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1. 发明申请

WO2007016150A3 MUTATED PSEUDOMONAS EXOTOXINS WITH REDUCED ANTIGENICITY 审中-公开
标题翻译：具有降低抗原性的突变假单孢菌外毒素
公开(公告)号：WO2007016150A3
公开(公告)日：2007-08-09
申请号：PCT/US2006028986
申请日：2006-07-25
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , FITZGERALD DAVID , KREITMAN ROBERT , LEE BYUNGKOOK
发明人： PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , FITZGERALD DAVID , KREITMAN ROBERT , LEE BYUNGKOOK
IPC分类号： C07K14/195 , A61K38/16 , A61K47/48 , C07K14/21 , C07K19/00
CPC分类号： A61K47/48484 , A61K38/00 , A61K47/6829 , C07K14/21 , C07K2319/33
摘要： The invention provides mutated Pseudomonas exotoxins (PE) that have reduced immunogenicity compared to PEs containing the native sequence. The PEs of the invention have one or more individual mutations of positions of the native sequence of PE that reduce antibody binding to one or more PE epitopes. Nucleic acids encoding the mutated PEs, chimeric molecules comprising them, compositions comprising the chimeric molecules and methods of using them, are also provided.
摘要翻译：本发明提供与含有天然序列的PE相比具有降低的免疫原性的突变假单胞菌外毒素（PE）。本发明的PE具有减少抗体与一个或多个PE表位结合的PE天然序列位置的一个或多个单独突变。还提供了编码突变PE的核酸，包含它们的嵌合分子，包含嵌合分子的组合物和使用它们的方法。

2. 发明申请

WO0240545A9 REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT 审中-公开
标题翻译：通过打破FV的框架区域来降低免疫动力学的非特异性动物毒性以降低ISOELECTRIC POINT
公开(公告)号：WO0240545A9
公开(公告)日：2003-02-06
申请号：PCT/US0143602
申请日：2001-11-16
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
发明人： PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
IPC分类号： A61K47/48 , A61P35/00 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/28 , C07K16/30 , C12N1/21 , C07K19/00 , C12N15/62 , C12N15/70
CPC分类号： C07K16/28 , A61K47/6829 , A61K47/6849 , A61K47/6867 , A61K2039/505 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/2803 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K2317/56 , C07K2317/567 , C07K2317/624 , C07K2319/02
摘要： The invention provides recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. The immunotoxins are created by specifically mutating charged residues in the framework regions of the heavy chain, the light chain, or both, of the antibody portion or antigen-binding fragment thereof of the parental immunotoxin to reduce the pI of the antibody or fragment. In preferred forms, the antibody portion of the parental is an anti-Tac, anti-mesothelin, or anti-LewisY antigen antibody or antigen-binding fragment, and in particularly preferred forms the antibody portion is an M16 dsFv, a St6 dsFv or a Mt9 dsFv, or a sequence that has at least 90% sequence identity to one of these molecules but retain the particular mutations that lower pI without affecting antibody activity. The invention further provides nucleic acids encoding the recombinant immunotoxins of the invention, expression cassettes comprising the nucleic acids, and host cells comprising the expression cassettes. The invention also provides a method for killing a cell comprising an antigen on the surface of the cell, the method comprising contacting the cell with a recombinant immunotoxin of the invention that has an antibody or antigen-binding fragment thereof that binds specifically to the antigen on the surface of the cell, and uses of immunotoxins of the invention for the manufacture of medicaments.
摘要翻译：本发明提供已经从亲本免疫毒素修饰以降低肝毒性的重组免疫毒素。免疫毒素通过在亲本免疫毒素的抗体部分或其抗原结合片段的重链，轻链或两者的构架区中特异性突变带电残基而产生，以减少抗体或片段的pI。在优选形式中，亲本的抗体部分是抗Tac，抗间皮素或抗LewisY抗原抗体或抗原结合片段，并且在特别优选的形式中，抗体部分是M16 dsFv，St6 dsFv或 Mt9 dsFv或与这些分子之一具有至少90％序列同一性的序列，但保留降低pI而不影响抗体活性的特定突变。本发明还提供编码本发明的重组免疫毒素的核酸，包含核酸的表达盒和包含表达盒的宿主细胞。本发明还提供了一种用于杀死细胞表面上包含抗原的细胞的方法，所述方法包括使细胞与本发明的重组免疫毒素接触，所述重组免疫毒素具有抗体或其抗原结合片段，其特异性与抗原结合细胞的表面，以及本发明的免疫毒素用于制备药物的用途。

