CN109053616A - 前列腺特异性膜抗原(psma)的标记的抑制剂及其用途 - Google Patents

前列腺特异性膜抗原(psma)的标记的抑制剂及其用途 Download PDF

Info

Publication number
CN109053616A
CN109053616A CN201810815832.7A CN201810815832A CN109053616A CN 109053616 A CN109053616 A CN 109053616A CN 201810815832 A CN201810815832 A CN 201810815832A CN 109053616 A CN109053616 A CN 109053616A
Authority
CN
China
Prior art keywords
compound
radionuclide
psma
cell
label
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810815832.7A
Other languages
English (en)
Other versions
CN109053616B (zh
Inventor
马蒂亚斯·埃德
克劳斯·科普卡
马丁·谢菲尔
乌尔丽克·鲍德-维斯特
乌韦·哈伯科恩
米夏埃尔·艾森胡特
马丁纳·贝内索娃
沃尔特·米尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Novartis Pharma AG
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
Universitaetsklinikum Heidelberg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51903864&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN109053616(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from EP20130004991 external-priority patent/EP2862857A1/en
Application filed by Deutsches Krebsforschungszentrum DKFZ, Universitaetsklinikum Heidelberg filed Critical Deutsches Krebsforschungszentrum DKFZ
Publication of CN109053616A publication Critical patent/CN109053616A/zh
Application granted granted Critical
Publication of CN109053616B publication Critical patent/CN109053616B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/0474Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/0402Organic compounds carboxylic acid carriers, fatty acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/041Heterocyclic compounds
    • A61K51/044Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04Organic compounds
    • A61K51/0497Organic compounds conjugates with a carrier being an organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/08Drugs for disorders of the urinary system of the prostate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002Heterocyclic compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D257/00Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/60Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本申请提供前列腺特异性膜抗原(PSMA)的标记的抑制剂及其用途。本发明总体上涉及放射药剂的领域和它们在核医学中作为示踪物、显影剂和用于治疗各种前列腺癌的疾病状态的用途。因此,本发明涉及由通式(1a)或(1b)表示的化合物。

