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公开(公告)号：US5106951A
公开(公告)日：1992-04-21
申请号：US332610
申请日：1989-03-31
申请人： Alton C. Morgan, Jr. , Ananthachari Srinivasan , John M. Reno , Alan R. Fritzberg , David C. Anderson
发明人： Alton C. Morgan, Jr. , Ananthachari Srinivasan , John M. Reno , Alan R. Fritzberg , David C. Anderson
IPC分类号： A61K31/495 , A61K31/505 , A61K31/675 , A61K31/70 , A61K39/395 , A61K47/48 , A61P35/00 , C07K14/00 , C07K16/00
CPC分类号： A61K47/48369 , A61K47/48384
摘要： There is disclosed an antibody and antibody-drug conjugate for targeting drug delivery as well as a class of chemicals, termed a drug-binding molecule of complementary structure (csDBM). The csDBM is designed to "fit" the drug by combining multiple non-covalent interactions between functional groups on the drug and opposing functional groups on the csDBM. The net result on the antibody-csDBM-drug conjugate is a drug stably bound to the csDBM so as not to dissociate during in vivo administration, but not so tightly bound to allow drug dissociation from the conjugate without significant loss of activity and retaining the drug's ability to bind to a higher affinity site on or within the target cell.
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公开(公告)号：US5252721A
公开(公告)日：1993-10-12
申请号：US591104
申请日：1990-09-28
IPC分类号： A61K51/04 , A61K51/10 , C07B59/00 , C07D495/04 , C07F13/00 , G01N33/534 , C07F5/00
CPC分类号： G01N33/534 , A61K51/0478 , A61K51/1093 , C07B59/004 , C07D495/04 , C07F13/005 , A61K2121/00 , A61K2123/00 , Y02P20/55
摘要： Novel chelating compounds and the corresponding radionuclide metal chelates are useful for radiolabeling proteins such as antibodies with radionuclide metals such as .sup.99m Tc, .sup.186 Re, and .sup.188 Re. The chelating compounds are of the following formulas: ##STR1## wherein each R is a protecting group;Q is hydrogen or a protecting group;each T is independently chosen from hydrogen, lower alkyl groups of from 1 to about 6 carbon atoms, electron withdrawing groups, and lower alkyl groups of from 1 to about 6 carbon atoms substituted with electron withdrawing group(s);X represents O, S, or NH;each R' is independently selected from:--(CH.sub.2).sub.n --COOH with n=0 to about 4,--(CH.sub.2).sub.n --Z, wherein Z represents a conjugation group and n is 0 to about 4,hydrogen, anda lower alkyl group of from 1 to about 6 carbon atoms;each R" is independently selected from:--(CH.sub.2).sub.n --COOH, with n=0 to about 4,hydrogen, anda lower alkyl group of from 1 to about 6 carbon atoms; and the compound comprises at least one --(CH.sub.2).sub.n --Z substituent.The conjugation group Z reacts with a protein to bind the chelating compound thereto. The radiolabeled proteins have diagnostic or therapeutic use, depending on the radionuclide metal chosen.