3. 发明申请

WO0240545A2 REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT 审中-公开
标题翻译：通过打破FV的框架区域来降低免疫动力学的非特异性动物毒性以降低ISOELECTRIC POINT
公开(公告)号：WO0240545A2
公开(公告)日：2002-05-23
申请号：PCT/US0143602
申请日：2001-11-16
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
发明人： PASTAN IRA H , ONDA MASANORI , NAGATA SATOSHI , TSUTSUMI YASUO , VINCENT JAMES J , KREITMAN ROBERT J , VASMATZIS GEORGE , LEE BYUNGKOOK
IPC分类号： A61K47/48 , A61P35/00 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/28 , C07K16/30 , C12N1/21 , C07K19/00 , C12N15/62 , C12N15/70
CPC分类号： C07K16/28 , A61K47/6829 , A61K47/6849 , A61K47/6867 , A61K2039/505 , C07K14/21 , C07K16/00 , C07K16/18 , C07K16/2803 , C07K16/2866 , C07K16/2896 , C07K16/30 , C07K2317/56 , C07K2317/567 , C07K2317/624 , C07K2319/02
摘要： The invention provides recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. The immunotoxins are created by specifically mutating charged residues in the framework regions of the heavy chain, the light chain, or both, of the antibody portion or antigen-binding fragment thereof of the parental immunotoxin to reduce the pI of the antibody or fragment. In preferred forms, the antibody portion of the parental is an anti-Tac, anti-mesothelin, or anti-LewisY antigen antibody or antigen-binding fragment, and in particularly preferred forms the antibody portion is an M16 dsFv, a St6 dsFv or a Mt9 dsFv, or a sequence that has at least 90% sequence identity to one of these molecules but retain the particular mutations that lower pI without affecting antibody activity. The invention further provides nucleic acids encoding the recombinant immunotoxins of the invention, expression cassettes comprising the nucleic acids, and host cells comprising the expression cassettes. The invention also provides a method for killing a cell comprising an antigen on the surface of the cell, the method comprising contacting the cell with a recombinant immunotoxin of the invention that has an antibody or antigen-binding fragment thereof that binds specifically to the antigen on the surface of the cell, and uses of immunotoxins of the invention for the manufacture of medicaments.
摘要翻译：本发明提供已经从亲本免疫毒素修饰以降低肝毒性的重组免疫毒素。免疫毒素通过在亲本免疫毒素的抗体部分或其抗原结合片段的重链，轻链或两者的构架区中特异性突变带电残基而产生，以减少抗体或片段的pI。在优选形式中，亲本的抗体部分是抗Tac，抗间皮素或抗LewisY抗原抗体或抗原结合片段，并且在特别优选的形式中，抗体部分是M16 dsFv，St6 dsFv或 Mt9 dsFv或与这些分子之一具有至少90％序列同一性的序列，但保留降低pI而不影响抗体活性的特定突变。本发明还提供编码本发明的重组免疫毒素的核酸，包含核酸的表达盒和包含表达盒的宿主细胞。本发明还提供了一种用于杀死细胞表面上包含抗原的细胞的方法，所述方法包括使细胞与本发明的重组免疫毒素接触，所述重组免疫毒素具有抗体或其抗原结合片段，其特异性与抗原结合细胞的表面，以及本发明的免疫毒素用于制备药物的用途。