Description

前列腺特异性膜抗原(PSMA)的标记的抑制剂及其用途
本申请是申请日为2014年10月17日的题为“前列腺特异性膜抗原(PSMA)的标记的抑制剂,它们作为显影剂和用于治疗前列腺癌的药剂的用途”的中国专利申请No.201480056250.5的分案申请。
技术领域
本发明总体上涉及放射性药物领域和它们作为示踪物、显影剂在核医学中的用途以及用于治疗各种前列腺癌的疾病状态。
背景技术
前列腺癌(PCa)是美国和欧洲人口中主要的癌症。在西半球至少1-2百万男性患有前列腺癌,并且据估计,该疾病会侵袭55至85岁之间的六分之一的男性。在美国每年诊断出超过300,000个前列腺癌的新病例。该疾病的死亡率仅次于肺癌。目前的解剖学方法,如计算机断层扫描(CT)、磁共振(MR)成像和超声波占前列腺癌的临床成像的主导地位。估计目前在世界范围内在外科手术、放射、药物疗法和微创治疗上花费了二十亿美元。然而,目前不存在对于复发性、转移性、雄激素非依赖性前列腺癌的有效疗法。
目前临床推行各种实验性的低分子量PCa显影剂,包括放射性标记的胆碱类似物[18F]氟代二羟基睾酮([18F]FDHT)、抗-1-氨基-3-[18F]氟代环丁基-1-羧酸(抗[18F]F-FACBC、[11C]乙酸酯和1-(2-脱氧-2-[18F]氟代-L-阿糖呋喃糖基)-5-甲基尿嘧啶(-[18F]FMAU)(Scher,B.;et al.Eur J Nucl Med Mol Imaging 2007,34,45-53;Rinnab,L;etal.BJU Int 2007,100,786,793;Reske,S.N.;et al.J Nucl Med 2006,47,1249-1254;Zophel,K.;Kotzerke,J.Eur J Nucl Med Mol Imaging 2004,31,756-759;Vees,H.;etal.BJU Int 2007,99,1415-1420;Larson,S.M.;et al.J Nucl Med 2004,45,366-373;Schuster,D.M.;et al.J Nucl Med 2007,48,56-63;Tehrani,O.S.;et al.J Nucl Med2007,48,1436-1441)。每种通过不同的机制运作并具有某些优势,例如[11C]胆碱的低尿排泄,和缺点,如正电子发射放射性核素的短物理半衰期。
众所周知肿瘤可以表达与它们的恶性表型相关的独特蛋白质,或可以以比正常细胞更大的数量过表达正常的组成蛋白。肿瘤细胞表面上的独特蛋白质的表达提供了通过探测该表型标识以及肿瘤的生物化学组合物及活性,诊断和表征疾病的可能性。选择性地结合至特定肿瘤细胞表面蛋白质的放射性分子提供了用于在非侵入条件下成像和治疗肿瘤的有吸引力的途径。有希望的新系列的低分子量显影剂靶标是前列腺特异性膜抗原(PSMA)(Mease R.C.et al.Clin Cancer Res.2008,14,3036-3043;Foss,C.A.;et al.ClinCancer Res 2005,11,4022-4028;Pomper,M.G.;et al.Mol Imaging 2002,1,96-101;Zhou,J.;etr al.Nat Rev Drug Discov 2005,4,1015-1026;WO 2013/022797)。
PSMA是在PCa表面上,特别是在雄激素非依赖性的、晚期的(advanced)和转移性的疾病中具有大量的且受限的表达的,跨膜的,750氨基酸II型糖蛋白(Schulke,N.;etal.Proc Natl Acad Sci U S A 2003,100,12590-12595)。后者是重要的,因为几乎所有的PCa会随时间变为雄激素非依赖性的。PSMA拥有用于治疗,即呈现于细胞表面但不脱落到循环系统,并且与酶或信号活性相关的,在疾病的所有阶段大量的且受限(于前列腺)的表达的有希望的靶标的标准(Schulke,N.;et al.Proc.Natl.Acad.Sci.U S A 2003,100,12590-12595)。PSMA基因位于染色体11的短臂并起叶酸水解酶和神经肽酶的作用。其具有相当于称作“大脑PSMA”的谷氨酸羧肽酶II(GCPII)的神经肽酶功能,并且通过将N-乙酰基天冬氨酰基谷氨酸酯(NAAG)剪切为N-乙酰基天冬氨酸(NAA)和谷氨酸来调节谷氨酸能传递(glutamatergic transmission)(Nan,F.;et al.J Med Chem 2000,43,772-774)。每个癌细胞存在最多达106个PSMA分子,进一步表明其对于使用基于发射性核素的技术的成像和治疗是理想的靶标(Tasch,J.;et al.Crit Rev Immunol 2001,21,249-261)。
抗-PSMA单克隆抗体(mAb)7E11的放射性免疫结合物,称为扫描,目前用于诊断前列腺癌的转移和复发。然而,该试剂趋向于产生对于解释有挑战性的图像(Lange,P.H.PROSTASCINT scan for staging prostate cancer.Urology 2001,57,402-406;Haseman,M.K.;et al.Cancer Biother Radiopharm 2000,15,131-140;Rosenthal,S.A.;et al.Tech Urol 2001,7,27-37)。已经新近开发出结合至PSMA的胞外域,并且已经放射性标记并在动物中示出聚集在PSMA阳性的前列腺肿瘤模型中的单克隆抗体。然而,使用单克隆抗体的诊断和肿瘤检测已被实体瘤中单克隆抗体的低渗透性限制。
对于成像或治疗目的,用放射性药物选择性靶向癌细胞是挑战性的。已知各种对放射性成像或癌放射疗法有用的放射性核素,包括111In、90Y、68Ga、177Lu、99mTc、123I和131I。近来已经示出,一些含有与放射性核素-配体结合物相连的谷氨酸-脲-谷氨酸(GUG)或谷氨酸-脲-赖氨酸(GUL)识别元素(recognition element)的化合物展现出对PSMA的高亲合性。
需要可以迅速可视化前列腺癌并特异靶向以允许放射线疗法存在的新试剂。
因此,本发明的目标是开发与PSMA相互作用并携带适当的放射性核素的配体,其提供用于检测、治疗和管理前列腺癌的有希望的和新型的靶向选择。
发明内容
通过提供在权利要求中表征的实施方式来实现所述目标的解决方案。
发明人发现了新的化合物,其是有用的放射药剂,以及它们在核医学中作为示踪物、显影剂的用途和用于治疗各种前列腺癌的疾病状态。
具有连接基区域中的结构改变的新型显影剂具有改善的肿瘤靶向性能和药代动力学。药效团呈现三个能够与PSMA的相应侧链相互作用的羧基以及作为活性中心中的锌络合(zinc complexation)的部分的氧。除了这些必须的相互作用,发明人能够优化连接基区域中的亲脂性相互作用。
附图说明
图1:MB17的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像(whole-body coronal microPET image)。通过动态microPET扫描评估[68Ga]MB17的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。图A示出了肾脏和膀胱相应的时间-活性曲线,并且图B为心脏、肌肉和肿瘤相应的时间-活性曲线。数值表示为平均SUV(标准化吸收值)。
图2:注射后1h的器官分布
0.06nmol的68Ga标记的PSMA抑制物MB17注射后一小时的器官分布。通过共给予2mg/kg体重的2-PMPA的PSMA阻断表示在肿瘤和肾脏中的PSMA特异吸收。数据表示为平均%ID/g组织±SD(n=3)。
图3:MB4的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB4的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。图A示出了肾脏和膀胱相应的时间-活性曲线,并且图B为心脏、肌肉和肿瘤相应的时间-活性曲线。数值表示为平均SUV(标准化吸收值)。
图4:0.06nmol的177Lu标记的MB17注射后24h表示为%ID/g组织±SD(n=5)的器官 分布
177Lu的器官分布示出,较高的初始肾脏吸收在24小时之后接近完全洗出(2.13±1.36%ID/g),而肿瘤吸收保持较高并且甚至增加(10.58±4.50%ID/g)。其他器官,如肝脏(0.08±0.03%ID/g)、肺(0.11±0.13%ID/g)和脾(0.13±0.05%ID/g)示出了非常低的吸收。有利的药物动力学导致24小时之后极高的肿瘤与背景比率(肿瘤/血液:1058;肿瘤/肌肉:529)。
图5:MB2的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB2的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图6:MB3的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB3的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图7:MB10的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB10的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图8:MB:17.D的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB17.D的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
MB17D:MB17(L)的立体异构体;基于Fmoc-3(2-萘基)-D-甘氨酸合成
图9:MB22的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB22的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图10:MB24的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB24的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图11:MB25的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB25的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图12:MB31的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB31的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图13:MB33的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB33的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图14:MB35的PET成像
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。通过动态microPET扫描评估[68Ga]MB35的肿瘤靶向疗效和药代动力学性能。大约注射15MBq/鼠。
图15:用68Ga-CHX-DTPA注射的小鼠的PET扫描
左侧为尾侧视图(caudal),中间为背侧视图(dorsal)并且右侧为侧面视图(lateral)。该图片覆盖20-40分钟(顶部)、40-60分钟(中间)和120-140分钟(底部)的时间间隔。
图16:MB-17相对于MB-17.D
携带LNCaP肿瘤异种移植的无胸腺雄性裸鼠的全身冠侧microPET图像。在注射后2小时直接比较立体异构体MB-17和MB-17D的肿瘤靶向疗效和药代动力学性能。
图17a和17b:68Ga标记MB17的人类PET/CT成像
(a)具有68Ga标记的MB17PET/CT的第一临床经验表明在注射后1小时检测到小淋巴结的转移,主要是由于较高的放射示踪物吸收。红色箭头指向注射后一小时具有36.5的最大SUV和52.1的肿瘤与背景比率的代表性病灶。MIP=注射后1h PET的最大密度投影。
(b)68Ga标记的MB17PET/CT的显著优势是即使在低PSA水平下对病灶灵敏的探测。
图18a和18b:具有多重前列腺癌转移(multiple prostate cancer metastasis) 的患者的PET成像
(a)第一扫描显示了具有14的血液PSA值的,具有多重前列腺癌转移的患者的初始PET成像。两个月后施加3.3GBq的177Lu标记的MB17。在此时间点,血液中的PSA量达到38的值。在第一循环(cycle)后,PSA水平降至8。在第一循环后三个月施加另外4GBq的177Lu标记的MB17。在第二循环后一个月进行对照PET扫描(control PET scan)。该疗法示出对肿瘤病灶(lesion)和PSA值的显著影响并导致骨痛的减少。
(b)该图表明对PSA值的显著影响,其在首次施加治疗剂量的177Lu标记的MB17之后降低。
具体实施方式
本发明涉及放射药剂和它们在核医学中作为示踪物、显影剂的用途和用于治疗各种前列腺癌的疾病状态。
因此,本发明涉及由通式(1a)或(1b)表示的化合物:
式(1a)
式(1b)
其中:
如果不另外说明,在本发明中“烷基”残基(优选地:C1至C10)可以是线性的或支链的,未取代的或取代的。优选的烷基残基是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基。同样也适用于优选地具有3至10个碳原子的相应环烷基化合物。
“芳基”是指具有6至14个碳原子,优选地6至10个碳原子的芳香族单环或多环的环系统。芳基基团可以是适当地由一个或多个环取代基,如烷基基团取代的。优选的芳基基团是苯基、苄基或萘基。
虽然Z-基团是-CO2H是优选的,其可以容易地由生物异构体替换物替换,如-SO2H、-SO3H、-SO4H、-PO2H、-PO3H、-PO4H2,见,例如“The Practice of Medicinal Chemistry”(Academic Press New York,1996),203页。
在本发明的含义内,认为所有残基是可结合的,除非在残基的定义中另有说明。其所有可以想到的子群(subgrouping)被认为是公开的。
在优选的实施方式中,特异地结合至赘生性细胞(neoplastic cell)的细胞膜的基序是特异地结合癌性细胞的细胞膜的基序,优选地,其中所述基序包含前列腺特异性膜抗原(PSMA),具体地,其中所述PSMA包含根据方案1中的下式的谷氨酸-脲-赖氨酸基序。
因此,本发明的优选的分子由三种主要组分组成(方案1):亲水PSMA结合基序(Glu-脲-Lys;=Glu-NH-CO-NH-Lys)、可变的连接基和优选地是DOTA的螯合剂。
方案1:本发明优选的化合物的结构
以下示出不同的优选的连接基,其中R=Glu-脲-Lys并且R'=DOTA(作为螯合剂的优选实例),如以上示出。
MB2连接基
化学式:C36H54N8O15
分子量:838,88g/mol
MB3连接基
化学式:Ο44Η61N9O16
分子量:972,03g/mol
MB4连接基
化学式:C52H68N10O17
分子量:1105,18g/mol
MB10连接基
化学式:C65H70N11O8
分子量:1238,33g/mol
MB17连接基
化学式:C49H71N9O16
分子量:1042,16g/mol
MB22连接基
化学式:C36H60N8O15
分子量:844,92g/mol
本发明优选的化合物例如
本发明还涉及通式(1a)和/或(1b)的化合物的药学上可接受的盐。本发明还涉及,化合物的溶剂化物,包括其盐和活性代谢物,以及,适当的,包括前体药物制剂的根据通式(1a)和/或(1b)的它们的互变异构体。
“药学上可接受的盐”是本发明的化合物的药学上可接受的,有机或无机酸或碱的盐。代表性的药学上可接受的盐包括,例如碱金属盐、碱土盐、铵盐、可溶于水的和不可溶于水的盐,如乙酸盐、碳酸盐、氯化物、葡萄糖酸盐、谷氨酸盐、乳酸盐、月桂酸盐、苹果酸盐或酒石酸盐。
术语“前体药物”是指药物的前体,其是当给予患者时,在变为活性药理学试剂之前必须经受由代谢过程的化学转化的化合物。示例性的根据式(1a)和/或(1b)的化合物的前体药物是酯和酰胺,优选地脂肪酸酯的烷基酯。此处前体药物制剂包含所有的由酶、代谢或任何其他方式的简单转化,包括水解、氧化或还原形成的物质。适合的前体药物含有,例如通式(1a)和/或(1b)通过可酶剪切的连接基(例如氨基甲酸酯、磷酸酯、N-葡萄糖苷或二硫基团)结合至溶解性改善物质(例如四乙二醇、糖类、甲酸或葡糖醛酸等)的物质。可以将这样的根据本发明的化合物的前体药物施加于患者,并且该前体药物可以转变为通式(1a)和/或(1b)的物质以获得期望的药理学效果。
以消旋体、它们的对映异构体的形式,和可选地以它们的非对应异构体及其所有可能的混合物的形式包含一些式(1a)和/或(1b)的化合物。
根据本发明,所有的手性C原子应当具有D-和/或L-构型;在一个化合物内的组合也应该是可能的,即一些手性C原子可以是D-并且其他可以是L-构型。
可以可选地通过已知的方法(例如Allinger,N.L.und Elliel E.L.in“Topics inStereochemistry”Vol.6,Wiley Interscience,1971)将获得的化合物分离为它们的对映异构体和/或非对映异构体。一种可能的对映异构分离方法是使用层析。
本发明还涉及含有治疗有效量的活性成分(根据本发明的式(1a)或(1b)的化合物)连同有机或无机固体或液体的,适于预期的给予,且与活性成分相互作用而没有缺点的药学上可接受的载体的药物制剂。
在本文中采用的词组“药学上可接受的”是指在合理的医学判断范围内,适合用于与患者的组织接触而没有过多的毒性、刺激、过敏反应、或其他问题或并发症,与合理的益处/风险比例相当的那些化合物、材料、组合物和/或剂型。
“患者”包括动物,如人类、猴子、奶牛、马、猫或狗。动物可以是哺乳动物如非灵长类和灵长类(例如猴子和人类)。在一个实施方式中,患者是人类。
通常,式(1a)或(1b)的化合物或其药物组合物可以口服或通过非肠道途径,通常注射或输液给予。
“非肠道给予途径”是指除肠和局部给予之外的给予模式,通常通过注射,并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心脏内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内的注射和输液。
根据本发明的化合物的剂量是通过医师基于患者特定的参数,如年龄重量、性别、疾病的严重度等确定的。剂量优选地为0.00001mg/kg至100mg/kg体重,优选地0.001至50mg/kg体重并且最优选地0.01至10mg/kg体重。
对应于给予的种类,适当地配制药剂,例如以溶液或悬浮液、简单片剂或糖衣丸、硬或软胶囊、栓剂、卵状小体(ovule)、用于注射的制剂的形式,其是根据常用的医学方法制备的。
根据本发明的化合物可以适当的地连同另外的活性物质以及与药物组合物中常用的赋形剂和载体配制,例如(取决于要生产的制剂)滑石、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、可可脂、含水和非水载体、动物或植物来源的脂肪体、石蜡衍生物、乙二醇(特别是聚乙二醇)、各种增塑剂、分散剂或乳化剂、药学上相容的气体(例如空气、氧气、二氧化碳等)、防腐剂。
为了生产液体制剂,可以使用添加剂如氯化钠溶液、乙醇、山梨醇、丙三醇、橄榄油、扁桃仁油、丙二醇或乙二醇。
当使用用于输液或注射的溶液时,它们优选地是含水溶液或悬浮液,可以在使用之前生产它们,例如由冻干制剂,其含有这样的活性物质或连同载体,如甘露醇、乳糖、葡萄糖、白蛋白等。杀菌已经制成的溶液并且适当地与赋形剂,例如与防腐剂、稳定剂、乳化剂、增溶剂、缓冲剂和/或用于调节渗透压的盐混合。可以通过使用具有,组合物可以根据其适当地冻干的较小孔径的过滤器,无菌过滤来获得杀菌作用。还可以加入少量的抗生素以确保维持无菌。
如在本文中使用的短语“有效量”或“治疗有效量”意指包含本发明的化合物或其他活性成分(其对于在动物中的至少子群体的细胞中,以适合于任何医学处理的合理的益处/风险比例,有效地产生期望的疗效)的化合物、材料、或组合物的量。对于本发明的化合物的治疗有效量意指在疾病的预防治疗中提供治疗益处的单独的,或与其他疗法结合的治疗剂的量。与本发明的化合物联合使用,该术语可以包括改善总体疗法,减少或避免疾病的症状或起因,或增强治疗效能或与另一种治疗剂的协同作用的量。
如在本文中使用的术语“治疗(treating)”或“疗法(treatment)”旨在还包括诊断、防疫、预防、治疗法(therapy)和治愈(cure)。
术语“预防(prevent)”、“预防了(preventing)”、和“预防(prevention)”是指通过给予预防或治疗剂,预防患者疾病的发作、复发、或传播。
取决于发明的式(1a)和/或(1b)化合物用作放射性显影剂还是放射性药物,将不同的放射性核素络合至螯合剂。示例性的放射性核素包括,例如89Zr、44Sc、111In、90Y、66Ga、67Ga、68Ga、177Lu、99mTc、61Cu、62Cu、64Cu、67Cu、149Tb、152Tb、155Tb、161Tb、153Gd、155Gd、157Gd、213Bi、225Ac、230U、223Ra、165Er、和Fe。根据本发明的一个方面,放射性核素是111In、90Y、68Ga、64Cu、153Gd、155Gd、213Bi、225Ac、Fe、或177Lu。
如上所述,根据式(1a)或(1b)的化合物的络合物可以含有一种或多种适合用作放射性显影剂或治疗剂,用于治疗迅速增生的细胞,例如PSMA表达的前列腺癌细胞的放射性核素。根据本发明,将它们称为“金属络合物”或“放射性药物”。
优选的成像方法是正电子发射断层成像(PET)或单光子发射计算机断层成像(SPECT)。
因此,在一个实施方式中,提供包括络合物的药物组合物,该络合物包括放射性核素和式(1a)或式(1b)的化合物、其盐、溶剂化物、立体异构体或互变异构体、以及药学上可接受的载体。