摘要翻译： 新型螯合化合物和相应的放射性核素金属螯合物可用于放射性标记蛋白质，例如具有放射性核素金属如99mTc，186Re和188Re的抗体。 螯合化合物具有下式：其中每个R是保护基; Q是氢或保护基; 每个T独立地选自氢，1至约6个碳原子的低级烷基，吸电子基团和1至6个碳原子被吸电子基取代的低级烷基; X表示O，S或NH; 每个R'独立地选自： - （CH 2）n -COOH，其中n = 0至约4， - （CH 2）n Z，其中Z表示共轭基团，n为0至约4，氢和低级烷基 1至约6个碳原子; 每个R“独立地选自： - （CH 2）n -COOH，n = 0至约4，氢和1至约6个碳原子的低级烷基; 并且所述化合物包含至少一个 - （CH 2）n-Z取代基。 缀合基团Z与蛋白质反应以结合螯合化合物。 放射性标记的蛋白质具有诊断或治疗用途，这取决于所选择的放射性核素金属。
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23.发明授权
公开(公告)号：US5625075A
公开(公告)日：1997-04-29
申请号：US459414
申请日：1995-06-02
IPC分类号： A61K47/48 , A61K51/10 , C07C327/30 , C07C327/32 , C07D207/46 , C07D209/48 , C07D307/18 , C07D405/12 , C07C67/00 , C07C233/01 , C07D315/00
CPC分类号： C07D209/48 , A61K47/48707 , A61K51/1093 , C07C327/30 , C07C327/32 , C07D207/46 , C07D307/18 , C07D405/12 , A61K2121/00 , A61K2123/00
摘要： The present invention provides metal chelating compounds, to chelates and chelate-targeting agent conjugates formed from the chelating compounds, and to methods for making and using these compositions. The chelating compounds incorporate two nitrogen atoms and three sulfur atoms ("N.sub.2 S.sub.3 "), two nitrogen atoms and four sulfur atoms ("N.sub.2 S.sub.4 "), or three nitrogen atoms and three sulfur atoms ("N.sub.3 S.sub.3 "). Metals, and metal oxides, capable of being chelated by the compounds include those that are radionuclides, such as .sup.99m Tc and .sup.186/188 Re.The targeting agent portion of the chelate-targeting agent conjugates provided includes antibodies, peptides, hormones, enzymes and biological response modifiers. Methods for making the conjugates are provided and encompass the addition of a metal, or metal oxide, to a chelating compound prior to attachment to a targeting agent as well as subsequent to the attachment.Another aspect of the invention provides kits for producing chelate-targeting agent conjugates for radiopharmaceutical use.An additional aspect of the invention provides methods for using the chelate-targeting agent conjugates for diagnostic and therapeutic purposes, such as detection of a target site and delivery of a radionuclide to the site, respectively.
摘要翻译： 本发明提供金属螯合化合物，由螯合化合物形成的螯合物和螯合靶向试剂缀合物，以及制备和使用这些组合物的方法。 螯合化合物包含两个氮原子和三个硫原子（“N2S3”），两个氮原子和四个硫原子（“N2S4”）或三个氮原子和三个硫原子（“N3S3”）。 能够被化合物螯合的金属和金属氧化物包括那些是放射性核素，例如99mTc和186 / 188Re。 提供的螯合靶向药物缀合物的靶向剂部分包括抗体，肽，激素，酶和生物反应调节剂。 提供了制备缀合物的方法，并且包括在附着到靶向剂之前以及在附着之后将金属或金属氧化物加入到螯合化合物中。 本发明的另一方面提供了用于制备用于放射性药物用途的螯合靶向剂缀合物的试剂盒。 本发明的另一方面提供了用于诊断和治疗目的的螯合靶向剂缀合物的使用方法，例如分别检测靶位点和将放射性核素递送至位点。
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24.发明授权
公开(公告)号：US5436352A
公开(公告)日：1995-07-25
申请号：US804123
申请日：1991-12-06
IPC分类号： A61K47/48 , A61K51/10 , C07C327/30 , C07C327/32 , C07D207/46 , C07D209/48 , C07D307/18 , C07D405/12 , C07C67/00 , C07C233/01 , C07D315/00
CPC分类号： C07D209/48 , A61K47/48707 , A61K51/1093 , C07C327/30 , C07C327/32 , C07D207/46 , C07D307/18 , C07D405/12 , A61K2121/00 , A61K2123/00
摘要： The present invention provides metal chelating compounds, to chelates and chelate-targeting agent conjugates formed from the chelating compounds, and to methods for making and using these compositions. The chelating compounds incorporate two nitrogen atoms and three sulfur atoms ("N.sub.2 S.sub.3 "), two nitrogen atoms and four sulfur atoms ("N.sub.2 S.sub.4 "), or three nitrogen atoms and three sulfur atoms ("N.sub.3 S.sub.3 "). Metals, and metal oxides, capable of being chelated by the compounds include those that are radionuclides, such as .sup.99m Tc and .sup.186/188 Re.The targeting agent portion of the chelate-targeting agent conjugates provided includes antibodies, peptides, hormones, enzymes and biological response modifiers. Methods for making the conjugates are provided and encompass the addition of a metal, or metal oxide, to a chelating compound prior to attachment to a targeting agent as well as subsequent to the attachment.Another aspect of the invention provides kits for producing chelate-targeting agent conjugates for radiopharmaceutical use.An additional aspect of the invention provides methods for using the chelate-targeting agent conjugates for diagnostic and therapeutic purposes, such as detection of a target site and delivery of a radionuclide to the site, respectively.
