JP5746615B2 - 癌細胞への抗体の動員のためのキメラ小分子 - Google Patents
癌細胞への抗体の動員のためのキメラ小分子 Download PDFInfo
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- JP5746615B2 JP5746615B2 JP2011509481A JP2011509481A JP5746615B2 JP 5746615 B2 JP5746615 B2 JP 5746615B2 JP 2011509481 A JP2011509481 A JP 2011509481A JP 2011509481 A JP2011509481 A JP 2011509481A JP 5746615 B2 JP5746615 B2 JP 5746615B2
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Description
本願は、2008年5月13日に出願した米国仮出願番号US61/127,539号、発明の名称「Chimeric Small Molecules for the Recruitment of Antibodies to Cancer Cells」について優先権の利益を主張し、その全内容が本願に援用される。
Bは、この患者における細胞の細胞表面の前立腺特異的膜抗原に結合可能な細胞結合部分であり、
Lは、分子において、[CON]をA又はBに結合するリンカー分子であり、
[CON]は、リンカー分子をA又はBに結合する結合又は連結分子であり、
分子中の各nは、独立して1〜15、1〜10、1〜5、1〜3、2〜3、2〜5の整数である。
・DHEAなどの副腎アンドロゲンの産生を阻害するケトコナゾール及びアミノグルテチミドなどの薬剤。これらの薬剤は、精巣において産生される95%のアンドロゲンを阻害することができる他の方法と組み合わせてのみ一般的に使用される。これらの組み合わされた方法は、完全アンドロゲン除去療法(TAB)と呼ばれ、抗アンドロゲン剤を用いても達成され得る。
・作動薬及び拮抗薬を含む、GnRHモジュレータ。GnRH拮抗薬は、LHの産生を直接抑制し、一方でGnRH作動薬は、初期刺激作用の後に下方制御の過程によってLHを抑制する。アバレリックスは、GnRH拮抗薬の例であり、一方でGnRH作動薬としては、ロイプロリド、ゴセレリン、トリプトレリン及びブセレリンが挙げられる。
・酢酸アビラテロンは、70%の患者でPSA値及び悪性の末期前立腺癌における腫瘍の寸法を減少させるのに使用され得る。ソラフェニブもまた、転移性前立腺癌を治療するのに使用されてもよい。
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基である。
Xは、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2、又はOS(O)2Oであり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基である。
R1'は、H又はC1〜C3のアルキル基であり;
ここで、Zは、結合、単糖、二糖、オリゴ糖、糖タンパク又は糖脂質、好ましくは糖基、より好ましくは、アルドース及びケトースを含む単糖、並びに下記に述べる二糖を含む二糖から選択される糖基である。単糖のアルドースは、アルドトリオース(特に、D−グリセルアルデヒド)、アルドテトロース(特に、D−エリスロース及びD−スレオース)、アルドペントース(特に、D−リボース、D−アラビノース、D−キシロース、D−リキソース)、アルドヘキソース(特に、D−アロース、D−アルトロース、D−グルコース、D−マンノース、D−グロース、D−イドース、D−ガラクトース及びD−タロース)などの単糖を含み、単糖のケトースは、ケトトリオース(特に、ジヒドロキシアセトン)、ケトテトロース(特に、D−エリスルロース)、ケトペントース(特に、D−リブロース及びD−キシルロース)、ケトヘキソース(特に、D−サイコン、D−フルクトース、D−ソルボース、D−タガトース)、特にガラクトサミン、シアル酸、N−アセチルグルコサミンを含むアミノ糖、特にスルホキノボースを含むスルホ糖などの単糖を含む。