根据另一方面,提供药物组合物,其适用于体内成像和放射疗法。适合的药物组合物可以含有放射性显影剂,或足以成像的量的,具有作为元素,即放射性碘,或式(1a)和/或(1b)的化合物的放射性金属螯合复合物的放射治疗剂,连同药学上可接受的放射学介质(vehicle)。放射学介质应当适用于注射或吸入,如人血清白蛋白;含水缓冲溶液,例如三(羟基甲基)氨基甲烷(及其盐)、磷酸盐、柠檬酸盐、碳酸氢盐等;无菌水、生理盐水;以及含有氯和/或碳酸氢盐,或正常血浆的阳离子如钙、钾、钠和镁的平衡的离子溶液。
显影剂或治疗剂在放射学介质中的浓度应足以提供符合要求的成像。例如,当使用含水溶液时,剂量为约1.0至100毫居里。然而,给予患者用于成像或治疗目的实际剂量是由给予治疗的医师确定的。应当给予显影剂或治疗剂以保持在患者中约1小时至10天,尽管更长和更短的时间段是可接受的。因此,可以制备含有1至10mL的含水溶液的方便的安瓿瓶。
可以以标准方式进行成像,例如通过注射足量的成像组合物以提供足够的成像,并且然后用适合的成像或扫描机,如断层成像或伽马相机进行扫描。在某些实施方式中,成像患者中的区域的方法包括以下步骤:(i)给予患者诊断有效量的络合有放射性核素的化合物;使患者的区域暴露至扫描设备;以及(ii)获得患者的区域的图像。在某些实施方式中,成像的区域是头部或胸部。在其他实施方式中,式(1a)和/或(1b)的化合物和络合物靶向PSMA蛋白质。
因此,在一些实施方式中,提供成像组织如脾脏组织、肾脏组织、或PSMA表达的肿瘤组织的方法,包括将组织与通过将放射性核素与式(1a)和/或式(1b)的化合物接触合成的络合物接触。
本发明的化合物,或包含金属与根据式(1a)和/或(1b)的化合物的络合物,或其盐、溶剂化物、立体异构体、或互变异构体的络合物的制剂(给予患者)的量取决于医师常规使用的多个生理学因素,包括进行成像的性质、靶向用于成像或治疗的组织以及使用放射药剂成像或治疗的患者的体重和病史。
因此在另一方面中,本发明提供通过将治疗有效量的式(1a)和/或(1b)的络合至放射性核素的化合物或该络合物的药学上可接受的盐或溶剂化物给予患者来治疗患者的方法,以治疗遭受细胞增生疾病或失调的患者。具体地,使用根据本发明的化合物、药物组合物或放射药剂治疗或成像的细胞增生疾病或失调是癌症,例如前列腺癌和/或在例如肺脏、肝脏、肾脏、骨、脑、脊髓、膀胱等中的前列腺癌转移。
在实施例部分中详细描述本发明的化合物的合成。在考虑DOTA连接的PSMA抑制剂的方案2中举例说明该合成的概况。然而,本领域技术人员能够通过,例如使用另一种螯合剂修改该反应。因此,该方案不应理解为将本发明的化合物仅限于DOTA螯合剂。
方案2
通过RP-HPLC、MS、和/或NMR化学表征合成的化合物。
具有连接基区域中的结构改变的新型螯合剂连接的显影剂具有改善的肿瘤靶向性能和药代动力学。药效团呈现为三个能够与PSMA的相应侧链相互作用的羧基以及作为活性中心中的锌络合的部分的氧。除了这些必须的相互作用,发明人能够优化连接基区域中的亲脂性相互作用。
临床前的评估包括体外试验(亲和性,内化)和体内实验(μPET筛选和器官分布)。
本发明的化合物在肾脏清除和肿瘤中富集方面优于已知的参考化合物。本发明的PSMA抑制剂的结合亲和性可以受连接基改变的影响。该物质中的连接基区域中的两个环状基序和至少一个芳香族部分看起来是优选的,并且导致高亲合性的MB4和MB17化合物。在这方面,非常有希望的化合物是MB17。
因此本发明的化合物代表了,具有也由器官分布和小动物PET成像确认的最佳特性的新型的PSMA靶向探针。本发明的化合物示出了高度的PSMA特异性肿瘤吸收。此外,它们特征在于膀胱中的早期富集以及最大的肾脏吸收。在治疗用途方面,其给出本发明的化合物相比其他的PSMA抑制剂的明显的临床优势。在PET图中,本发明的化合物,特别是MB17示出了迅速的背景清除以及2小时之后肾脏中富集的显著降低,同时其进一步聚集并保留在PSMA表达的肿瘤中。使用MB17的体内治疗也首先示出了有希望的数据(参见图17a、17b和18a、18b)。
以下的实施例更详细地说明本发明,但不应解释为以任何方式将本发明仅限制于举例说明的实施方式。
实施例
实施例1:DOTA-连接的抑制剂的合成
通过固相肽合成来合成DOTA连接的PSMA抑制剂(参见方案2)。在第一步骤中,通过在5℃下3h中将在200mL的干燥CH2Cl2中的3mmol的双(叔丁基)-L-谷氨酸盐酸盐和3mL的N-乙基二异丙胺(DIPEA)加入在10mL的干燥CH2Cl2中1mmol的三光气的溶液中原位生成谷氨酰基部分的异氰酸酯。在反应之后加入0.5mmol的树脂固定的(2-氯-三苯甲基树脂)ε-烯丙氧基羰基保护的赖氨酸并在缓和搅拌下反应16h。将树脂滤除并使用在4mL CH2Cl2中的50mg四(三苯基)钯和400μL吗啉在2h中移除烯丙氧基保护基团。
根据标准的Fmoc流程进行随后的拟肽PSMA结合基序的合成。使用在最终体积4mLDMF中的2mmol的相应的Fmoc保护的酸、3.96mmol的HBTU和2mmol的N-乙基-二异丙胺进行连接基部分的随后的连接。在用3.95eq的HBTU和DIPEA活化2h后,将相对于树脂负载4eq的三(叔丁基)-DOTA(CheMatech)在最终体积3mL的DMF中反应。将产物从在2mL由三氟乙酸、三异丙基硅烷、和水(95:2.5:2.5)组成的混合物中树脂上剪切。
还通过使用HBTU活化的DOTA-NHS酯(CheMatech)或DOTA-TFP酯连接螯合剂(MierW.,Hoffend J.,Kramer S.,Schuhmacher J.,Hull W.E.,Eisenhut M.,Haberkorn U.,Bioconjugate Chem.2005,16:237-240)。
使用具有线性A-B梯度(6分钟内从0%B至100%B)的反相高效液相色谱(RP-HPLC;Chromolith RP-18e,100×4.6mm;Merck,Darmstadt,Germany)以4mL/min(分析)或6mL/min(纯化)的流速进行合成分子的分析。溶剂A由0.1%的TFA水溶液组成并且溶剂B是在CH3CN中的0.1%的TFA。HPLC系统(L6200A;Merck-Hitachi,Darmstadt,Germany)配备有UV和伽马探测器(gamma detector)(Bioscan;Washington,USA)。在214nm下测量UV吸光度。用MALDI-MS Daltonics Microflex系统(Bruker Daltonics,Bremen,Germany)进行质谱分析。
实施例2:放射性标记
通常,将1.5nmol实施例1的合成化合物(溶解在0.1M的pH7.5的HEPES缓冲液中)以100μL的体积加入10μL的2.1M的HEPES溶液和40μL的[68Ga]Ga3+洗脱液(40MBq)的混合物。将标记溶液的pH调节至4.5。
化合物的放射性标记导致在95℃下15分钟之后>97%的放射性化学产率,并且由RP-HPLC和TLC测定。使用Sep-Pak C18夹座(cartridge)完成随后的纯化。
实施例3:化合物MB4和MB17的合成
通过在0℃下在4h中,将在200mL干燥CH2Cl2中3mmol的双(叔丁基)L-谷氨酸盐酸盐和1.5mL的N-乙基二异丙胺(DIPEA)的混合物加入在10mL干燥CH2Cl2中1mmol三光气的溶液,原位生成谷氨酰基部分的异氰酸酯。在将反应混合物在25℃下搅拌1h之后,加入在4mL DCM中的0.5mmol的树脂固定的(2-氯-三苯甲基树脂)ε-烯丙氧基羰基保护的赖氨酸并在缓和搅拌下反应16h。将树脂滤除并使用在4mL CH2Cl2中的30mg四(三苯基)钯(0)和400μL吗啉在3h中移除烯丙氧基保护基团。随后三次连接4-(Fmoc-氨甲基)苯甲酸(MB4的情况)或Fmoc-3-(2-萘基)-L-甘氨酸和反式-4-(Fmoc-氨甲基)环己烷羧酸(MB17的情况),分别是使用在4mL最终体积的DMF中的2mmol的Fmoc保护的酸、1.96mmol的HBTU和2mmol的N-乙基二异丙胺逐步进行的。在用3.95eq的HBTU和DIPEA活化2h后,将相对于树脂负载4eq的三(叔丁基)-DOTA(Chematech)在最终体积3mL的DMF中反应3h。将产物从在2mL由三氟乙酸、三异丙基硅烷、和水(95:2.5:2.5)组成的混合物中的树脂上剪切。使用RP-HPLC进行纯化并通过分析型RP-HPLC和MALDI-MS分析纯化的产物。
为制备作为MB17(L)的立体异构体的MB-17D,基于Fmoc-3(2-萘基)-D-甘氨酸合成。如果不另外说明,在本说明书中MB-17意指L-立体异构体。
实施例4:连接至各种螯合剂
通过固相合成将螯合剂(DOTA、NOTA、NODAGA、DTPA、CHX-DTPA、PCTA、Do3A)连接至MB17连接基。通常,将13μmol的与PSMA结合基序连接的树脂在带有过滤器的注射器中用DCM溶胀。在用DMF洗涤树脂5次之后,将其用在DMF中的20%的哌啶温育5分钟2次以将N-末端去保护。随后用DMF另外洗涤5次。
将1.5和4当量之间的螯合剂(取决于螯合剂)、0.98×n螯合剂HATU(如果需要的话)和10当量的DIPEA溶解在500μl的DMF中,将溶液吸入含有树脂的注射器中并温育过夜。然后,将树脂用DMF、甲醇、DCM和二乙醚各洗涤5次并在真空中干燥。
使用测试分离物以检查反应的状态。这是通过将少量树脂用DCM洗入过滤器尖端(filter tip)并加入含有95%的TFA、2.5%的水和2.5%的TIPS的100μl的分离溶液实现的。在温育30分钟之后,将溶液吸移入冰冷的二乙醚中并离心。将二乙醚倾析并将残余的颗粒溶解在35μl的ACN:H2O(1:1)中,并通过HPLC(5分钟内在水中0-100%ACN)和LC/MS分析。
如果获得期望的产物,将完全的肽(complete peptide)与树脂分离。将干燥的树脂用500μl的分离溶液(95%TFA、25%H2O、2.5%TIPS)温育2小时。将得到的溶液与用冰冷的二乙醚混合并离心(4000min-1,5分钟)。弃去上层清液,加入新的二乙醚并剧烈摇晃容器以再悬浮颗粒。再次,将溶液离心(4000min-1,5分钟)并弃去得到的上层清液。然后真空干燥颗粒并最终再悬浮在1mL的ACN:H2O(1:1)中。
通过制备型HPLC实现纯化,通过分析型HPLC(5分钟内在水中0-100%的ACN)和LC/MS分析峰并将含有产物的那些汇聚(pool)并冻干。
实施例5:放射性标记
177Lu标记
177Lu(大约100MBq)与200μl的含有Chelex的0.4M醋酸钠缓冲液(pH=5)混合。将10μl的在水中的10%DMSO中的该化合物的1mM溶液、2μl的抗坏血酸的饱和溶液和40μl的含有177Lu的溶液混合并加热至95℃ 10分钟。通过放射HPLC(5分钟内,在水中0-100%ACN,Monolith柱)检查标记。
68Ga标记
对于PET扫描,用68Ga标记CHX-DTPA。用0.6M的HCl从68Ge/68Ga生成器中洗脱1ml的68Ga。加入298μl的NaOAc缓冲液和1μl的在DMSO中的10mM CHX-DTPA溶液并温育5分钟。然后使用SOLA夹座纯化产物。使用0.9%的NaCl溶液完成洗涤并使用乙醇洗脱。然后将乙醇蒸发并将剩余的产物溶解在100μl的0.9%的NaCl溶液和10μl的磷酸盐缓冲液中。
实施例6:IC50值的测定
在室温下用100μl的PBS,用每孔1%的BSA温育滤板MultiScreenHTS-DV 30分钟。在移除PBS/BSA之后将在50μl的Opti-MEM中105LNCaP细胞的溶液施加于每个孔。将在300μl的Opti-MEM中不同浓度的化合物(导致每孔中0、0.5、1、2.5、5、10、25、50、100、500、1000和5000nM浓度)与3μl的在Opti-MEM中的150nM的125I标记的MIP-1466的溶液混合。将50μl得到的溶液加入每个孔中,将每个浓度一式四份地(in quadruples)吸移。现在每个孔含有0.75nM浓度的放射性标记的配体,以及上述浓度的竞争性未标记配体。然后将板在室温下在摇床上温育45分钟。
温育之后,将细胞用100μl冰冷的PBS洗涤2次并用200μl冰冷的PBS洗涤1次。最终,收集过滤器并用伽马计数器(gamma counter)测量剩余的放射性。每个管测量5分钟。
用Graphpad Prism评估由伽马计数器测量的数据以得到针对放射性标记的MIP-1095的抑制浓度50(IC50)。
连接物 IC<sub>50</sub>[nM]
MB17-DOTA 0.13±0.08
MB17-NOTA 0.14±0.08
MB17-DTPA 0.12±0.05
MB17-CHX-DTPA 0.06±0.04
MB17-PCTA 0.10±0.06
MB17-DO3A 0.10±0.05
MB17-NODAGA 0.09±0.08
实施例7:使用CHX-DTPA-MB17的μPET成像
在注射入小鼠之前,将含有纯化的68Ga-CHX-DTPA连接的PSMA抑制剂的溶液无菌过滤。将100μl的该溶液吸入注射器并且然后注射入BALB/c裸鼠的LNCaP异种移植,静脉内注入尾部静脉。用Siemens InveonPET记录PET扫描140分钟(图15)。
实施例8:竞争性结合亲合性的测定
为比较新型化合物的系列,使用PSMA表达的细胞系LNCaP分析竞争性结合亲合性和特异性内化。为确定特异性细胞吸收,用2-(膦酰基甲基)-戊二酸(PMPA)阻断细胞。还通过基于酶的NAALADase试验研究抑制效力。
细胞培养
对于结合研究和体内实验,将LNCaP细胞(人类前列腺腺癌的转移性病灶,ATCCCRL-1740)在补充有10%胎牛血清和Glutamax(PAA,奥地利)的RPMI介质中培养。在细胞培养过程中,细胞在37℃下在具有加湿空气的,用5%的CO2平衡的恒温箱器中生长。使用胰蛋白酶-乙二胺四乙酸(胰蛋白酶-EDTA;0.25%胰蛋白酶,0.02%EDTA,均来自PAA,奥地利)收获细胞并用PBS洗涤。
细胞结合和内化
如先前描述的进行竞争性细胞结合试验和内化(internalization)实验(Eder etal.2012)。简要地,将相应的细胞(105每孔)用放射性配体(68Ga标记的[Glu-脲-Lys(Ahx)]2-HBED-CC)在12种不同浓度的分析物(0-5000nM,100μL/孔)的存在下温育(Schafer etal.,2012)。温育后,使用多滤网真空歧管(multiscreen vacuum manifold)(Millipore,Billerica,MA)进行洗涤。使用伽马计数器(Packard Cobra II,GMI,Minnesota,USA)测量细胞结合放射性。通过使用非线性回归算法(Graphpad软件)拟合数据来计算50%抑制浓度(IC50)。实验进行三次。
为测定特异性细胞吸收和内化,在温育之前24h将105细胞种在聚-L-赖氨酸涂覆的24孔细胞培养板中。洗涤后,将细胞用25nM的放射性标记化合物分别在37℃和4℃下温育45分钟。通过用2-(膦酰基甲基)戊二酸(500μΜ最终浓度,PMPA,Axxora,Loerrach,Germany)的竞争性阻断测定特异性细胞吸收。通过用1mL的冰冷的PBS洗涤4次来终止细胞吸收。随后将细胞用在PBS中0.5mL的甘氨酸-HCl(50mM,pH=2.8)温育5分钟两次以去除表面结合的部分。用1mL的用冰冷的PBS洗涤细胞并使用0.3N NaOH(0.5mL)溶解。在伽马计数器中测量表面结合的和内化的部分。细胞吸收计算为结合至106细胞的初始加入的放射性的百分比[%ID/106细胞]。
Naaladase试验
将重组体人类PSMA(rhPSMA,R&D systems,Wiesbaden,Germany)在试验缓冲液(50mM HEPES,0.1M NaCl,pH 7.5)中稀释至0.4μg/mL。在最终体积125μL的试验缓冲液中,以0.05nM至1000nM范围的浓度将底物Ac-Asp-Glu(Sigma,Taufkirchen,Germany,40μΜ最终浓度)与natGa标记的分析物混合。将混合物与125μL的rhPSMA溶液(0.4μg/mL)结合并在37℃下温育一小时。通过在95℃下加热5分钟来停止反应。将250μL的15mM的邻-邻苯二甲醛(Sigma,Taufkirchen,Germany)溶液加入所有的小管中并在室温下温育10分钟。最后,将200μL的反应溶液加载在F16Black Maxisorp Plate(Nunc,Langenselbold,Germany)上并分别在330nm和450nm的激发和发射波长下使用酶标仪(microplatereader)(DTX-880,Beckman Coulter,Krefeld,Germany)读数。通过Graphpad(Graphpad Software,California,USA)的一点-总结合回归算法分析数据。
生物分布
将7至8周大的雄性BALB/c nu/nu小鼠(Charles River Laboratories)用5×106细胞的LNCaP(在50%基质胶中,Becton Dickinson,Heidelberg,Germany)皮下接种入右侧躯干。使得肿瘤生长直至约1cm3的尺寸。将放射性标记化合物注射入尾部静脉(约1MBq/鼠;0.06nmol)。在注射后1h杀死动物。将感兴趣的器官解剖、吸干(blot dry)、并称重。使用伽马计数器测量放射性并计算为%ID/g。
MicroPET
将10-25MBq的放射性标记化合物以0.15mL的体积(~0.5nmol)通过侧尾部静脉注射入带有LNCaP肿瘤异种移植的小鼠,用于microPET研究。将麻醉的动物(2%七氟醚(sevoflurane),Abbott,Wiesbaden,Germany)以卧姿(prone position)放入Inveon小动物PET扫描仪(Siemens,Knoxville,Tenn,USA)以进行动态microPET扫描和20分钟静态扫描,参见图1、3、5-14。
表A
本实施例示出,PSMA抑制剂的结合亲和度可以受连接基改变的影响。该物质中的连接基区域中的两个环状基序和至少一个芳香族部分看起来是优选的,并且导致高亲合性的MB4和MB17化合物。这些新型的变体示出了对LNCaP细胞系的低纳摩尔亲合性,并且具体地在37℃下内化最多达48%ID/106细胞。先前的研究示出,除结合亲合性外,PSMA靶向探针的内化性能也是高度重要的,并且高内化速率对于高体内肿瘤吸收和存留是必要的。因此MB17代表了,具有也由器官分布和小动物PET成像确认的最佳特性的新型的PSMA靶向探针。MB17示出了较高的PSMA特异性肿瘤吸收(图2)。此外MB17的动态PET成像(图2)示出了膀胱中的早期富集并且最大的肾脏吸收(时间-活性曲线的最高点)早在放射示踪物注射后15分钟,且基本上在20分钟后已经减少。在治疗用途方面,其给出MB17相比其他的PSMA抑制剂的明显的临床优势。在PET图(图1)中,MB17示出了迅速的背景清除以及2小时之后肾脏中富集的显著降低,同时其进一步聚集并保留在PSMA表达的肿瘤中。
此外,177Lu的器官分布(图4)示出,24小时之后较高的初始肾脏吸收接近完全洗出(2.13±1.36%ID/g),而肿瘤吸收保持较高并且甚至增加(10.58±4.50%ID/g)。其他器官,如肝脏(0.08±0.03%ID/g)、肺脏(0.11±0.13%ID/g)和脾脏(0.13±0.05%ID/g)示出了非常低的吸收。有利的药代动力学导致24小时之后极高的肿瘤与背景比率(肿瘤/血液:1058;肿瘤/肌肉:529)。
表A清楚地确定,分子的连接基区域的化学改变影响了生物学性质,例如亲合性和内化疗效。MB17和MB4示出了最有希望的细胞结合性。
实施例9:关于MB17的临床数据
使用用Ga-68标记的放射示踪物MB17进行PET/CT成像(参见图17a、17b)。
用于产生放射药剂的68Ge/68Ga生成器购自IDB-Holland BV(Baarle-Nassau,TheNetherlands)。用于放射合成的,包括GMP兼容等级的前体的一次性卡座试剂盒和化学品获得自ABX advanced biochemical compounds(Radeberg,Germany)。配备有ChromolithPerformance RP-18e柱(100×4.6mm,Merck)和Nal放射探测器(Raytest)的Ultimate3000HPLC系统(Dionex)(乙腈(A)、水+0.1%TFA(B);梯度:0.5分钟95%B、10.0分钟80%A,流速:2mL/分钟)用于测定放射化学品纯度。使用6850系列气相色谱仪(AgilentTechnologies)测定残留溶剂。用-PTS设备(Charles River)进行内毒素测试。
将2μg的MB17溶解在1.5M的pH 4.5的乙酸盐缓冲液(1mL)和1M的抗坏血酸(10μL)中并移入反应容器。用10mL的0.6M HCl洗脱68Ge/68Ga生成器并用9mL的超纯水稀释洗出液。然后将混合物移至阳离子卡座(cartridge)(Macherey-Nagel PS-H+,尺寸M)并用5M的NaCl溶液(1.2mL)洗脱入预热的反应容器中(100℃)。加热反应混合物10分钟。然后将粗反应混合物移出反应容器并移至预处理的(10mL EtOH/10mL超纯水)C18卡座(Waters Sep-Paklight)。使用9mL超纯水冲洗反应容器并经过C18卡座。用另外5mL的超纯水洗涤C18卡座。用2mL的EtOH/H2O(v:v 1:1)从C18卡座洗脱最终产物,无菌过滤(Millipore Cathivex-GV,0.22μm)并用10mL的pH 7.4的磷酸盐缓冲盐水(PBS)溶液稀释(根据欧洲药典8.0(4005000))。将68Ga-MB17络合物溶液通过静脉推注(intravenous bolus)施加于患者。
实施例10:使用177Lu标记的MB17的人类治疗
用Lu-177放射性标记PSMA配体MB17,用于治疗。177LuCl3获得自Perkin Elmer(4GBq,NEZ307D,0,04M HCl)。将80纳摩尔的MB17溶解在补充有5μL的20%抗坏血酸的400μL醋酸钠缓冲液中。将溶液移至177LuCl3,并在95℃下温育10分钟。最后加入2mL 0.9%的NaCl。为了质量控制进行ITLC和放射HPLC。
177Lu标记的MB17通过静脉推注(5mL,30秒内,缓慢)施加于患者。该静脉内施加伴有注射之前0.5h开始的4.5h的0.9%NaCl的输液。参考图18a、18b。