摘要翻译： 本发明提供金属螯合化合物，由螯合化合物形成的螯合物和螯合靶向试剂缀合物，以及制备和使用这些组合物的方法。 螯合化合物包含两个氮原子和三个硫原子（“N2S3”），两个氮原子和四个硫原子（“N2S4”）或三个氮原子和三个硫原子（“N3S3”）。 能够被化合物螯合的金属和金属氧化物包括那些是放射性核素，例如99mTc和186 / 188Re。 提供的螯合靶向药物缀合物的靶向剂部分包括抗体，肽，激素，酶和生物反应调节剂。 提供了制备缀合物的方法，并且包括在附着到靶向剂之前以及在附着之后将金属或金属氧化物加入到螯合化合物中。 本发明的另一方面提供了用于制备用于放射性药物用途的螯合靶向剂缀合物的试剂盒。 本发明的另一方面提供了用于诊断和治疗目的的螯合靶向剂缀合物的使用方法，例如分别检测靶位点和将放射性核素递送至位点。
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25.发明授权Cleavable linkers for the reduction of non-target organ retention of immunoconjugates 失效用于减少免疫缀合物的非目标器官保留的可切割接头
公开(公告)号：US5171563A
公开(公告)日：1992-12-15
申请号：US830973
申请日：1992-02-10
申请人： Paul G. Abrams , John M. Reno , Alan R. Fritzberg , Ananthachari Srinivasan , David C. Anderson
发明人： Paul G. Abrams , John M. Reno , Alan R. Fritzberg , Ananthachari Srinivasan , David C. Anderson
CPC分类号： A61K47/48338 , A61K51/088 , A61K51/1093 , A61K2121/00 , A61K2123/00 , Y10S514/836 , Y10S514/922 , Y10S530/807
摘要： A process for reducing the non-target organ accumulation of immunoconjugates administered in vivo during therapeutic or diagnostic procedures involves the use of immunoconjugates comprising linkers that are cleavable at the non-target organs. The linkers are cleavable under conditions present, or induced, at one or more non-target organs, which include the kidneys or the liver.
摘要翻译： 在治疗或诊断过程中减少在体内施用的免疫缀合物的非靶器官积累的方法涉及使用包含在非靶器官可切割的接头的免疫缀合物。 接头可在包括肾脏或肝脏的一个或多个非靶器官存在或诱导的条件下切割。
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26.发明授权
公开(公告)号：US5075099A
公开(公告)日：1991-12-24
申请号：US589449
申请日：1990-09-27
IPC分类号： A61K47/48 , A61K51/10 , C07C327/30 , C07C327/32 , C07D207/46 , C07D209/48 , C07D307/18 , C07D405/12
CPC分类号： C07D209/48 , A61K47/48707 , A61K51/1093 , C07C327/30 , C07C327/32 , C07D207/46 , C07D307/18 , C07D405/12 , A61K2121/00 , A61K2123/00
摘要： The present invention provides metal chelating compounds, to chelates and chelate-targeting agent conjugates formed from the chelating compounds, and to methods for making and using these compositions. The chelating compounds incorporate two nitrogen atoms and three sulfur atoms ("N.sub.2 S.sub.3 "), two nitrogen atoms and four sulfur atoms ("N.sub.2 S.sub.4 "), or three nitrogen atoms and three sulfur atoms ("N.sub.3 S.sub.3 "). Metals, and metal oxides, capable of being chelated by the compounds include those that are radionuclides, such as .sup.99m Tc and .sup.186/188 Re.The targeting agent portion of the chelate-targeting agent conjugates provided includes antibodies, peptides, hormones, enzymes and biological response modifiers. Methods for making the conjugates are provided and encompass the addition of a metal, or metal oxide, to a chelating compound prior to attachment to a targeting agent as well as subsequent to the attachment.Another aspect of the invention provides kits for producing chelate-targeting agent conjugates for radiopharmaceutical use.An additional aspect of the invention provides methods for using the chelate-targeting agent conjugates for diagnostic and therapeutic purposes, such as detection of a target site and delivery of a radionuclide to the site, respectively.