4. 发明申请

WO0195942A3 PEGYLATION OF LINKERS IMPROVES ANTITUMOR ACTIVITY AND REDUCES TOXICITY OF IMMUNOCONJUGATES 审中-公开
标题翻译：链接的聚合改善抗肿瘤活性并降低免疫球蛋白的毒性
公开(公告)号：WO0195942A3
公开(公告)日：2003-07-31
申请号：PCT/US0118503
申请日：2001-06-08
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , TSUTSUMI YASUO , ONDA MASANORI , NAGATA SATOSHI , LEE BYUNGKOOK , KREITMAN ROBERT J
发明人： PASTAN IRA H , TSUTSUMI YASUO , ONDA MASANORI , NAGATA SATOSHI , LEE BYUNGKOOK
IPC分类号： A61K38/00 , A61K39/395 , A61K47/48 , A61P35/00 , A61P43/00
CPC分类号： A61K47/6849 , A61K47/6829
摘要： The present invention is directed to the site-specific PEGylation of immunoconjugates. In particular, the present invention provides immunoconjugates wherein a connector molecule attaching a targeting molecule to an effector molecule is conjugated to one or more polyethylene glycol molecules. The present invention further provides methods for increasing the antitumor activity of an immunotoxin, comprising attaching in a site-specific manner one or more polyethylene glycol molecules to a linker connecting a toxic moiety to a targeting moiety of an immunotoxin.
摘要翻译：本发明涉及免疫缀合物的位点特异性PEG化。特别地，本发明提供免疫偶联物，其中将靶向分子连接至效应分子的连接分子与一个或多个聚乙二醇分子缀合。本发明还提供了增加免疫毒素的抗肿瘤活性的方法，包括以位点特异性方式将一个或多个聚乙二醇分子连接到将毒性部分连接到免疫毒素的靶向部分的连接体上。

5. 发明申请

WO2007040653A3 ANTI-CD30 ANTIBODIES THAT BIND TO INTACT CD30 BUT NOT SOLUBLE CD30 审中-公开
标题翻译：抗CD30抗体，结合CD30而不是可溶性CD30
公开(公告)号：WO2007040653A3
公开(公告)日：2007-08-02
申请号：PCT/US2006019128
申请日：2006-05-16
申请人： US GOV HEALTH & HUMAN SERV , HOPE CITY , PASTAN IRA H , NAGATA SATOSHI , ONDA MASANORI , ISE TOMOKO , RAUBITSCHEK ANDREW
发明人： PASTAN IRA H , NAGATA SATOSHI , ONDA MASANORI , ISE TOMOKO , RAUBITSCHEK ANDREW
IPC分类号： C07K16/28 , A61K39/395 , A61K47/48 , A61P35/00 , C07K16/30 , C12N15/13
CPC分类号： C07K16/2878 , A61K47/6829 , A61K47/6849 , A61K51/1039 , C07K16/30
摘要： Because CD30 is highly expressed on Hodgkin's lymphoma and anaplastic large cell lymphoma, it is a promising target for immunotherapy. The extracellular portion of CD30 is cleaved, releasing a form known as soluble CD30 ("sCD30"), which can reduce the effects of CD30-targeting agents by competitive binding. The invention relates in part to the discovery of two epitopes on membrane-associated CD30 that are missing on soluble CD30 due to a conformational change upon shedding that a conformational change occurs when CD30 is cleaved, making these epitopes unavailable for binding. Ligands that bind to these epitopes can be used to target cells with intact CD30 without competition from sCD30.
摘要翻译：因为CD30在霍奇金淋巴瘤和间变性大细胞淋巴瘤中高度表达，所以它是免疫疗法的有希望的靶标。 CD30的胞外部分被切割，释放称为可溶性CD30（“sCD30”）的形式，其可通过竞争性结合减少CD30-靶向剂的作用。本发明部分涉及在膜相关CD30上发现两个在可溶性CD30上缺失的表位，这是由于当释放CD30时发生构象变化时发生构象变化，使得这些表位不可用于结合。与这些表位结合的配体可用于靶向具有完整CD30的细胞，而不会与sCD30竞争。