Claims (30)

1.一种下式的化合物:
2.根据权利要求1所述的化合物,其中所述化合物是冻干的。
3.根据权利要求1所述的化合物,还包括药学上可接受的载体,其中所述化合物和所述药学上可接受的载体是冻干的。
4.根据权利要求3所述的化合物,其中所述药学上可接受的载体选自甘露醇、乳糖、葡萄糖、和白蛋白。
5.一种化合物
和/或化合物
6.一种下式的化合物:
其中R’是下式的螯合剂:
放射性核素络合至所述螯合剂。
7.根据权利要求6所述的化合物,其中所述放射性核素选自89Zr、44Sc、111In、90Y、68Ga、177Lu、99mTc、64Cu、67Cu、153Gd、155Gd、157Gd、213Bi、和225Ac。
8.根据权利要求7所述的化合物,其中所述放射性核素选自64Cu、67Cu、68Ga、177Lu、和225Ac。
9.根据权利要求7所述的化合物,其中所述放射性核素是68Ga。
10.根据权利要求7所述的化合物,其中所述放射性核素是177Lu。
11.根据权利要求7所述的化合物,其中所述放射性核素是225Ac。
12.根据权利要求7所述的化合物,其中所述放射性核素选自64Cu和67Cu。
13.根据权利要求6所述的化合物,其中所述放射性核素选自64Cu、67Cu、68Ga、177Lu、和225Ac。
14.根据权利要求6所述的化合物,其中所述放射性核素是68Ga。
15.根据权利要求6所述的化合物,其中所述放射性核素是177Lu。
16.根据权利要求6所述的化合物,其中所述放射性核素是225Ac。
17.根据权利要求6所述的化合物,其中所述放射性核素选自64Cu和67Cu。
18.一种组合物,包含:
(1)下式的化合物:
其中R’是下式的螯合剂:
放射性核素络合至所述螯合剂;以及
(2)药学上可接受的载体。
19.根据权利要求18所述的组合物,其中所述放射性核素选自89Zr、44Sc、111In、90Y、68Ga、177Lu、99mTc、64Cu、67Cu、153Gd、155Gd、157Gd、213Bi、和225Ac;且其中所述组合物进一步包含赋形剂,所述赋形剂与所述药学上可接受的载体不同。
20.根据权利要求19所述的组合物,其中所述放射性核素选自64Cu、67Cu、68Ga、177Lu、和225Ac。
21.根据权利要求19所述的组合物,其中所述放射性核素是68Ga。
22.根据权利要求19所述的组合物,其中所述放射性核素是177Lu。
23.根据权利要求19所述的组合物,其中所述放射性核素是225Ac。
24.根据权利要求19所述的组合物,其中所述放射性核素选自64Cu和67Cu。
25.根据权利要求19所述的组合物,其中所述组合物是缓冲溶液。
26.根据权利要求18所述的组合物,其中所述放射性核素选自64Cu、67Cu、68Ga、177Lu、和225Ac。
27.根据权利要求18所述的组合物,其中所述放射性核素是68Ga。
28.根据权利要求18所述的组合物,其中所述放射性核素是177Lu。
29.根据权利要求18所述的组合物,其中所述放射性核素是225Ac。
30.根据权利要求18所述的组合物,其中所述放射性核素选自64Cu和67Cu。
CN201810815832.7A 2013-10-18 2014-10-17 前列腺特异性膜抗原(psma)的标记的抑制剂及其用途 Active CN109053616B (zh)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP13004991.9 2013-10-18
EP20130004991 EP2862857A1 (en) 2013-10-18 2013-10-18 Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
EP14175612 2014-07-03
EP14175612.2 2014-07-03
CN201480056250.5A CN105636924B (zh) 2013-10-18 2014-10-17 前列腺特异性膜抗原(psma)的标记的抑制剂,它们作为显影剂和用于治疗前列腺癌的药剂的用途
PCT/EP2014/002808 WO2015055318A1 (en) 2013-10-18 2014-10-17 Labeled inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201480056250.5A Division CN105636924B (zh) 2013-10-18 2014-10-17 前列腺特异性膜抗原(psma)的标记的抑制剂,它们作为显影剂和用于治疗前列腺癌的药剂的用途

Publications (2)

Publication Number Publication Date
CN109053616A true CN109053616A (zh) 2018-12-21
CN109053616B CN109053616B (zh) 2022-08-19

Family

ID=51903864

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201810815832.7A Active CN109053616B (zh) 2013-10-18 2014-10-17 前列腺特异性膜抗原(psma)的标记的抑制剂及其用途
CN201480056250.5A Active CN105636924B (zh) 2013-10-18 2014-10-17 前列腺特异性膜抗原(psma)的标记的抑制剂,它们作为显影剂和用于治疗前列腺癌的药剂的用途

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201480056250.5A Active CN105636924B (zh) 2013-10-18 2014-10-17 前列腺特异性膜抗原(psma)的标记的抑制剂,它们作为显影剂和用于治疗前列腺癌的药剂的用途

Country Status (30)

Country Link
US (7) US20160228587A1 (zh)
EP (6) EP3038996B1 (zh)
JP (7) JP2016535013A (zh)
KR (3) KR101947053B1 (zh)
CN (2) CN109053616B (zh)
AU (3) AU2014336638C1 (zh)
CA (1) CA2924360C (zh)
CL (1) CL2016000883A1 (zh)
DE (2) DE202014011600U1 (zh)
DK (1) DK4095130T3 (zh)
EA (1) EA037778B1 (zh)
FI (1) FI4095130T3 (zh)
GE (4) GEP20237496B (zh)
HK (1) HK1221711A1 (zh)
HR (1) HRP20240398T1 (zh)
IL (2) IL245113B (zh)
LT (1) LT4095130T (zh)
MX (3) MX2016005013A (zh)
MY (2) MY188934A (zh)
NZ (1) NZ718812A (zh)
PE (2) PE20211760A1 (zh)
PH (1) PH12016500656A1 (zh)
PL (1) PL4095130T3 (zh)
RS (1) RS65324B1 (zh)
SA (1) SA516370842B1 (zh)
SG (1) SG11201602249RA (zh)
SI (1) SI4095130T1 (zh)
TN (1) TN2016000137A1 (zh)
WO (1) WO2015055318A1 (zh)
ZA (2) ZA201603380B (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112062695A (zh) * 2020-08-14 2020-12-11 北京大学第一医院 一种前列腺特异性膜抗原靶向抑制剂及应用和探针
CN113372285A (zh) * 2021-05-28 2021-09-10 西南医科大学附属医院 前列腺特异性膜抗原抑制剂、其放射性核素标记物及制法和应用
CN114874122A (zh) * 2022-05-31 2022-08-09 南京航空航天大学 一种新的小分子抑制剂及其制备方法和应用

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI2097111T1 (sl) 2006-11-08 2016-02-29 Molecular Insight Pharmaceuticals, Inc. Heterodimeri glutaminske kisline
EP3858347A3 (en) 2007-08-17 2021-12-01 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US9951324B2 (en) 2010-02-25 2018-04-24 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
MX2015006109A (es) 2012-11-15 2016-02-05 Endocyte Inc Conjugados para el tratamiento de enfermedades causadas por celulas que expresan psma.
RS65324B1 (sr) * 2013-10-18 2024-04-30 Novartis Ag Obeleženi inhibitori membranskog antigena specifičnog za prostatu (psma), njihova upotreba kao agenasa za snimanje i farmaceutskih agenasa za lečenje karcinoma prostate
US10188759B2 (en) 2015-01-07 2019-01-29 Endocyte, Inc. Conjugates for imaging
BR112018005899A2 (pt) * 2015-09-30 2018-10-16 Deutsches Krebsforschungszentrum composto e composição farmacêutica
US10688200B2 (en) 2015-12-31 2020-06-23 Five Eleven Pharma Inc. Urea-based prostate specific membrane antigen (PSMA) inhibitors for imaging and therapy
AU2017238181B2 (en) * 2016-03-22 2021-05-27 The Johns Hopkins University Prostate-specific membrane antigen targeted high-affinity agents for endoradiotherapy of prostate cancer
WO2018108287A1 (en) * 2016-12-15 2018-06-21 The European Atomic Energy Community (Euratom), Represented By The European Commission Treatment of pmsa expressing cancers
JP7396897B2 (ja) * 2017-04-05 2023-12-12 コーネル ユニバーシティー 画像化および抗腫瘍治療において有用な調整可能な薬物動態を有する三官能性構築物
US11491247B2 (en) 2017-05-02 2022-11-08 Cornell University Methods and reagents for tumor targeting with greater efficacy and less toxicity
US10093741B1 (en) 2017-05-05 2018-10-09 Fusion Pharmaceuticals Inc. IGF-1R monoclonal antibodies and uses thereof
CA3062553C (en) 2017-05-05 2024-02-06 Fusion Pharmaceuticals Inc. Pharmacokinetic enhancements of bifunctional chelates and uses thereof
AU2018261890A1 (en) 2017-05-05 2019-11-28 Centre For Probe Development And Commercialization IGF-1R monoclonal antibodies and uses thereof
WO2018233798A1 (en) 2017-06-20 2018-12-27 ITM Isotopen Technologien München AG NOVEL PSMA BINDING AGENTS AND USE THEREOF
US11629201B2 (en) * 2017-05-24 2023-04-18 ITM Isotope Technologies Munich SE PSMA-binding agents and uses thereof
US11478558B2 (en) 2017-05-30 2022-10-25 The Johns Hopkins University Prostate-specific membrane antigen targeted high-affinity agents for endoradiotherapy of prostate cancer
JP2020525408A (ja) 2017-06-09 2020-08-27 ジェモアブ モノクローナルズ ゲゼルシャフト ミット ベシュレンクテル ハフツングGEMoaB Monoclonals GmbH 共通キメラ抗原受容体発現免疫細胞のためのターゲティングモジュールならびに癌、感染および自己免疫障害の処置における使用
CN207184660U (zh) 2017-09-15 2018-04-03 南昌欧菲光电技术有限公司 摄像模组
CN109510921A (zh) 2017-09-15 2019-03-22 南昌欧菲光电技术有限公司 摄像模组
CN109510925A (zh) 2017-09-15 2019-03-22 南昌欧菲光电技术有限公司 摄像模组
KR20200100043A (ko) * 2017-10-22 2020-08-25 프로빈셜 헬스 서비시즈 오쏘리티 전립선 특이적 막 항원-발현 암의 진단 또는 치료를 위한 신규한 라디오메탈-결합 화합물
WO2019092242A1 (en) * 2017-11-13 2019-05-16 Deutsches Krebsforschungszentrum A double-labeled probe for molecular imaging and use thereof
EP3713606A1 (en) 2017-11-21 2020-09-30 Deutsches Krebsforschungszentrum A double-labeled probe for molecular imaging and use thereof
RS63279B1 (sr) * 2017-12-11 2022-06-30 Univ Muenchen Tech Psma ligandi za snimanje i endoradioterapiju
US10377778B2 (en) * 2017-12-13 2019-08-13 Sciencons AS Lead and thorium compounds
CN112020497A (zh) * 2018-02-06 2020-12-01 约翰霍普金斯大学 用于癌症放射治疗的psma靶向的放射性卤化尿素-聚氨基羧酸盐
MX2018003175A (es) * 2018-03-14 2019-09-16 Instituto Nac De Investigaciones Nucleares 177lu-dota-hynic-ipsma como un radiofarmaco terapeutico dirigido al antigeno prostatico especifico de membrana.
KR102156385B1 (ko) 2018-03-30 2020-09-15 (주)퓨쳐켐 전립선암 진단 및 치료를 위한 psma-표적 방사성의약품
CA3097381A1 (en) * 2018-04-17 2019-10-24 Endocyte, Inc. Methods of treating cancer
JP7429688B2 (ja) * 2018-09-21 2024-02-08 エンドサイト・インコーポレイテッド シールド剤およびそれらの使用
CN113164631A (zh) * 2018-09-21 2021-07-23 恩多塞特公司 治疗癌症的方法
WO2020065045A1 (en) 2018-09-28 2020-04-02 Universität Heidelberg Labeled inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of psma-expressing cancers
DE102018126558A1 (de) 2018-10-24 2020-04-30 Helmholtz-Zentrum Dresden - Rossendorf E.V. Markierungsvorläufer mit Quadratsäure-Kopplung
WO2020108753A1 (en) 2018-11-28 2020-06-04 ITM Isotopen Technologien München AG Novel tumor antigen binding agents and uses thereof
KR20210110834A (ko) * 2018-12-18 2021-09-09 프로빈셜 헬스 서비시즈 오쏘리티 이중 방식의 18f-표지된 테라노스틱 화합물 및 그 용도
JP2022520799A (ja) 2019-02-14 2022-04-01 ルプレヒト-カールス-ウニベルジテート ハイデルベルク 改善された組織特異性を有する前立腺特異的膜抗原(psma)リガンド
WO2020165409A1 (en) 2019-02-14 2020-08-20 Deutsches Krebsforschungszentrum Prostate specific membrane antigen (psma) ligands comprising an amylase cleavable linker
US11396535B2 (en) 2019-03-01 2022-07-26 Provincial Health Services Authority Cyclic peptide analogs of melanocortin and amanitin and methods of making such
PL239934B1 (pl) 2019-04-12 2022-01-31 Narodowe Centrum Badan Jadrowych Osrodek Radioizotopow Polatom Pochodne inhibitorów PSMA do znakowania ⁹⁹ᵐTc poprzez HYNIC, zestaw radiofarmaceutyczny, preparat radiofarmaceutyczny oraz ich zastosowanie w diagnostyce raka prostaty
CA3136979A1 (en) * 2019-04-17 2020-10-22 Provincial Health Services Authority Radiolabelled compounds for diagnosis or treatment of prostate-spe cific membrane antigen-expressing cancer
EP3972627A4 (en) * 2019-05-20 2023-06-21 Endocyte, Inc. METHODS FOR PRODUCTION OF PSMA CONJUGATES
JP2022537773A (ja) 2019-06-21 2022-08-29 プロビンシャル・ヘルス・サービシーズ・オーソリティ 前立腺特異的膜抗原を標的とする放射性標識化合物
AU2020299974A1 (en) * 2019-07-02 2022-01-27 Advanced Accelerator Applications (Italy) Srl Prostate specific membrane antigen (PSMA) ligands and uses thereof
AR119479A1 (es) 2019-07-25 2021-12-22 Bayer As Radiofármacos dirigidos para diagnóstico y tratamiento de cáncer
DE102019135564B4 (de) 2019-12-20 2022-05-19 Johannes-Gutenberg-Universität Mainz Verbindung für Smart-Drug-Delivery und pharmazeutisches Kit für duale nuklearmedizinisch-cytotoxische Theranostik
WO2021202376A1 (en) 2020-03-30 2021-10-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method for blocking uptake of prostate-specific membrane antigen (psma)-targeted radionuclides by exocrine organs
KR20230027004A (ko) * 2020-05-06 2023-02-27 코넬 유니버시티 구리-함유 테라그노스틱 화합물 및 사용 방법
EP3919082A1 (en) * 2020-06-04 2021-12-08 Rigshospitalet Psma targeting urea-based ligands for prostate cancer radiotherapy and imaging
CA3185565A1 (en) 2020-07-13 2022-01-20 Joe Mccann Radiopharmaceutical and methods
US11129912B1 (en) 2020-07-13 2021-09-28 POINT Biopharma Inc. Radiopharmaceutical and methods
US20230338587A1 (en) 2020-08-31 2023-10-26 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022043557A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
CN112321673B (zh) * 2020-11-04 2022-09-20 北京市肿瘤防治研究所 一种前列腺特异性膜抗原靶向抑制剂及应用和探针
WO2022096103A1 (en) 2020-11-05 2022-05-12 ITM Isotopen Technologien München AG Combination of para-aminohippuric acid (pah) and radiolabeled complexes for treating cancer
WO2022106633A1 (en) * 2020-11-19 2022-05-27 Novartis Ag Synthesis of prostate specific membrane antigen (psma) ligands
WO2022111800A1 (en) 2020-11-25 2022-06-02 Itm Solucin Gmbh Stable formulations for radionuclide complexes
CN114685599A (zh) * 2020-12-30 2022-07-01 南京江原安迪科正电子研究发展有限公司 一种psma靶向抑制剂及放射性核素标记的psma靶向抑制剂、制备方法和用途
DE102021101216A1 (de) 2021-01-21 2022-07-21 Johannes Gutenberg-Universität Mainz, Körperschaft des öffentlichen Rechts Markierungsvorläufer und Radiotracer zur nuklearmedizinischen Diagnose und Therapie von Prostatakrebs induzierten Knochenmetastasen
CN112851637B (zh) * 2021-01-22 2022-11-18 北京瑞达福明科技有限公司 一种psma抑制剂、化合物及其制备方法与用途
CN112898270B (zh) * 2021-01-22 2023-03-21 周彤 一种诊疗一体的psma抑制剂、化合物及其制备方法与用途
CN116745323A (zh) 2021-01-22 2023-09-12 拜耳股份有限公司 Lrrc15抗体及其缀合物
EP4288116A1 (en) 2021-02-08 2023-12-13 Stichting Radboud universitair medisch centrum Psma-targeting ligands for multimodal applications
WO2022226326A1 (en) * 2021-04-23 2022-10-27 Wisconsin Alumni Research Foundation Psma-targeting ligands with optimal properties for imaging and therapy
IL308731A (en) * 2021-05-21 2024-01-01 Northstar Medical Tech Llc UROKINASE PLASMINOGEN RECEPTOR TARGETED RADIOPHARMACEUTICALS
DE102021114711B4 (de) 2021-06-08 2023-11-02 Medianezia GmbH Trislinker-konjugierte dimere Markierungsvorläufer und daraus abgeleitete Radiotracer
AU2022320317A1 (en) 2021-07-30 2024-02-15 Osaka University Radiolabeled compound and use thereof
CN117615795A (zh) * 2021-09-01 2024-02-27 天津恒瑞医药有限公司 前列腺特异性膜抗原的抑制剂及其医药用途
CN115745903A (zh) * 2021-09-03 2023-03-07 晶核生物医药科技(南京)有限公司 一种肽脲素衍生物、含其的药物组合物及其应用
CN114014843B (zh) * 2021-11-17 2022-09-20 北京大学第一医院 一种psma靶向核素/荧光双模态配体和分子探针与应用
WO2023143612A1 (zh) * 2022-01-30 2023-08-03 晶核生物医药科技(南京)有限公司 一种肽脲素衍生物、含其的药物组合物及其应用
WO2023208928A1 (en) 2022-04-26 2023-11-02 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Dosage of psma-ligands for fluorescence based detection of cancerous tissue
WO2023222680A1 (en) 2022-05-17 2023-11-23 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Prostate specific membrane antigen (psma) ligands
WO2023222679A1 (en) 2022-05-17 2023-11-23 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Prostate specific membrane antigen (psma) ligands
WO2023222682A1 (en) 2022-05-17 2023-11-23 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Prostate specific membrane antigen (psma) ligands
WO2023222681A1 (en) 2022-05-17 2023-11-23 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Prostate specific membrane antigen (psma) ligands with improved renal clearance
WO2023240135A2 (en) 2022-06-07 2023-12-14 Actinium Pharmaceuticals, Inc. Bifunctional chelators and conjugates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013022797A1 (en) * 2011-08-05 2013-02-14 Molecular Insight Pharmaceuticals Radiolabeled prostate specific membrane antigen inhibitors