本発明で使用される例示の二糖は、特に、スクロース(任意にN−アセチル化されたグルコースを有してもよい)、ラクトース(任意にN−アセチル化されたガラクトース及び/又はグルコースを有してもよい)、マルトース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、トレハロース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、セルビオース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、コージビオース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、ニゲロース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、イソマルトース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、β,β−トレハロース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、ソホロース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、ラミナリビオース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、ゲンチオビオース(任意にN−アセチル化されたグルコース残基の一方又は両方を有してもよい)、ツラノース(任意にN−アセチル化されたグルコース残基を有してもよい)、マルツロース(任意にN−アセチル化されたグルコース残基を有してもよい)、パラチノース(任意にN−アセチル化されたグルコース残基を有してもよい)、ゲンチオビルオース(任意にN−アセチル化されたグルコース残基を有してもよい)、マンノビオース、メリビオース(任意にN−アセチル化されたグルコース残基及び/又はガラクトース残基を有してもよい)、メリビウロース(任意にN−アセチル化されたガラクトース残基を有してもよい)、ルチノース(任意にN−アセチル化されたグルコース残基を有してもよい)、ルチヌロース及びキシロビオースを含む。Zとして本発明に用いるオリゴ糖は、上述された個々の糖(糖類)単位(すなわち、あらゆる順序での、上述のいずれか1つ以上の糖単位、特に、上述のグルコース及び/又はガラクトース単位を含む)の3つ又はそれ以上(約100まで)のいかなる糖、すなわち例えば、フルクト−オリゴ糖、ガラクトオリゴ糖及び大きさにおいて3から10〜15の範囲の糖単位のマンナン−オリゴ糖を含むことができる。本発明に用いる糖タンパク質は、例えば、特に、ムチン、コラーゲン、トランスフェリン、セルロプラスミン、主要組織適合性複合タンパク質(MHC)、酵素、レクチン及びセレクチン、カルネキシン、カルレチクリン、並びにインテグリン糖タンパク質IIb/IIaを含むN−グリコシル化及びO−グリコシル化糖タンパク質を含む。本発明に用いる糖脂質は、例えば、特に、グリセロ糖脂質(ガラクトリピッド、スルフォリピッド)、セレブロシドなどのグリコスフィンゴリピッド、ガラクトセレブロシド、グルコセレブロシド(グルコビカラナテオエツを含む)、ガングリオシド、グロボシド、スルファチド、グリコホスホフィンゴリピッド及びグリコカリクスを含む。
X3は、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2又はOS(O)2Oであり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基であり;
kは、0〜20、8〜12、1〜15、1〜10、1〜8、1〜6、1、2、3、4、5又は6の整数である。
mは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5の整数である。
上記の−(CH2)i基は、Z又はZ’に存在する場合、連結子、ABT又はCBTと結合され;
各Rは、H、又はC1〜C3のアルキル基若しくはアルカノール基であり;
各R2は、独立に、H又はC1〜C3のアルキル基であり;
各Yは、独立に、結合、O、S又はN−Rであり;
各iは、独立に、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
Dは、
jは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
m’は、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
nは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
