、W)で5用量投与して処置し、(b)ビヒクルで処置した動物(図10B)及び(c)PMPAと一緒に結合体で処置した動物と比較した。1μmol/kgでの処置は、処置の期間中に腫瘍サイズ(出発腫瘍サイズはおよそ250mm3)の連続的な減少を示す。図10Aに示す1μmol/kgの低い用量では、腫瘍体積は、投与を中止すると反発した。2μmol/kg以上のより高い用量では、腫瘍の完全な消滅が試験期間中に観察された。競合実験(図10Cを参照すること)から、移植腫瘍の治療が成功したことは、PSMA仲介送達の選択的又は特異的標的化に関係することが示される。
効能研究(1μmol/kgを1日おきに10日間、すなわち5用量)。データは(図11を参照すること)、処置動物の腫瘍が処置期間中にサイズを減少したことを示す。
PSMA標的治療剤のインビトロ評価。培養中のLNCaP細胞に対するSK71(図12A)、SK77(図12B)、SK37(図12C)及びSK45(図12D)の毒性の分析。LNCaP細胞を、濃度を増加させたSK71又はSK77により、100倍モル過剰のPMPAの(▲)存在下又は(■)不在下で2時間パルスした。2回洗浄した後、細胞を、新たな培地中で37℃で更に66時間インキュベートした。次に細胞生存率を、本明細書に記載されている〔3H〕−チミジン取り込みアッセイを使用して分析した。データは1回の実験から得て、エラーバーは、標準偏差を表す(n=1つの濃度につき3つのウエル)。
インビボ効力。処置マウスの皮下腫瘍の増殖(図13A及び13C)及び体重(図13B及び13D)に対するSK71の効果。HCマトリゲル中のLNCaP細胞を、n/n雄マウスの肩に皮下移植した。いったん腫瘍が100mm3(13A、13B)又は330
m3(13C、13D)の体積に達すると、動物をSK71〔1.5μmol/kg(a、b)又は2.0μmol/kg(c、d)〕で処置した。(■)処置マウス、(●)未処置マウス、(▲)100倍(13A、13B)又は(▼)30倍(13C、13D)モル過剰のPMPAが予め注射された処置マウス。データは1回の実験から得て、エラーバーは、標準偏差を表す〔n=4(13A、13B)又は3(13C、13D)〕。図10は、SK71のインビボ効力を示す。
Claims (24)
- 式:B−L−IAの化合物またはその医薬的に許容できる塩であって、
Bは式:
(式中、R1は水素であり、R2は、置換されたカルボン酸である)の前立腺特異的膜抗原(PSMA)のリガンドであり、
Lは式:
(式中、*はそれぞれBまたはIAへの結合点を表す)
を含むリンカーであり、
IAは
からなる群から選択される画像化剤である、化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - Lが式
を含むリンカーである、請求項1の化合物またはその医薬的に許容できる塩。 - IAが
のフルオレセインである、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のAlexaFluor 647である、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のDyLight 680である、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のDyLight 800である、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のCW800である、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のAlexaFluor 488である、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のOregon Green 488である、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のRhodamineである、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - IAが
のBODIPYである、請求項1〜11のいずれかの化合物またはその医薬的に許容できる塩。 - 式:
を有する、請求項1の化合物またはその医薬的に許容できる塩。 - 式:
(nは5である)
を有する、請求項1の化合物またはその医薬的に許容できる塩。 - 式
または
(式中、nは5である)
を有する、請求項1の化合物またはその医薬的に許容できる塩。 - 請求項1〜23のいずれかの化合物またはその医薬的に許容できる塩の有効量と、担体、希釈剤または賦形剤の1つまたはそれ以上、並びにそれらの組み合わせからなる群より選択される構成成分とを含む、患者の組織を画像化するための医薬組成物。
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US10828282B2 (en) | 2007-08-17 | 2020-11-10 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
US11083710B2 (en) | 2007-08-17 | 2021-08-10 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
US11298341B2 (en) | 2007-08-17 | 2022-04-12 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
US11318121B2 (en) | 2007-08-17 | 2022-05-03 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
US11369590B2 (en) | 2007-08-17 | 2022-06-28 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
US11717514B2 (en) | 2007-08-17 | 2023-08-08 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
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