摘要翻译： 本发明提供金属螯合化合物，由螯合化合物形成的螯合物和螯合靶向试剂缀合物，以及制备和使用这些组合物的方法。 螯合化合物包含两个氮原子和三个硫原子（“N2S3”），两个氮原子和四个硫原子（“N2S4”）或三个氮原子和三个硫原子（“N3S3”）。 能够被化合物螯合的金属和金属氧化物包括那些是放射性核素，例如99mTc和186 / 188Re。 提供的螯合靶向药物缀合物的靶向剂部分包括抗体，肽，激素，酶和生物反应调节剂。 提供了制备缀合物的方法，并且包括在附着到靶向剂之前以及在附着之后将金属或金属氧化物加入到螯合化合物中。 本发明的另一方面提供了用于制备用于放射性药物用途的螯合靶向剂缀合物的试剂盒。 本发明的另一方面提供了用于诊断和治疗目的的螯合靶向试剂缀合物的使用方法，例如分别检测靶位点和将放射性核素递送至位点。
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公开(公告)号：US5736120A
公开(公告)日：1998-04-07
申请号：US660262
申请日：1996-06-07
IPC分类号： A61K51/08 , C07C227/18 , C07C229/16 , C07C229/24 , A61K51/00 , A61M36/14
CPC分类号： C07C227/18 , A61K51/083 , A61K51/088 , Y02P20/55
摘要： A method for radiolabelling peptides using polyaminocarboxylate ligands having suitable protecting groups such that they can be added to peptides by standard solid phase or solution phase peptide synthetic chemistry and can be deproteced using standard cleavage/deprotection reagents and produce the peptide/chelate conjugate as a high purity monoaddition product is provided. The cleaved and deprotected ligand-peptide molecules can then be labeled with lanthanide or actinide radionuclides. The protected polyaminocarboxylate ligands form mono-anhydrides or mono-active esters under solid phase or solution phase conditions and permit only the desired monoaddition chelate-peptide conjugate to be formed.
摘要翻译： 使用具有合适保护基团的聚氨基羧酸配体放射性标记肽的方法，使得它们可以通过标准固相或溶液相肽合成化学物质加入到肽中，并且可以使用标准的切割/去保护试剂去脱蛋白，并产生高/低的肽/螯合物缀合物 提供纯度单加成产物。 然后可以用镧系元素或锕系元素放射性核素标记裂解和去保护的配体 - 肽分子。 保护的多氨基羧酸盐配体在固相或溶液相条件下形成单酸酐或单官能酯，并且仅允许形成所需的单加成螯合物 - 肽缀合物。
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公开(公告)号：US5734011A
公开(公告)日：1998-03-31
申请号：US469028
申请日：1995-06-06
IPC分类号： A61K51/00 , A61K49/04 , C07C271/22 , C07K1/02 , C07K1/04 , C07K1/06 , C07K1/107 , C07K4/00 , C07K5/09 , C07K5/093 , A61K38/03
CPC分类号： C07K1/1075 , C07K1/02 , C07K1/04 , C07K5/0815 , C07K5/0819 , Y02P20/55
摘要： Compositions and methods of incorporating ligand precursors and ligands at any location within a peptide during peptide synthesis are disclosed. Derivatives of 2,4,5-triaminopentanoic acid and .gamma.-aminoglutamic acid are selectively incorporated into the peptide during solid phase or liquid phase synthesis, depending upon the choice of protecting groups. Ligand synthesis may then be completed at a later time to produce N.sub.3 S, N.sub.2 S.sub.2, and EDTA type chelating agents.