X1は、O、S又はN−Rであり;
Rは、上述の通りであり、
又は、その医薬的に許容可能な塩である。
X3は、O、S、NR4であり;
R4は、H、C1〜C3のアルキル基若しくはアルカノール基、又は−C(O)(C1〜C3)の基である。
Xは、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2、又はOS(O)2Oであり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基であり;
X’は、CH2、O、N−R1'又はS、好ましくはOであり;
R1'は、H又はC1〜C3のアルキル基であり;
Zは、結合、単糖、二糖、オリゴ糖、糖タンパク又は糖脂質であり;
Xbは、結合、O、CH2、NR1又はSであり;
X’’は、O、CH2、NR1であり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基であり;
Bは、次の化学式による細胞結合末端である。
X3は、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2又はOS(O)2Oであり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基であり;
kは、0〜20、8〜12、1〜15、1〜10、1〜8、1〜6、1、2、3、4、5又は6の整数であり;
Lは、次の化学式によるリンカー
ここで、Raは、H、C1〜C3のアルキル基若しくはアルカノール、又はR3(プロリン)と共に環を形成し、そしてR3は、アミノ酸に由来する側鎖であり、好ましくはアラニン(メチル)、アルギニン(プロピレングアニジン)、アスパラギン(メチレンカルボキシアミド)、アスパラギン酸(エタン酸)、システイン(チオール、還元又は酸化ジチオール)、グルタミン(エチルカルボキシアミド)、グルタミン酸(プロパン酸)、グリシン(H)、ヒスチジン(メチレンイミダゾール)、イソロイシン(1−メチルプロパン)、ロイシン(2−メチルプロパン)、リジン(ブチレンアミン)、メチオニン(エチルメチルチオエーテル)、フェニルアラニン(ベンジル)、プロリン(R3が、Ra及び隣接する窒素基と環を形成し、ピロリジン基を形成する)、セリン(メタノール)、スレオニン(エタノール、1−ヒドロキシエタン)、トリプトファン(メチレンインドール)、チロシン(メチレンフェノール)又はバリン(イソプロピル)からなる群から選択され;
mは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5の整数である。
上記−(CH2)i基は、Z又はZ’ に存在する場合、もし存在するならば[CON]、ABT又はCBTに結合され;
各Rは、独立に、H、又はC1〜C3のアルキル基若しくはアルカノール基であり;
各R2は、独立に、H又はC1〜C3のアルキル基であり;
各Yは、独立に、結合、O、S又はN−Rであり;
各iは、独立に、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
Dは、
jは、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
m’は、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
n’は、1〜100、1〜75、1〜60、1〜55、1〜50、1〜45、1〜40、2〜35、3〜30、1〜15、1〜10、1〜8、1〜6、1、2、3、4又は5であり;
X1は、O、S又はN−Rであり;
Rは、上述の通りであり;
連結部分[CON]は、結合又は次の化学構造による部分であり、
X3は、NR4、O又はSであり;
R4は、H、C1〜C3のアルキル基若しくはアルカノール基、又は−C(O)(C1〜C3)の基である。
X’は、Oであり;
Zは、結合、単糖又は二糖である。
本発明によるキメラ抗体動員化合物は、必要であれば適当な保護基と共に、リンカー並びに細胞結合末端(CBT)及び抗体結合末端(ABT)との間の標準的な化学結合性を用いて、容易に合成される。この手法は、リンカーを介して細胞結合部分を抗体結合部分に結合するために、標準的な官能基化学反応を用い、好ましい態様では、CBTがリンカーを介してABT抗体結合へ共有結合(連結)される場合に形成される任意の連結部分(官能基、使用する反応等に依存して、リンカーとABTとの間、又はリンカーとCBTとの間)をもたらす。ここで、連結部分それ自体は必要ではなく、本願の他で述べられるように、リンカーは、特定の連結部分を形成することなく、CBT及び/又はABTに直接共有結合されてもよいという事実が特筆される。本発明において、好ましくは本発明のキメラ抗体動員化合物に含まれる連結部分は、本願の他で開示されるように、その形成が、キメラ化合物を提供する望ましい合成化学を反映したものであることを示す。