Family Cites Families (342)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713249A (en) 1981-11-12 1987-12-15 Schroeder Ulf Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof
EP0116208B1 (en) 1982-12-07 1988-03-30 Kyowa Hakko Kogyo Co., Ltd. Mitomycin analogues
JPS60255789A (ja) 1984-06-01 1985-12-17 Kyowa Hakko Kogyo Co Ltd マイトマイシン誘導体,その製造法および抗腫瘍剤
US5266333A (en) 1985-03-06 1993-11-30 American Cyanamid Company Water dispersible and water soluble carbohydrate polymer compositions for parenteral administration of growth hormone
EP0280741B1 (en) 1986-08-29 1994-12-07 Kyowa Hakko Kogyo Kabushiki Kaisha Mitomycin derivatives
USH806H (en) 1987-07-16 1990-08-07 Fmc Corporation Herbicidal clomazone compositions and methods of use tolerant to corn and other crops
WO1991007418A1 (en) 1989-11-13 1991-05-30 Xoma Corporation Chimeric mouse-human a10 antibody with specificity to a human tumor cell antigen
US5627165A (en) 1990-06-13 1997-05-06 Drug Innovation & Design, Inc. Phosphorous prodrugs and therapeutic delivery systems using same
AU653565B2 (en) 1990-12-21 1994-10-06 Nikken Corporation Raw sewage disposal apparatus and prefab for accomodating the same
US6342491B1 (en) 1991-05-21 2002-01-29 American Home Products Corporation Method of treating estrogen receptor positive carcinoma with 17 α-dihydroequilin
US6291196B1 (en) 1992-01-31 2001-09-18 Research Corporation Technologies, Inc. Melanoma and prostate cancer specific antibodies for immunodetection and immunotherapy
US7070782B1 (en) 1992-11-05 2006-07-04 Sloan-Kettering Institute For Cancer Research Prostate-specific membrane antigen
US5674977A (en) 1993-02-05 1997-10-07 The Ontario Cancer Institute Branched synthetic peptide conjugate
GB9314623D0 (en) 1993-07-14 1993-08-25 Nordion Int Inc Localization and therapy with agents directed against prostate specific antigen in breast cancer
US6569432B1 (en) 1995-02-24 2003-05-27 Sloan-Kettering Institute For Cancer Research Prostate-specific membrane antigen and uses thereof
JP3538221B2 (ja) 1993-11-19 2004-06-14 富士写真フイルム株式会社 定着濃厚液およびそれを用いたハロゲン化銀写真感光材料の処理方法
US5417982A (en) 1994-02-17 1995-05-23 Modi; Pankaj Controlled release of drugs or hormones in biodegradable polymer microspheres
US5866679A (en) 1994-06-28 1999-02-02 Merck & Co., Inc. Peptides
US6946133B1 (en) 1996-03-20 2005-09-20 The United States Of America As Represented By The Department Of Health And Human Services Prostate specific antigen oligo-epitope peptide
DK0907379T3 (da) 1996-04-01 2004-08-16 Epix Medical Inc Bioaktiveret diagnostisk billeddannelseskontrastmiddel
CA2251186A1 (en) 1996-04-05 1997-10-16 The Johns Hopkins University A method of enriching rare cells
US5795877A (en) 1996-12-31 1998-08-18 Guilford Pharmaceuticals Inc. Inhibitors of NAALADase enzyme activity
US5902817A (en) 1997-04-09 1999-05-11 Guilford Pharmaceuticals Inc. Certain sulfoxide and sulfone derivatives
US5863536A (en) 1996-12-31 1999-01-26 Guilford Pharmaceuticals Inc. Phosphoramidate derivatives
US6054444A (en) 1997-04-24 2000-04-25 Guilford Pharmaceuticals Inc. Phosphonic acid derivatives
US5672592A (en) 1996-06-17 1997-09-30 Guilford Pharmaceuticals Inc. Certain phosphonomethyl-pentanedioic acid derivatives thereof
US5998362A (en) 1996-09-12 1999-12-07 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US6368598B1 (en) 1996-09-16 2002-04-09 Jcrt Radiation Oncology Support Services, Inc. Drug complex for treatment of metastatic prostate cancer
US5962521A (en) 1997-04-04 1999-10-05 Guilford Pharmaceuticals Inc. Hydroxamic acid derivatives
US6177404B1 (en) 1996-10-15 2001-01-23 Merck & Co., Inc. Conjugates useful in the treatment of benign prostatic hyperplasia
US5948750A (en) 1996-10-30 1999-09-07 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US6548260B1 (en) 1997-01-21 2003-04-15 Bayer Corporation Detection of PSA-α2-macroglobulin complex in a biological fluid
ES2402947T3 (es) 1997-04-10 2013-05-10 Stichting Katholieke Universiteit University Medical Centre Nijmegen PCA3, genes PCA3 y métodos de uso
US6504014B1 (en) 1997-05-19 2003-01-07 The John Hopkins University Tissue specific prodrug
AU7582298A (en) 1997-05-19 1998-12-11 Johns Hopkins University School Of Medicine, The Tissue specific prodrug
US6127333A (en) 1997-07-10 2000-10-03 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US6391305B1 (en) 1997-09-10 2002-05-21 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US20020115596A1 (en) 1997-10-27 2002-08-22 Merk & Co., Inc. Conjugates useful in the treatment of prostate cancer
ZA9810974B (en) 1997-12-02 1999-06-03 Merck & Co Inc Conjugates useful in the treatment of prostate cancer
US20040081659A1 (en) 1997-12-02 2004-04-29 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
HUP0100350A3 (en) 1997-12-02 2001-09-28 Merck & Co Inc Conjugates useful in the treatment of prostate cancer, pharmaceutical compositions comprising thereof, process for their preparation and their use
EP1068518A2 (en) 1998-03-03 2001-01-17 Exact Sciences Corporation Purification and detection processes using reversible affinity electrophoresis
US20020103136A1 (en) 1998-03-05 2002-08-01 Dong-Mei Feng Conjugates useful in the treatment of prostate cancer
US6232287B1 (en) 1998-03-13 2001-05-15 The Burnham Institute Molecules that home to various selected organs or tissues
US6093382A (en) 1998-05-16 2000-07-25 Bracco Research Usa Inc. Metal complexes derivatized with folate for use in diagnostic and therapeutic applications
FR2778820B1 (fr) 1998-05-20 2000-07-28 Rhone Poulenc Agrochimie Melanges herbicides a base d'aclonifen et de clomazone
US6833438B1 (en) 1999-06-01 2004-12-21 Agensys, Inc. Serpentine transmembrane antigens expressed in human cancers and uses thereof
DK1086223T3 (da) 1998-06-01 2009-11-30 Agensys Inc Nye serpentintransmembranantigener udtrykt i humane cancerformer og anvendelser deraf
US6518033B1 (en) 1998-08-05 2003-02-11 The Research Foundation Of State University Of New York Method of detecting the presence of CD155 for diagnosis of cancer and to determine treatment
US20070020327A1 (en) 1998-11-10 2007-01-25 John Fikes Inducing cellular immune responses to prostate cancer antigens using peptide and nucleic acid compositions
US6174858B1 (en) 1998-11-17 2001-01-16 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US6602274B1 (en) 1999-01-15 2003-08-05 Light Sciences Corporation Targeted transcutaneous cancer therapy
US20030207808A1 (en) 1999-02-18 2003-11-06 Kinneret Savitzky Novel nucleic acid and amino acid sequences
WO2000059930A1 (en) 1999-04-05 2000-10-12 Merck & Co., Inc. A method of treating cancer
US6528499B1 (en) 2000-04-27 2003-03-04 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
JP5095050B2 (ja) 1999-04-28 2012-12-12 ジョージタウン ユニバーシティー 代謝調節型グルタミン酸受容体のリガンド、及び、NAALADaseの阻害剤
AUPQ014799A0 (en) 1999-05-04 1999-05-27 Access Pharmaceuticals Australia Pty Limited Amplification of folate-mediated targeting to tumor cells using polymers
US7166573B1 (en) 1999-05-28 2007-01-23 Ludwig Institute For Cancer Research Breast, gastric and prostate cancer associated antigens and uses therefor
US20040146516A1 (en) 1999-06-17 2004-07-29 Utah Ventures Ii L.P. Lumen-exposed molecules and methods for targeted delivery
PL354186A1 (en) 1999-07-13 2003-12-29 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, asTHE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY OF THE DEPARTMENT OF represented by THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH AND HUMAN SERVICES T-cell receptor gamma alternate reading frame protein, (tarp) and uses thereof
AU6620300A (en) 1999-08-03 2001-02-19 Ohio State University, The Polypeptides and polynucleotides for enhancing immune reactivity to her-2 protein
US7361338B2 (en) 1999-10-05 2008-04-22 Agensys, Inc. Methods to inhibit growth of prostate cancer cells
US6692724B1 (en) 1999-10-25 2004-02-17 Board Of Regents, The University Of Texas System Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging
WO2001030804A2 (en) 1999-10-27 2001-05-03 Merck & Co., Inc. Salt form of a conjugate useful in the treatment of prostate cancer
US6428785B1 (en) 1999-10-28 2002-08-06 Immunolytics Inc. Method and composition for treating prostate cancer
US6511676B1 (en) 1999-11-05 2003-01-28 Teni Boulikas Therapy for human cancers using cisplatin and other drugs or genes encapsulated into liposomes
CA2391534A1 (en) 1999-11-15 2001-05-25 Drug Innovation & Design, Inc. Selective cellular targeting: multifunctional delivery vehicles
US7033594B2 (en) 2000-03-31 2006-04-25 Purdue Research Foundation Method of treatment using ligand-immunogen conjugates
US20030072794A1 (en) 2000-06-09 2003-04-17 Teni Boulikas Encapsulation of plasmid DNA (lipogenes™) and therapeutic agents with nuclear localization signal/fusogenic peptide conjugates into targeted liposome complexes
EP1332227A4 (en) 2000-10-16 2005-08-24 Gilead Sciences Inc NUCLEAR ACID LIGHTS ON THE PROSTATE-SPECIFIC MEMBRANEANT
US20020132983A1 (en) 2000-11-30 2002-09-19 Junghans Richard P. Antibodies as chimeric effector cell receptors against tumor antigens
US7468354B2 (en) 2000-12-01 2008-12-23 Genspera, Inc. Tissue specific prodrugs
JP2004536034A (ja) 2001-01-08 2004-12-02 ネオルクス コーポレイション 治療的および診断的化合物、組成物および方法
DE60214134T2 (de) 2001-02-07 2007-07-19 Beth Israel Deaconess Medical Center, Boston Modifizierte psma-liganden und deren verwendung
AU2002306766A1 (en) 2001-03-16 2002-10-03 Johns Hopkins University School Of Medicine Immune modulation by transduced hematopoietic stem cells expressing antigens and antigen-presenting cell regulatory molecules
ATE298341T1 (de) 2001-03-21 2005-07-15 Molteni & C Metallsubstituierte, nicht zentrosymmetrische phthalocyanin-analoga, deren herstellung und verwendung zur photodynamischen therapie, und als in-vivo-diagnostikum
ES2622468T3 (es) 2001-03-29 2017-07-06 Synergy Pharmaceuticals, Inc. Agonistas del receptor de guanilato ciclasa para el tratamiento de inflamación tisular y carcinogénesis
DE60231868D1 (de) 2001-04-24 2009-05-20 Purdue Research Foundation Folat-mimetika und deren folatrezeptorbindende konjugate
WO2002087424A2 (en) 2001-05-02 2002-11-07 Purdue Research Foundation Treatment and diagnosis of macrophage mediated disease
US20040092890A1 (en) 2001-05-10 2004-05-13 Ash Stephen R. Catheter lock solution including a photo-oxidant
US7109165B2 (en) 2001-05-18 2006-09-19 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US7666414B2 (en) 2001-06-01 2010-02-23 Cornell Research Foundation, Inc. Methods for treating prostate cancer using modified antibodies to prostate-specific membrane antigen
WO2002098897A2 (en) 2001-06-01 2002-12-12 Cornell Research Foundation, Inc. Modified antibodies to prostate-specific membrane antigen and uses thereof
US7514078B2 (en) 2001-06-01 2009-04-07 Cornell Research Foundation, Inc. Methods of treating prostate cancer with anti-prostate specific membrane antigen antibodies
US20040018203A1 (en) 2001-06-08 2004-01-29 Ira Pastan Pegylation of linkers improves antitumor activity and reduces toxicity of immunoconjugates
EP1410022B1 (en) 2001-06-21 2009-05-06 GlycoMimetics, Inc. Detection and treatment of prostate cancer
EP1409017A4 (en) 2001-06-25 2006-05-24 Drug Innovation & Design Inc CELL TARGETING INVOLVING THE RECONNAISSANCE OF EXPONENTIAL FORMS, COMPOSITIONS, METHODS AND ANTICANCER APPLICATIONS
US7755757B2 (en) 2007-02-14 2010-07-13 Chemimage Corporation Distinguishing between renal oncocytoma and chromophobe renal cell carcinoma using raman molecular imaging
US6613793B2 (en) 2001-07-02 2003-09-02 Dabur Research Foundation Anticancer activity of imino acid conjugates or methylglyoxal
WO2003003978A2 (en) 2001-07-02 2003-01-16 Dabur Research Foundation An oral formulation of methylglyoxal and its imino acid conjugates for human use
US7893223B2 (en) 2001-07-17 2011-02-22 Bracco Imaging S.P.A. Multidentate AZA ligands able to complex metal ions and the use thereof in diagnostics and therapy
AU2002331720B2 (en) 2001-08-24 2007-10-11 Johns Hopkins University Proaerolysin containing protease activation sequences and methods of use for treatment of prostate cancer
US20030049203A1 (en) 2001-08-31 2003-03-13 Elmaleh David R. Targeted nucleic acid constructs and uses related thereto
WO2003024388A2 (en) 2001-09-20 2003-03-27 Cornell Research Foundation, Inc. Methods and compositions for treating and preventing skin disorders using binding agents specific for psma
US20030232760A1 (en) 2001-09-21 2003-12-18 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
ES2338305T3 (es) 2001-09-28 2010-05-06 Purdue Research Foundation Metodo de tratamiento que utiliza conjugados ligando-inmunogeno.
US20030215456A1 (en) 2001-10-02 2003-11-20 Sui-Long Yao Method of treating cancer
US20030133927A1 (en) 2001-10-10 2003-07-17 Defeo-Jones Deborah Conjugates useful in the treatment of prostate cancer
US20040058857A1 (en) 2001-11-29 2004-03-25 Siu-Long Yao Method of treating cancer
US20070031438A1 (en) 2001-12-10 2007-02-08 Junghans Richard P Antibodies as chimeric effector cell receptors against tumor antigens
WO2003060074A2 (en) 2001-12-21 2003-07-24 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Novel metastasis suppressor gene on human chromosome 8
EP1472541B1 (en) 2002-01-10 2009-09-16 The Johns Hopkins University Imaging agents and methods of imaging naaladase of psma
JP2006502964A (ja) 2002-02-06 2006-01-26 ジョンズ ホプキンス ユニバーシティ スクール オブ メディシン 特定の器官または組織に対する全身性免疫応答の標的化のための方法および組成物
US20040002587A1 (en) 2002-02-20 2004-01-01 Watkins Jeffry D. Fc region variants
US8491896B2 (en) 2002-06-14 2013-07-23 Immunomedics, Inc. Anti-pancreatic cancer antibodies
WO2003074450A2 (en) 2002-02-28 2003-09-12 The University Of Tennessee Research Corporation Radiolabeled selective androgen receptor modulators and their use in prostate cancer imaging and therapy
US9770517B2 (en) 2002-03-01 2017-09-26 Immunomedics, Inc. Anti-Trop-2 antibody-drug conjugates and uses thereof
US9745380B2 (en) 2002-03-01 2017-08-29 Immunomedics, Inc. RS7 antibodies
US20170281791A1 (en) 2002-03-01 2017-10-05 Immunomedics, Inc. Anti-trop-2 antibody-drug conjugates and uses thereof