摘要翻译： 公开了在肽合成期间将配体前体和配体掺入肽内的任何位置的组合物和方法。 取决于保护基团的选择，2,4,5-三氨基戊酸和γ-氨基谷氨酸的衍生物在固相或液相合成期间选择性地掺入肽中。 随后可以在稍后完成配体合成以产生N 3 S，N 2 S 2和EDTA型螯合剂。
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公开(公告)号：US5618513A
公开(公告)日：1997-04-08
申请号：US480372
申请日：1995-06-07
IPC分类号： A61K51/08 , C07C227/18 , C07C229/16 , C07C229/24 , A61K51/00 , A61M36/14
CPC分类号： A61K51/088 , A61K51/083 , C07C227/18 , Y02P20/55
摘要： A method for radiolabelling peptides using polyaminocarboxylate ligands having suitable protecting groups such that they can be added to peptides by standard solid phase or solution phase peptide synthetic chemistry and can be deproteced using standard cleavage/deprotection reagents and produce the peptide/chelate conjugate as a high purity mono-addition product is provided. The cleaved and deprotected ligand-peptide molecules can then be labeled with lanthanide or actinide radionuclides. The protected polyaminocarboxylate ligands form mono-anhydrides or mono-active esters under solid phase or solution phase conditions and permit only the desired monoaddition chelate-peptide conjugate to be formed.
摘要翻译： 使用具有合适保护基团的聚氨基羧酸配体放射性标记肽的方法，使得它们可以通过标准固相或溶液相肽合成化学物质加入到肽中，并且可以使用标准的切割/去保护试剂去脱蛋白，并产生高/低的肽/螯合物缀合物 提供纯度单加成产物。 然后可以用镧系元素或锕系元素放射性核素标记裂解和去保护的配体 - 肽分子。 保护的多氨基羧酸盐配体在固相或溶液相条件下形成单酸酐或单官能酯，并且仅允许形成所需的单加成螯合物 - 肽缀合物。
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30.发明授权
公开(公告)号：US5563250A
公开(公告)日：1996-10-08
申请号：US242702
申请日：1994-05-13
IPC分类号： A61K47/48 , A61K51/04 , A61K51/10 , C07H15/04 , C07H15/12 , C07H15/18 , C07H15/252 , C07K1/107 , C07H3/02 , C07D207/04 , C07D295/04 , C07D307/12 , C07D307/14 , C07D333/00 , C07H5/02 , C07H5/04
CPC分类号： A61K51/0491 , A61K47/48338 , A61K47/48715 , A61K51/1093 , C07H15/04 , C07H15/12 , C07H15/18 , C07H15/252 , C07K1/1077 , A61K2121/00 , A61K2123/00
摘要： The present invention provides cleavable conjugates whose linkers contain a labile bond that is cleavable under a variety of mild conditions, including weakly acidic. Since the agent may be bonded directly to the linker, cleavage can result in release of native agent. The invention also provides methods for producing cleavable conjugates. Preferred agents include drugs, toxins, biological response modifiers, radiodiagnostic compounds, radiotherapeutic compounds, and derivatives thereof. The targeting molecule employed in the invention may be an intact molecule, a fragment thereof, or a functional equivalent thereof. In a particularly preferred embodiment, the targeting molecule is a monoclonal antibody directed towards a tumor-associated antigen in man. The invention further provides methods for delivering to the cytoplasm of a target cell an agent free of its targeting molecule carrier. A diagnostically/therapeutically effective dose of a cleavable conjugate is administered to a warm-blooded animal such as man.
摘要翻译： 本发明提供了可切割的缀合物，其接头含有在多种温和条件下可裂解的不稳定键，包括弱酸性。 由于试剂可以直接与接头键合，所以裂解可导致天然试剂的释放。 本发明还提供了用于产生可切割缀合物的方法。 优选的试剂包括药物，毒素，生物反应调节剂，放射性诊断化合物，放射治疗化合物及其衍生物。 本发明中使用的靶向分子可以是完整分子，其片段或其功能等同物。 在特别优选的实施方案中，靶向分子是针对人类中与肿瘤相关抗原的单克隆抗体。 本发明还提供了向靶细胞的细胞质递送不含其靶向分子载体的试剂的方法。 将可切割缀合物的诊断/治疗有效剂量施用于温血动物如人。
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