複数の高い親和性を有するリガンドは、PSMAを選択的に標的化するように開発された。Slusherら著、Nature Medicine、1999年、5巻、1396頁参照。図1は、本発明によるキメラ抗体動員化合物の原理機序を示すと一般的に理解される小分子の鋳型免疫治療を示す。PC−ARM(3、図3)は、非常に高い親和性(2、Ki=0.9nM)を有する尿素ベースのテトラゾールを含有するリガンドにより刺激を与えられ(Kozikowski著、J.Med.Chem.、2004年、47巻、1729頁参照)、溶媒に暴露された付属肢を受容するように分子モデリングで精製された(図2A)。この全体に三重複合体のモデル(図2B)は、かなり大きな繋がりの長さ(8〜12のポリエチレングリコール単位)が必要であることを示唆した。
あるいは、上記の一般的な手法に依拠して、分子(4)(図9)が容易に合成され、本発明による二量体化合物の化学合成のシントンとして使用されてもよい。プロパルギルの結合を有する化合物4又は同様の合成で扱える分子は、クリック化学に用いられ得る(スキーム1a、図9)。Sharpless及びManetsch著、Expert Opinion on Drug Discovery、2006年、1巻、525〜538頁参照。この分子を種々の長さを有するポリエチレングリコール単位を有するアジド5及び6に処理することで、異なる結合長のキメラ動員分子の群に迅速に入ることができる。鎖長を変更する柔軟性を有することは、最適なCBT−ABT距離を確認することを支援するのに重要である。
多価誘導体は、上記に提案された中間体から、分岐の方法で合成され得る。合成的に相補なビス−アルキニル及びトリス−アジジル化合物は公知であり、この研究において非常に効果的に用いられ得る。ビス−アルキニル20は、クリック条件下で長鎖のPEG−由来アジド−DNP19を用いて変換され、所望のビス−ジDNP類似体21を生成することができる(スキーム4a、図12)。
他で述べる事項を除き、全ての反応は、窒素雰囲気下で、炎で乾燥したガラス製品中で行われる。全ての試薬は、市販業者から購入され、次に記載する場合を除いて更なる精製を行わずに用いた:トリエチルアミンは、水素化カルシウムで蒸留された。CH2Cl2、PhMe、DMF及びTHFは、溶媒調剤システムを用いて精製された。水は、ミリQ精製システムを用いて精製された。
40mMのNaOH中のN−アセチル−アスパルチル−グルタメート(NAAG)の10mM原液を、Tris緩衝液(0.1MのTris−HCl、pH7.5)中で40μMに希釈し、384ウェルプレート(1ウェル当たり25μL)に加えた。Km測定及び対照のために、NAAGの2倍の希釈(40μM〜312nM)系列を作成し、別のウェルに添加した。IC50の測定に対して、水中の動員分子3(1ウェル当たり2μL、希釈系列)の溶液をウェルに添加した。他のすべてのウェルに対して2μLの水を添加した。反応を開始するため、Tris緩衝液で希釈したrhPSMA(R&Dリサーチ)(20pg/mL)を各ウェルに添加した(1ウェル当たり25μL)。陰性対照に対して、Tris緩衝液を添加した(1ウェル当たり25μL)。プレートを覆って15分間インキュベートし、この時プレートを95℃で3分間加熱することによりタンパク質を失活した。プレートを冷却した後、Amplex(登録商標)−Redのグルタミン酸/グルタミン酸オキシダーゼ試験キット(Invitrogen)を用いて、グルタミン酸の放出を可視化した。Km及びIC50値は、グラフパッドプリスムソフトウェアを用いて算出し、Kiは、チェン−プルソフの式を用いてこれらの値から算出した。この過程は、3つの試料で行われ、3度の実施の平均値±標準偏差として報告する。