DE60325184D1 (de) 2002-03-01 2009-01-22 Immunomedics Inc Rs7 antikörper
JP2005518822A (ja) 2002-03-07 2005-06-30 ザ ジョンズ ホプキンス ユニバーシティー スクール オブ メディシン 後生的に沈黙化されたガン関連遺伝子のゲノムスクリーニング
US7534580B2 (en) 2002-05-01 2009-05-19 Ambrilia Biopharma Inc. PSP94 diagnostic reagents and assays
DK2151250T3 (da) 2002-05-06 2013-12-16 Endocyte Inc Vitamin-targetede billeddannelsesmidler
DE60326833D1 (de) 2002-05-15 2009-05-07 Endocyte Inc Vitamin-mitomycin-konjugate
MXPA04012656A (es) 2002-06-14 2005-08-15 Immunomedics Inc Anticuerpo hpam4 monoclonal humanizado.
US7767803B2 (en) 2002-06-18 2010-08-03 Archemix Corp. Stabilized aptamers to PSMA and their use as prostate cancer therapeutics
WO2004010957A2 (en) 2002-07-31 2004-02-05 Seattle Genetics, Inc. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
AR040956A1 (es) 2002-07-31 2005-04-27 Schering Ag Nuevos conjugados de efectores, procedimientos para su preparacion y su uso farmaceutico
WO2006028429A2 (en) 2002-08-05 2006-03-16 The Johns Hopkins University Peptides for targeting the prostate specific membrane antigen
AU2003259761A1 (en) 2002-08-08 2004-02-25 Johns Hopkins University Enhancement of adenoviral oncolytic activity in prostate cells by modification of the e1a gene product
US8487128B2 (en) 2002-11-26 2013-07-16 Chs Pharma, Inc. Protection of normal cells
EP1572242B1 (en) 2002-12-13 2014-04-16 Immunomedics, Inc. Immunoconjugates with an intracellularly-cleavable linkage
US8420086B2 (en) 2002-12-13 2013-04-16 Immunomedics, Inc. Camptothecin conjugates of anti-CD22 antibodies for treatment of B cell diseases
WO2004058158A2 (en) 2002-12-20 2004-07-15 The Johns Hopkins University Treatment of metastatic cancer with the b-subunit of shiga toxin
US7166691B2 (en) 2002-12-20 2007-01-23 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Saposin C and receptors as targets for treatment of benign and malignant disorders
US20080008649A1 (en) * 2003-01-13 2008-01-10 Bracco Imaging S.P.A. Gastrin Releasing Peptide Compounds
US7226577B2 (en) * 2003-01-13 2007-06-05 Bracco Imaging, S. P. A. Gastrin releasing peptide compounds
EP2529758A3 (en) 2003-01-27 2013-01-02 Endocyte, Inc. Vitamin receptor binding drug delivery conjugates
DK1587837T3 (da) 2003-01-28 2012-09-24 Proscan Rx Pharma Inc Epitopsekvenser til diagnose og behandling af prostatacancer
EP1444990A1 (en) 2003-02-07 2004-08-11 Amersham plc Improved Radiometal Complex Compositions
WO2004072081A1 (en) 2003-02-10 2004-08-26 Cellular Genomics, Inc. Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of kinase activity
WO2004080412A2 (en) 2003-03-07 2004-09-23 The University Of Toledo Paclitaxel hybrid derivatives
US7638122B2 (en) 2003-03-07 2009-12-29 University Of South Florida Stat3 antagonists and their use as vaccines against cancer
US20070179100A1 (en) 2003-04-09 2007-08-02 Muthiah Manoharan Protected monomers
ES2702942T3 (es) 2003-04-17 2019-03-06 Alnylam Pharmaceuticals Inc Agentes de ARNi modificados
EP1641742A4 (en) 2003-05-01 2006-11-29 Nst Neurosurvival Technologies COMPOUNDS BINDING SELECTIVELY TO MEMBRANES OF APOPTOTIC CELLS
US8088387B2 (en) 2003-10-10 2012-01-03 Immunogen Inc. Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates
CA2529027C (en) 2003-06-13 2013-09-10 Immunomedics, Inc. D-amino acid peptides
US7232805B2 (en) 2003-09-10 2007-06-19 Inflabloc Pharmaceuticals, Inc. Cobalamin conjugates for anti-tumor therapy
WO2005051315A2 (en) 2003-11-24 2005-06-09 The Regents Of The University Of California On-demand cleavable linkers for radioconjugates for cancer imaging and therapy
FR2864546A1 (fr) 2003-12-24 2005-07-01 Assist Publ Hopitaux De Paris Methode d'identification et de preparation de lymphocytes t regulateurs/suppresseurs, compositions et utilisations
ATE437184T1 (de) 2004-01-12 2009-08-15 Applied Molecular Evolution Varianten der fc-region
US8586932B2 (en) 2004-11-09 2013-11-19 Spectrum Dynamics Llc System and method for radioactive emission measurement
DE102004004787A1 (de) 2004-01-30 2005-08-18 Schering Ag Neue Effektor-Konjugate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
EP1718667B1 (en) 2004-02-23 2013-01-09 Genentech, Inc. Heterocyclic self-immolative linkers and conjugates
US20070254317A1 (en) 2004-03-03 2007-11-01 Biomerieux Method for Detecting the Activatable Free Form of Psa and the Use Thereof for Diagnosing Benign Pathologies of the Prostate and Adenocarcinoma of the Prostate
EP1610818A4 (en) 2004-03-03 2007-09-19 Millennium Pharm Inc MODIFIED ANTIBODIES AGAINST A PROSTATE-SPECIFIC MEMBRANE-ANTIGEN AND USE THEREOF
ES2311895T3 (es) 2004-03-15 2009-02-16 F. Hoffmann-La Roche Ag El uso de los peptidos tipo bnp y de los peptidos tipo anf para evaluar el riesgo de padecer una complicacion cardio-vascular como frecuencia de sobrecarga del volumen.
EP1737879B1 (en) 2004-04-19 2012-10-10 Archemix LLC Aptamer-mediated intracellular delivery of therapeutic oligonucleotides
CA2606138A1 (en) 2004-04-19 2005-10-27 Proscan Rx Pharma Prostate cancer diagnosis and treatment
US7517903B2 (en) 2004-05-19 2009-04-14 Medarex, Inc. Cytotoxic compounds and conjugates
US7691962B2 (en) 2004-05-19 2010-04-06 Medarex, Inc. Chemical linkers and conjugates thereof
US20080008719A1 (en) 2004-07-10 2008-01-10 Bowdish Katherine S Methods and compositions for the treatment of prostate cancer
US8288557B2 (en) 2004-07-23 2012-10-16 Endocyte, Inc. Bivalent linkers and conjugates thereof
US20060148741A1 (en) 2004-07-26 2006-07-06 Government Of The Usa, Represented By The Secretary, Department Of Health And Human Services Metastasis suppressor gene on human chromosome 8 and its use in the diagnosis, prognosis and treatment of cancer
KR100864549B1 (ko) 2004-08-04 2008-10-20 어플라이드 몰리큘라 에볼류션, 인코포레이티드 변이체 fc 영역
US20060045883A1 (en) 2004-08-26 2006-03-02 Jeffrey Molldrem Anti-cancer vaccines
CA2577398A1 (en) 2004-08-30 2006-03-09 Neuromed Pharmaceuticals Ltd. Urea derivatives as calcium channel blockers
US8194660B2 (en) 2004-09-09 2012-06-05 Amx Llc System, method, and computer-readable medium for dynamic device discovery for servers binding to multiple masters
US7713944B2 (en) 2004-10-13 2010-05-11 Isis Pharmaceuticals, Inc. Oligomers comprising activated disulfides which bind to plasma proteins and their use for delivery to cells
ATE460412T1 (de) 2004-10-27 2010-03-15 Janssen Pharmaceutica Nv Trisubstituierte thiophene als progesteronreceptor-modulatoren
EP1827505A4 (en) 2004-11-09 2017-07-12 Biosensors International Group, Ltd. Radioimaging
US8000773B2 (en) 2004-11-09 2011-08-16 Spectrum Dynamics Llc Radioimaging
US20060140871A1 (en) 2004-11-30 2006-06-29 Sillerud Laurel O Magnetic resonance imaging of prostate cancer
US20060155021A1 (en) 2005-01-13 2006-07-13 Lenges Christian P Coating compositions containing rheology control agents
US7872235B2 (en) 2005-01-13 2011-01-18 Spectrum Dynamics Llc Multi-dimensional image reconstruction and analysis for expert-system diagnosis
US7741510B2 (en) 2005-01-13 2010-06-22 E. I. Du Pont De Nemours And Company Rheology control agents
WO2006083986A2 (en) 2005-02-01 2006-08-10 Government Of The U.S.A, As Represented By The Secretary Department Of Health & Human Services Biomarkers for tissue status
WO2006093991A1 (en) 2005-03-02 2006-09-08 The Cleveland Clinic Foundation Compounds which bind psma and uses thereof
WO2006096754A2 (en) 2005-03-07 2006-09-14 Archemix Corp. Stabilized aptamers to psma and their use as prostate cancer therapeutics
US8088908B2 (en) 2005-05-10 2012-01-03 City Of Hope Humanized anti-prostate stem cell antigen monoclonal antibody
KR101068612B1 (ko) 2005-05-24 2011-09-30 휴마시스 주식회사 유사구조 단백질 비율 측정을 이용한 진단장치
AU2006257664B2 (en) 2005-06-14 2013-01-10 Protox Therapeutics Incorporated Method of treating or preventing benign prostatic hyperplasia using modified pore-forming proteins
CN103127523A (zh) 2005-06-20 2013-06-05 Psma开发有限公司 Psma抗体-药物缀合物
JP5175723B2 (ja) 2005-07-05 2013-04-03 パーデュー・リサーチ・ファウンデーション 単球介在性疾患を治療するための組成物の調製
US20070010014A1 (en) 2005-07-06 2007-01-11 General Electric Company Compositions and methods for enhanced delivery to target sites
US8644910B2 (en) 2005-07-19 2014-02-04 Biosensors International Group, Ltd. Imaging protocols
WO2007022511A2 (en) 2005-08-19 2007-02-22 Cerus Corporation Listeria-induced immunorecruitment and activation, and methods of use thereof
KR101364912B1 (ko) 2005-08-19 2014-02-21 엔도사이트, 인코포레이티드 복수-약제 리간드 공액체
WO2007022493A2 (en) 2005-08-19 2007-02-22 Endocyte, Inc. Ligand conjugates of vinca alkaloids, analogs, and derivatives
US20100144641A1 (en) 2005-09-12 2010-06-10 Popel Aleksander S Compositions Having Antiangiogenic Activity and Uses Thereof
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
CA2670355A1 (en) 2005-11-21 2008-04-24 Medivas, Llc Polymer particles for delivery of macromolecules and methods of use
ES2548518T3 (es) 2005-11-23 2015-10-19 Ventana Medical Systems, Inc. Conjugado molecular
US20100047170A1 (en) 2006-01-05 2010-02-25 Denmeade Samuel R Peptide Prodrugs
US8258256B2 (en) 2006-01-05 2012-09-04 The Johns Hopkins University Compositions and methods for the treatment of cancer
US7635682B2 (en) 2006-01-06 2009-12-22 Genspera, Inc. Tumor activated prodrugs
WO2007089871A2 (en) 2006-02-01 2007-08-09 The Johns Hopkins University Polypeptide-nucleic acid conjugate for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders
WO2007106869A1 (en) 2006-03-14 2007-09-20 Cancer Targeted Technology Llc Peptidomimetic inhibitors of psma,compounds comprising them, and methods of use
CA2646329C (en) 2006-03-20 2018-07-03 The Regents Of The University Of California Engineered anti-prostate stem cell antigen (psca) antibodies for cancer targeting
US20070225213A1 (en) 2006-03-23 2007-09-27 Kosak Matthew K Nucleic acid carriers for delivery of therapeutic agents
US20140314864A1 (en) 2006-03-31 2014-10-23 Massachusetts Institute Of Technology System for Targeted Delivery of Therapeutic Agents
ES2776100T3 (es) 2006-03-31 2020-07-29 Massachusetts Inst Technology Sistema para el suministro dirigido de agentes terapéuticos
US7842280B2 (en) 2006-09-06 2010-11-30 Case Western Reserve University Flexibly labeling peptides
EP2087337A4 (en) 2006-11-03 2010-09-08 Purdue Research Foundation METHOD AND DEVICE FOR EX-VIVO FLOW CYTOMETRY
SI2097111T1 (sl) 2006-11-08 2016-02-29 Molecular Insight Pharmaceuticals, Inc. Heterodimeri glutaminske kisline
US9387344B2 (en) 2006-11-21 2016-07-12 The Johns Hopkins University Methods for determining absorbed dose information
WO2008070118A1 (en) 2006-12-05 2008-06-12 Landec Corporation Drug delivery
US8507434B2 (en) 2007-01-03 2013-08-13 The Johns Hopkins University Peptide modulators of angiogenesis and use thereof
CA2675202C (en) 2007-01-11 2014-09-16 Immunomedics, Inc. Methods and compositions for improved f-18 labeling of proteins, peptides and other molecules
US20080214436A1 (en) 2007-01-26 2008-09-04 City Of Hope Methods and compositions for the treatment of cancer or other diseases
AU2008213702B2 (en) 2007-02-07 2014-04-24 Purdue Research Foundation Positron emission tomography imaging method
US20100104626A1 (en) 2007-02-16 2010-04-29 Endocyte, Inc. Methods and compositions for treating and diagnosing kidney disease
NZ580132A (en) 2007-03-14 2012-11-30 Endocyte Inc Binding ligand linked drug delivery conjugates of tubulysins to vitamins
CA2683643C (en) 2007-04-10 2015-11-24 Martin G. Pomper Imaging and therapy of virus-associated tumors
AU2008268432B2 (en) 2007-06-25 2015-01-15 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
CN101784192B (zh) 2007-06-26 2015-03-18 约翰·霍普金斯大学 标记的前列腺特异性膜抗原(psma)的抑制子、生物学评估及作为成像试剂的用途
GB0723246D0 (en) 2007-07-03 2008-01-09 Barton Michelle p53 modulator
AU2008293885A1 (en) 2007-07-13 2009-03-05 The John Hopkins University B7-DC variants
EP2178896A1 (en) 2007-07-31 2010-04-28 The Johns Hopkins University Polypeptide-nucleic acid conjugate for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders
WO2009021178A1 (en) 2007-08-08 2009-02-12 Chemimage Corporation Raman difference spectra based disease classification
EP3858347A3 (en) 2007-08-17 2021-12-01 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
US8865875B2 (en) 2007-08-22 2014-10-21 Medarex, L.L.C. Site-specific attachment of drugs or other agents to engineered antibodies with C-terminal extensions
WO2009033161A1 (en) 2007-09-07 2009-03-12 The John Hopkins University Adenosine receptor agonists and antagonists to modulate t cell responses
HUE035101T2 (hu) 2007-09-28 2018-05-02 Pfizer Ráksejtek célzása nanorészecskék alkalmazásával
EP2209374B1 (en) 2007-10-25 2014-12-03 Endocyte, Inc. Tubulysins and processes for preparing
US8450290B2 (en) 2007-11-26 2013-05-28 Enzon Pharmaceuticals, Inc. Methods for treating androgen receptor dependent disorders including cancers
US9422234B2 (en) 2007-11-30 2016-08-23 The Johns Hopkins University Prostate specific membrane antigen (PSMA) targeted nanoparticles for therapy of prostate cancer
US8507455B2 (en) 2007-12-04 2013-08-13 Alnylam Pharmaceuticals, Inc. Folate conjugates
WO2009076434A1 (en) 2007-12-12 2009-06-18 Molecular Insight Pharmaceuticals, Inc. Inhibitors of integrin vla-4
JP2011509304A (ja) 2008-01-09 2011-03-24 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド 炭酸脱水酵素ixの阻害剤
US8565945B2 (en) 2008-01-17 2013-10-22 Lockheed Martin Corporation Method for managing vital train movements
JP2011516178A (ja) 2008-04-04 2011-05-26 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド 放射能標識治療物質注入システム、装置、およびそれを使用する方法
ITTO20080313A1 (it) 2008-04-22 2009-10-23 Marco Colombatti Anticorpo monoclonale isolato o suo frammento legante l'antigene specifico di membrana della prostata, suoi coniugati e suoi usi
WO2009137807A2 (en) 2008-05-08 2009-11-12 Asuragen, Inc. Compositions and methods related to mirna modulation of neovascularization or angiogenesis
US8852630B2 (en) 2008-05-13 2014-10-07 Yale University Chimeric small molecules for the recruitment of antibodies to cancer cells
PL2291659T3 (pl) 2008-05-13 2016-04-29 Univ Yale Małe cząsteczki chimerowe do rekrutacji przeciwciał do komórek nowotworowych