抗体動員フローサイトメトリー:LNCaP及びDU145細胞を脱離させ、計数し、洗浄し、フローサイトメトリー緩衝液(25mMのTris−HCl、150mMのNaCl、1.5%のBSA、5mMのグルコース、1.5mMのMgCl2、pH7.2)に、2×105細胞/mLの緩衝液の密度で再懸濁し、実験毎に各エッペンドルフ管に1mL添加した。水中の3(2μL、実験毎に種々の濃度)のフローサイトメトリー緩衝液の溶液を細胞に添加し、細胞を4℃で60分間インキュベートした。細胞結合末端競合試験に関して、水中のPMPA溶液(2μL、種々の濃度)をインキュベーションの前に添加した。インキュベーションに続いて、フローサイトメトリー緩衝液で細胞を3回洗浄した。1mg/mLのヒトIgGを有するマウス血清の20μLを各管に添加し、管を室温で5分間インキュベートし、Fc受容体を阻害した。200μLのフローサイトメトリー緩衝液を添加し、これに、2mg/mLのAlexaFluor488共役ウサギ抗ジニトロフェニルIgG−KLH画分2μLを添加した。抗体結合末端競合実験に関して、ジ−DNPリジンの溶液(5mMの水中の溶液2μL)をインキュベーションの前に添加した。管を4℃で60分間インキュベートし、850μLのフローサイトメトリー緩衝液で採取した。細胞を遠沈し、フローサイトメトリー緩衝液で洗浄した(2×1mL)。細胞を1mLのTris緩衝生理食塩水(25mMのTrisHCl、150mMのNaCl、pH7.2)で採取し、500μg/mLのポリピジウムヨーダイド2μLを添加し、FACSCalibur装置(Becton Dickinson)で試料を直ちに分析した。FlowJo(Tree Star Inc.)を用いてデータを分析し、FL−3上に生細胞をゲートでコントロールした。3を除外した実験を対照として行った。実験は、再現性を確保するため、3つの試料で繰り返された。
Claims (22)
- 次の化学構造であり、
Xは、O、CH2、NR1、S(O)、S(O)2、−S(O)2O、−OS(O)2、又はOS(O)2Oであり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基であり;
Bは、前記患者における細胞の細胞表面の前立腺特異的膜抗原に結合可能な次の化学構造による細胞結合部分(CBT)であり;
X3は、O、CH2、S(O)、S(O)2、−S(O)2O、−OS(O)2又はOS(O)2Oであり;
R1は、H、C1〜C3のアルキル基、又は−C(O)(C1〜C3)の基であり;
kは、1〜10の整数であり;
Lは、[CON]を分子におけるA又はBに結合する次の化学式によるリンカーであり;
ここで、Raは、H、C1〜C3のアルキル基若しくはアルカノール、又はR3(プロリン)と共に環を形成し、そしてR3は、アミノ酸に由来する側鎖であり;
mは、1〜15の整数であり;
[CON]は、次の化学構造による部分であり;
化合物又はその医薬的に許容可能な塩、溶媒和物若しくは多形体。 - 前記リンカーは、1〜10のグリコール単位を有するポリエチレングリコールに基づくリンカーである、請求項1から4のいずれかに記載の化合物。
- 医薬的に許容可能なキャリア、添加物又は賦形剤と組み合わされた、請求項1から9のいずれかに記載のキメラ化合物の有効量を含む医薬組成物。
- 追加の抗癌剤の有効量をさらに含む、請求項10に記載の医薬組成物。
- 前記追加の抗癌剤は、代謝拮抗剤、トポイソメラーゼI及びIIの阻害剤、アルキル化剤、微小管阻害剤又はこれらの混合物である、請求項11に記載の医薬組成物。
- 前記抗癌剤は、アルデスロイキン;アレムツズマブ;アリトレチノイン;アロプリノール;アルトレタミン;アミホスチン;アナストロゾール;三酸化ヒ素;アスパラギナーゼ;生BCG;ベキサロテンカプセル;ベキサロテンゲル;ブレオマイシン;静注ブスルファン;経口ブスルファン;カルステロン;カペシタビン;カルボプラチン;カルムスチン;ポリフェプロサン20インプラントを有するカルムスチン;セレコキシブ;クロラムブシル;シスプラチン;クラドリビン;シクロホスファミド;シタラビン;シタラビンリポソーマル;ダカルバジン;ダクチノマイシン;アクチノマイシンD;ダルベポエチン アルファ;ダウノルビシンリポソーマル;ダウノルビシン;ダウノマイシン;デニロイキン ディフティトックス;デクスラゾキサン;ドセタキセル;ドキソルビシン;ドキソルビシンリポソーマル;プロピオン酸ドロモスタノロン;エリオットB溶液;エピルビシン;エポエチン アルファ エストラムスチン;リン酸エトポシド;エトポシド(VP−16);エキセメスタン;フィルグラスチム;フロクスリジン(動脈内);フルダラビン;フルオロウラシル(5−FU);フルベストラント;ゲムツズマブ オゾガマイシン;酢酸ゴセレリン;ヒドロキシウレア;イブリツモマブ チウキセタン;イダルビシン;イフォスファミド;メシル酸イマチニブ;インターフェロン アルファ−2a;インターフェロン