PT2774608T (pt) 2008-06-16 2020-01-17 Pfizer Nanopartículas poliméricas carregadas com fármaco e métodos de produção e utilização das mesmas
US20110305768A1 (en) 2008-07-01 2011-12-15 The Johns Hopkins University Quick-dissolving oral thin film for targeted delivery of therapeutic agents
CA2987744C (en) 2008-08-01 2022-11-15 The Johns Hopkins University Psma-binding agents and uses thereof
US8685937B2 (en) 2008-08-09 2014-04-01 University Of Iowa Research Foundation Nucleic acid aptamers
US8816095B2 (en) 2008-08-15 2014-08-26 Georgetown University Na channels, disease, and related assays and compositions
PL2326350T3 (pl) 2008-09-08 2014-03-31 Psma Dev Company L L C Związki do zabijania eksprymujących PSMA, opornych na taksan komórek rakowych
EP2166021A1 (en) 2008-09-16 2010-03-24 Ganymed Pharmaceuticals AG Monoclonal antibodies for treatment of cancer
CA2737496A1 (en) 2008-09-17 2010-03-25 Endocyte, Inc. Folate receptor binding conjugates of antifolates
US20110288152A1 (en) 2008-10-17 2011-11-24 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
AU2009322167B2 (en) 2008-12-05 2014-11-20 Molecular Insight Pharmaceuticals, Inc. Technetium- and rhenium-bis(heteroaryl) complexes and methods of use thereof for inhibiting PSMA
US8211402B2 (en) 2008-12-05 2012-07-03 Molecular Insight Pharmaceuticals, Inc. CA-IX specific radiopharmaceuticals for the treatment and imaging of cancer
WO2010065899A2 (en) 2008-12-05 2010-06-10 Molecular Insight Pharmaceuticals, Inc. Technetium-and rhenium-bis(heteroaryl)complexes and methods of use thereof
CN102448494B (zh) 2009-02-13 2016-02-03 免疫医疗公司 具有胞内可裂解的键的免疫共轭物
ES2712732T3 (es) 2009-02-17 2019-05-14 Cornell Res Foundation Inc Métodos y kits para el diagnóstico de cáncer y la predicción de valor terapéutico
CA2754217A1 (en) 2009-03-02 2010-09-10 Massachusetts Institute Of Technology Methods and systems for treatment and/or diagnosis
EP2408465A4 (en) 2009-03-17 2012-11-28 Univ Johns Hopkins METHOD AND COMPOSITIONS FOR DETECTING CANCER
US10717750B2 (en) 2009-03-19 2020-07-21 The Johns Hopkins University 68Ga-labeled NOTA-chelated PSMA-targeted imaging and therapeutic agents
HRP20221195T1 (hr) 2009-03-19 2022-12-09 The Johns Hopkins University Spojevi koji ciljaju psma i njihova uporaba
US9757084B2 (en) 2011-12-22 2017-09-12 The Johns Hopkins University Method and system for administering radiopharmaceutical therapy (RPT)
AU2010249719A1 (en) 2009-05-19 2012-05-31 Aic Blab Company Composite current collector and methods therefor
US8465725B2 (en) 2009-06-15 2013-06-18 Molecular Insight Pharmaceuticlas, Inc. Process for production of heterodimers of glutamic acid
CN102549434A (zh) 2009-07-31 2012-07-04 恩多塞特公司 叶酸盐靶向的诊断和治疗
US8394922B2 (en) 2009-08-03 2013-03-12 Medarex, Inc. Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof
WO2011031517A1 (en) 2009-08-27 2011-03-17 Nuclea Biotechnologies, LLC Method and assay for determining fas expression
CA2782333C (en) 2009-12-02 2019-06-04 Imaginab, Inc. J591 minibodies and cys-diabodies for targeting human prostate specific membrane antigen (psma) and methods for their use
US8357401B2 (en) 2009-12-11 2013-01-22 Bind Biosciences, Inc. Stable formulations for lyophilizing therapeutic particles
JP5964756B2 (ja) 2010-02-04 2016-08-03 ラジウス ヘルス,インコーポレイテッド 選択的アンドロゲン受容体モジュレーター
US9951324B2 (en) 2010-02-25 2018-04-24 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
CA2790577A1 (en) 2010-02-25 2011-09-01 Purdue Research Foundation Psma binding ligand-linker conjugates and methods for using
WO2011109422A2 (en) 2010-03-02 2011-09-09 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Compositions and methods for the treatment of cancer
JP2010159277A (ja) 2010-03-04 2010-07-22 Sumitomo Chemical Co Ltd 有害生物防除組成物及び有害生物の防除方法
EP2371864A1 (en) 2010-03-23 2011-10-05 Ganymed Pharmaceuticals AG Monoclonal antibodies for treatment of cancer
WO2011127210A1 (en) 2010-04-06 2011-10-13 Massachusetts Institute Of Technology Targeted delivery of nucleic acids
BR112012026213B1 (pt) 2010-04-15 2021-12-28 Medimmune Limited Compostos de pirrolobenzodiazepinas, conjugado das mesmas, composição farmacêutica compreendendo o conjugado e uso do mesmo para o tratamento de uma doença proliferativa
HUE029293T2 (en) 2010-05-05 2017-02-28 Safety Syringes Inc Helical-shaped coil safety device for needle
CN101863924B (zh) 2010-05-17 2012-06-27 北京师范大学 99mTc标记肼基烟酰胺基-二氧辛酰-叶酸配合物及制备方法
CN103118678A (zh) 2010-07-16 2013-05-22 约翰斯·霍普金斯大学 用于癌症免疫治疗的方法和组合物
WO2012012710A2 (en) 2010-07-22 2012-01-26 The Johns Hopkins University Radiation sensitization agents for prostate cancer
WO2012033911A2 (en) 2010-09-08 2012-03-15 The Johns Hopkins University Polyionic papilloma virus-like particle (vlp) vaccines
KR101236142B1 (ko) 2010-09-30 2013-02-21 경북대학교 산학협력단 가돌리늄 착물을 함유하는 mri조영제
JP6275484B2 (ja) 2010-12-06 2018-02-07 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド Psma標的化デンドリマー
CN103561773A (zh) 2011-03-31 2014-02-05 约翰霍普金斯大学 治疗诊断显像剂和使用方法
US9074000B2 (en) 2011-04-01 2015-07-07 Memorial Sloan Kettering Cancer Center T cell receptor-like antibodies specific for a WT1 peptide presented by HLA-A2
WO2012143599A1 (en) 2011-04-21 2012-10-26 Orion Corporation Androgen receptor modulating carboxamides
US9180214B1 (en) 2011-04-22 2015-11-10 Stc.Unm Gonadotropin-releasing hormone receptor-targeting peptides and their use to treat and diagnose cancer
WO2012154511A2 (en) 2011-05-06 2012-11-15 The Johns Hopkins University Method and device for statistical tissue sampling using microdevices
US20140308363A1 (en) 2011-05-31 2014-10-16 Bind Therapeutics, Inc. Drug loaded polymeric nanoparticles and methods of making and using same
CA2839195C (en) * 2011-06-15 2021-10-26 Cancer Targeted Technology Llc Chelated psma inhibitors
WO2013028664A1 (en) 2011-08-22 2013-02-28 Siemens Medical Solutions Usa, Inc. Psma imaging agents
US9034318B2 (en) 2011-08-30 2015-05-19 The Regents Of The University Of Colorado, A Body Corporate Chemically modified cystathionine beta-synthase enzyme for treatment of homocystinuria
WO2013060793A1 (en) * 2011-10-25 2013-05-02 Technische Universität München Bifunctional ligands for radiometals
WO2013070457A2 (en) 2011-11-01 2013-05-16 The Johns Hopkins University Method and device for endoscopic abrasion
CN113149921A (zh) 2011-11-30 2021-07-23 约翰霍普金斯大学 前列腺特异性膜抗原(psma)的同源多价抑制剂和异源多价抑制剂以及其用途
US9120837B2 (en) 2012-01-06 2015-09-01 Molecular Insight Pharmaceuticals Metal complexes of poly(carboxyl)amine-containing ligands having an affinity for carbonic anhydrase IX
US9629918B2 (en) 2012-02-29 2017-04-25 Purdue Research Foundation Folate receptor alpha binding ligands
US9498546B2 (en) 2012-03-14 2016-11-22 The Johns Hopkins University Synthesis and application of novel imaging agents conjugated to DPA 713 analogs for imaging inflammation
WO2013166110A1 (en) 2012-05-02 2013-11-07 Yale University Tlr-agonist-conjugated antibody recruiting molecules (tlr_arms)
IN2014MN02492A (zh) 2012-06-08 2015-07-17 Aduro Biotech
SG11201500184TA (en) 2012-07-27 2015-04-29 Aragon Pharmaceuticals Inc Methods and compositions for determining resistance to androgen receptor therapy
US20140107316A1 (en) 2012-10-16 2014-04-17 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
CA2887727A1 (en) 2012-10-16 2014-04-24 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
US20140113322A1 (en) 2012-10-22 2014-04-24 The Johns Hopkins University Supramolecular nanobeacon imaging agents as protease sensors
US9180203B2 (en) 2012-10-23 2015-11-10 The Johns Hopkins University Self-assembling drug amphiphiles and methods for synthesis and use
MX2015006109A (es) 2012-11-15 2016-02-05 Endocyte Inc Conjugados para el tratamiento de enfermedades causadas por celulas que expresan psma.
US20140154702A1 (en) 2012-11-30 2014-06-05 Endocyte, Inc. Methods For Treating Cancer Using Combination Therapies
KR102002826B1 (ko) 2012-12-04 2019-07-23 삼성전자 주식회사 저장 장치, 플래시 메모리 및 저장 장치의 동작 방법
CN105246894A (zh) 2012-12-21 2016-01-13 斯皮罗根有限公司 用于治疗增殖性和自身免疫疾病的非对称吡咯并苯并二氮杂卓二聚物
EP2938364A1 (en) 2012-12-28 2015-11-04 Blend Therapeutics, Inc. Targeted conjugates encapsulated in particles and formulations thereof
CN105025933B (zh) 2013-01-14 2019-03-26 分子制药洞察公司 三嗪类放射性药物和放射性显影剂
US10207005B2 (en) 2013-02-15 2019-02-19 Case Western Reserve University Photodynamic therapy composition
WO2014127365A1 (en) 2013-02-15 2014-08-21 Case Western Reserve University Psma ligands and uses thereof
US20140249315A1 (en) 2013-03-01 2014-09-04 Endocyte, Inc. Processes for preparing tubulysins
US9255262B2 (en) 2013-03-06 2016-02-09 Vision Global Holdings Ltd. Albumin-binding arginine deminase and the use thereof
US9567402B2 (en) 2013-03-14 2017-02-14 The Regents Of The University Of California Internalizing human monoclonal antibodies targeting prostate and other cancer cells
US10434194B2 (en) 2013-06-20 2019-10-08 Case Western Reserve University PSMA targeted nanobubbles for diagnostic and therapeutic applications
US9764039B2 (en) 2013-07-10 2017-09-19 Sutro Biopharma, Inc. Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use
JP5817799B2 (ja) 2013-10-10 2015-11-18 ダイキン工業株式会社 空気調和機
EP3054983B1 (en) 2013-10-11 2019-03-20 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
US10232058B2 (en) 2013-10-14 2019-03-19 The Johns Hopkins University Prostate-specific membrane antigen-targeted photosensitizers for photodynamic therapy
US10406246B2 (en) 2013-10-17 2019-09-10 Deutsches Kresbsforschungszentrum Double-labeled probe for molecular imaging and use thereof
WO2015058151A2 (en) 2013-10-18 2015-04-23 Molecular Insight Pharmaceuticals, Inc. Methods of using spect/ct analysis for staging cancer
RS65324B1 (sr) * 2013-10-18 2024-04-30 Novartis Ag Obeleženi inhibitori membranskog antigena specifičnog za prostatu (psma), njihova upotreba kao agenasa za snimanje i farmaceutskih agenasa za lečenje karcinoma prostate
WO2015057250A1 (en) 2013-10-18 2015-04-23 Psma Development Company, Llc Combination therapies with psma ligand conjugates
WO2015073678A1 (en) 2013-11-14 2015-05-21 Endocyte, Inc. Compounds for positron emission tomography
ITAN20130219A1 (it) 2013-11-21 2015-05-22 Gianluca Valentini Farmaco anti-cancro, comprendente un radioisotopo del rame
WO2015075477A1 (en) 2013-11-25 2015-05-28 Oxford Biotherapeutics Ltd Antibodies anti matriptase for the treatment of cancer
US9346846B1 (en) 2013-12-02 2016-05-24 Yale University Anti-cancer compounds and methods for treating cancer
EP3082928A1 (en) 2013-12-18 2016-10-26 Koninklijke Philips N.V. System and method for enhancing sleep slow wave activity based on cardiac characteristics or respiratory characteristics
US11124845B2 (en) 2014-03-18 2021-09-21 The Johns Hopkins University PSMA-based molecular-genetic reporter system
US10683272B2 (en) 2014-05-06 2020-06-16 The Johns Hopkins University Metal/radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiotherapy
EP2944635B1 (en) 2014-05-15 2018-11-28 Council of Scientific & Industrial Research Pyrazole linked benzimidazole conjugates and a process for preparation thereof
US9814759B2 (en) 2014-07-02 2017-11-14 Cheer Global Ltd. Pharmaceutical composition comprising recombinant hemoglobin protein or subunit-based therapeutic agent for cancer targeting treatment
DK3177632T3 (da) 2014-08-06 2022-03-21 Univ Johns Hopkins Prodrugs af hæmmer af prostataspecifikt membranantigen (psma)
WO2016022809A2 (en) 2014-08-06 2016-02-11 The Johns Hopkins University Methods for treating inflammatory bowel disease using prostate specific membrane antigen (psma) inhibitors
EP2993171A1 (en) 2014-09-04 2016-03-09 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Method for the production of 18F-labeled PSMA-specific PET-tracers
WO2016030329A1 (en) 2014-08-24 2016-03-03 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Method for the production of 18f-labeled active esters and their application exemplified by the preparation of a psma-specific pet-tracer
WO2016033114A1 (en) 2014-08-25 2016-03-03 The Johns Hopkins University Methods and compositions related to prostate cancer therapeutics
JP2017530109A (ja) 2014-09-08 2017-10-12 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド 前立腺癌についてのpsmaを標的とした放射性核種治療中の臓器の保護
WO2016062370A1 (en) 2014-10-20 2016-04-28 Deutsches Krebsforschungszentrum 18f-tagged inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US10736974B2 (en) 2014-10-22 2020-08-11 The Johns Hopkins University Scaffolds and multifunctional intermediates for imaging PSMA and cancer therapy
EP3220900B1 (en) 2014-11-21 2020-09-23 University of Maryland, Baltimore Targeted structure-specific particulate delivery systems
KR101698654B1 (ko) 2014-12-24 2017-01-20 포항공과대학교 산학협력단 En2에 특이적으로 결합하는 dna 압타머 및 이의 용도
US10596226B2 (en) 2015-01-16 2020-03-24 The Johns Hopkins University Albumin-proaerolysin prodrugs
WO2016115445A1 (en) 2015-01-16 2016-07-21 The Johns Hopkins University Synthetic enhancement of the t-cell armamentarium as an anti-cancer therapy
WO2016168214A2 (en) 2015-04-13 2016-10-20 Aduro Biotech, Inc. Immunogenic fusion proteins for the treatment of cancer
ES2948133T3 (es) 2015-04-17 2023-08-31 Novartis Ag Métodos para mejorar la eficacia y expansión de células que expresan un receptor de antígeno quimérico
US9808538B2 (en) 2015-09-09 2017-11-07 On Target Laboratories, LLC PSMA-targeted NIR dyes and their uses
KR101639599B1 (ko) 2015-11-09 2016-07-14 서울대학교산학협력단 펩타이드 싸이오우레아 유도체, 이를 포함하는 방사성 동위원소 표지 화합물 및 이를 유효 성분으로 함유하는 전립선암 치료 또는 진단용 약학적 조성물
FR3043970B1 (fr) 2015-11-25 2019-06-21 Medtech Sa Systeme mecanique de stabilisation au sol pour vehicules a roulettes
US10688200B2 (en) 2015-12-31 2020-06-23 Five Eleven Pharma Inc. Urea-based prostate specific membrane antigen (PSMA) inhibitors for imaging and therapy
US10308606B2 (en) 2016-09-09 2019-06-04 On Target Laboratories, LLC PSMA-targeted NIR dyes and their uses
CN111801121B (zh) 2017-04-11 2023-12-01 约翰霍普金斯大学 在psma靶向癌症成像或放疗期间用于健康组织保护的2-pmpa前药
US10377778B2 (en) 2017-12-13 2019-08-13 Sciencons AS Lead and thorium compounds
WO2019165200A1 (en) 2018-02-22 2019-08-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer
KR20210023982A (ko) 2018-06-21 2021-03-04 리제너론 파아마슈티컬스, 인크. 이중특이적 항-psma x 항-cd28 항체 및 이의 용도