アルファ−2b;イリノテカン;レトロゾール;ロイコボリン;レバミソール;ロムスチン(CCNU);メクロレタミン(ナイトロジェンマスタード);酢酸メゲストロール;メルファラン(L−PAM);メルカプトプリン(6−MP);メスナ;メトトレキサート;メトクスサレン;マイトマイシンC;ミトタン;ミトキサントロン;フェンプロピオン酸ナンドロロン;ノフェツモマブ;LOddC;オプレルベキン;オキサリプラチン;パクリタキセル;パミドロネート;ペガデマーゼ;ペガスパルガーゼ;ペグフィルグラスチム;ペントスタチン;ピポブロマン;プリカマイシン;ミトラマイシン;ポルフィマーナトリウム;プロカルバジン;キナクリン;ラスブリカーゼ;リツキシマブ;サルグラモスチム;ストレプトゾシン;タルブビジン(LDT);タルク;タモキシフェン;テモゾロミド;テニポシド(VM−26);テストラクトン;チオグアニン(6−TG);チオテパ;トポテカン;トレミフェン;トシツモマブ;トラスツズマブ;トレチノイン(ATRA);ウラシルマスタード;バルルビシン;バルトルシタビン(モノバルLDC);ビンブラスチン;ビノレルビン;ゾレドロネート;及びこれらの混合物である、請求項11に記載の医薬組成物。
- 少なくとも1つの抗アンドロゲン化合物をさらに含む、請求項10から13のいずれかに記載の医薬組成物。
- 少なくとも1つのGNRhモジュレータをさらに含む、請求項10から14のいずれかに記載の医薬組成物。
- フルタミド、ビカルタミド、ニルタミド、酢酸シプロテロン、ケトコナゾール、アミノグルテチミド、アバレリックス、ロイプロリド、ゴセレリン、トリプトレリン、ブセレリン、酢酸アビラテロン、ソラフェニブ及びこれらの混合物からなる群から選択される少なくとも1つの薬剤をさらに含む、請求項10から15のいずれかに記載の医薬組成物。
- 前立腺肥大用剤、オイレキシン、フルタミド、ゴセレリン、ロイプロリド、ルプロン、ニランドロン、ニルタミド、ゾラデックス及びこれらの混合物からなる群から選択される少なくとも1つの薬剤をさらに含む、請求項10から15のいずれかに記載の医薬組成物。
- 経口の投与形態である、請求項10から17のいずれかに記載の医薬組成物。
- 薬剤の製造における請求項1から9のいずれかに記載の化合物の使用。
- 患者における癌の治療のための薬剤の製造における請求項10から13のいずれかに記載の医薬組成物の使用。
- 必要とする患者における前立腺癌の治療のための薬剤の製造における請求項10から17のいずれかに記載の医薬組成物の使用。
- 前記前立腺癌は転移性前立腺癌である、請求項21に記載の使用。
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US9951324B2 (en) | 2010-02-25 | 2018-04-24 | Purdue Research Foundation | PSMA binding ligand-linker conjugates and methods for using |
JP6155193B2 (ja) | 2010-11-18 | 2017-06-28 | イェール ユニバーシティーYale University | ヒト免疫不全ウイルスに対する抗体動員及び進入阻害活性を有する二官能性分子 |
US20140308342A1 (en) | 2011-11-11 | 2014-10-16 | Yale University | Reprogramming urokinase into an antibody-recruiting anticancer agent |
WO2013162757A1 (en) * | 2012-04-26 | 2013-10-31 | Yale University | Cytotoxic-drug delivering molecules targeting hiv (cdm-hs), cytotoxic activity against the human immunodeficiency virus and methods of use |
WO2013166110A1 (en) | 2012-05-02 | 2013-11-07 | Yale University | Tlr-agonist-conjugated antibody recruiting molecules (tlr_arms) |
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