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013022797A1 (en) * 2011-08-05 2013-02-14 Molecular Insight Pharmaceuticals Radiolabeled prostate specific membrane antigen inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112062695A (zh) * 2020-08-14 2020-12-11 北京大学第一医院 一种前列腺特异性膜抗原靶向抑制剂及应用和探针
CN112062695B (zh) * 2020-08-14 2021-04-06 北京大学第一医院 一种前列腺特异性膜抗原靶向抑制剂及应用和探针
CN113372285A (zh) * 2021-05-28 2021-09-10 西南医科大学附属医院 前列腺特异性膜抗原抑制剂、其放射性核素标记物及制法和应用
CN114874122A (zh) * 2022-05-31 2022-08-09 南京航空航天大学 一种新的小分子抑制剂及其制备方法和应用

Also Published As

Publication number Publication date
KR20190016133A (ko) 2019-02-15
GEP20237496B (en) 2023-04-10
EP3038996A1 (en) 2016-07-06
JP2016535013A (ja) 2016-11-10
JP7194161B2 (ja) 2022-12-21
US20160228587A1 (en) 2016-08-11
US20190060491A1 (en) 2019-02-28
DE202014011600U1 (de) 2023-05-31
MX2016005013A (es) 2017-02-28
AU2014336638C1 (en) 2020-09-17
CN109053616B (zh) 2022-08-19
EP4095130A1 (en) 2022-11-30
GEP20237479B (en) 2023-03-27
JP2024028742A (ja) 2024-03-05
WO2015055318A1 (en) 2015-04-23
KR102282378B1 (ko) 2021-07-27
SI4095130T1 (sl) 2024-05-31
EA201690495A1 (ru) 2016-10-31
US20190374660A1 (en) 2019-12-12
ZA201603380B (en) 2020-05-27
EP3038996B1 (en) 2022-06-15
KR101947053B1 (ko) 2019-02-12
JP6901451B2 (ja) 2021-07-14
IL245113B (en) 2020-08-31
PH12016500656B1 (en) 2016-06-13
EP3415489A1 (en) 2018-12-19
JP7036774B2 (ja) 2022-03-15
US10471160B2 (en) 2019-11-12
EA037778B1 (ru) 2021-05-20
JP2019011368A (ja) 2019-01-24
GEP20217330B (en) 2021-12-10
AU2018200419A1 (en) 2018-02-08
AU2018200419B2 (en) 2019-11-14
GEP20237497B (en) 2023-04-10
JP2022159345A (ja) 2022-10-17
HK1221711A1 (zh) 2017-06-09
IL268974A (en) 2019-10-31
MX2021008976A (es) 2021-08-18
CL2016000883A1 (es) 2016-10-21
JP6556805B2 (ja) 2019-08-07
AU2014336638A1 (en) 2016-04-14
IL268974B (en) 2020-08-31
MY194484A (en) 2022-11-30
MX2021008977A (es) 2021-09-08
RS65324B1 (sr) 2024-04-30
EP3495355A1 (en) 2019-06-12
KR20160063398A (ko) 2016-06-03
US20190008988A1 (en) 2019-01-10
CA2924360A1 (en) 2015-04-23
US11931430B2 (en) 2024-03-19
IL245113A0 (en) 2016-06-30
HRP20240398T1 (hr) 2024-06-07
DK4095130T3 (da) 2024-04-22
AU2014336638B2 (en) 2017-10-19
EP4095130B1 (en) 2024-01-31
TN2016000137A1 (en) 2017-10-06
US11951190B2 (en) 2024-04-09
PE20211760A1 (es) 2021-09-07
DE202014011593U1 (de) 2023-08-23
JP2021059557A (ja) 2021-04-15
JP2018058847A (ja) 2018-04-12
EP4374924A2 (en) 2024-05-29
US10398791B2 (en) 2019-09-03
MY188934A (en) 2022-01-13
EP3456700A1 (en) 2019-03-20
AU2020201086A1 (en) 2020-03-05
LT4095130T (lt) 2024-04-25
US20190336622A1 (en) 2019-11-07
US11045564B2 (en) 2021-06-29
PE20160678A1 (es) 2016-08-06
US20210283279A1 (en) 2021-09-16
AU2020201086B2 (en) 2021-07-08
NZ718812A (en) 2017-08-25
SG11201602249RA (en) 2016-05-30
SA516370842B1 (ar) 2020-06-07
KR102210931B1 (ko) 2021-02-02
CA2924360C (en) 2022-04-26
ZA201907607B (en) 2021-05-26
PH12016500656A1 (en) 2016-06-13
PL4095130T3 (pl) 2024-06-10
FI4095130T3 (fi) 2024-04-25
CN105636924A (zh) 2016-06-01
CN105636924B (zh) 2018-08-07
US20210177996A1 (en) 2021-06-17
KR20210013350A (ko) 2021-02-03
JP2019218351A (ja) 2019-12-26
JP7393485B2 (ja) 2023-12-06

Similar Documents

Publication Publication Date Title
CN105636924B (zh) 前列腺特异性膜抗原(psma)的标记的抑制剂,它们作为显影剂和用于治疗前列腺癌的药剂的用途
EP2862857A1 (en) Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
EP3209336A1 (en) 18f-tagged inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20230906

Address after: Basel, SUI

Patentee after: Novartis Pharma AG

Address before: Heidelberg, Germany

Patentee before: DEUTSCHES KREBSFORSCHUNGSZENTRUM

Patentee before: RUPRECHT-KARLS-UNIVERSITAT HEIDELBERG

Effective date of registration: 20230906

Address after: Basel, SUI

Patentee after: NOVARTIS AG

Address before: Basel, SUI

Patentee before: Novartis Pharma AG