6. 发明申请

WO2005080436A3 ANTIBODIES THAT BIND POTE AND USES THEREOF 审中-公开
标题翻译：抗体，其包装和其用途
公开(公告)号：WO2005080436A3
公开(公告)日：2007-12-06
申请号：PCT/US2005005419
申请日：2005-02-18
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA H , BERA TAPAN , LEE BYUNGKOOK , NAGATA SATOSHI , ISE TOMOKO
发明人： PASTAN IRA H , BERA TAPAN , LEE BYUNGKOOK , NAGATA SATOSHI , ISE TOMOKO
IPC分类号： C07K16/18 , C07K14/47 , C07K16/30 , G01N33/574
CPC分类号： G01N33/574 , C07K14/47 , C07K16/30
摘要： POTE-21 and its paralogs are expressed in cancer, such as breast, prostate, lung, colon, pancreatic and ovarian cancer. Antibodies are disclosed herein that bind the N-terminal (extracellular) portion of POTE, or a paralog of POTE. These antibodies are of use in the detection and treatment of cancer. Methods for the treatment of cancer using a POTE polypeptide or fragment thereof are also described.
摘要翻译： POTE-21及其旁系同源物在癌症中表达，如乳腺癌，前列腺癌，肺癌，结肠癌，胰腺癌和卵巢癌。本文公开了结合POTE的N末端（细胞外）部分或POTE的旁系同源物的抗体。这些抗体可用于癌症的检测和治疗。还描述了使用POTE多肽或其片段治疗癌症的方法。

7. 发明申请

WO2008103905A3 ANTIBODIES THAT SPECIFICALLY BIND IRTA AND METHODS OF USE 审中-公开
标题翻译：特异性IRTA和使用方法的抗体
公开(公告)号：WO2008103905A3
公开(公告)日：2008-12-31
申请号：PCT/US2008054720
申请日：2008-02-22
申请人： US GOV HEALTH & HUMAN SERV , PASTAN IRA , NAGATA SATOSHI , ISE TOMOKO
发明人： PASTAN IRA , NAGATA SATOSHI , ISE TOMOKO
IPC分类号： C07K16/28 , A61K39/395 , A61P35/00 , G01N33/569
CPC分类号： C07K16/283 , C07K14/70535 , G01N33/564 , G01N2800/065 , G01N2800/102 , G01N2800/104 , G01N2800/205
摘要： Antibodies that specifically bind the extracellular domain of IRT A3 immunoglobulin superfamily receptor translocation associated or that specifically bind the extracellular domain of IRTA5 are disclosed herein. Antibodies ' that specifically bind to IRT A3 do not specifically bind IRTAl, IRT A2, IRTA4, IRTA5, or IRTA6. Antibodies that specifically bind to IRTA5 do not specifically bind IRTAl, IRTA2, IRTA3, IRTA4, or IRTA6. The antibodies can be conjugated to effector molecules, including detectable labels, radionucleotides, toxins and chemotherapeutic agents. Nucleic acid molecules encoding these antibodies, expression vectors, host cells and methods for expressing the antibodies are also provided. Methods also are provided for detecting IRTA5 or for detecting IRT A3, as well as methods for treating various B cell malignancies. Methods are disclosed for assessing the efficacy of a therapy for an autoimmune disease.
摘要翻译：本文公开了特异性结合IRT A3免疫球蛋白超家族受体易位的胞外结构域或特异性结合IRTA5的细胞外结构域的抗体。特异性结合IRT A3的抗体不特异性结合IRTA1，IRT2A，IRTA4，IRTA5或IRTA6。特异性结合IRTA5的抗体不特异性结合IRTA1，IRTA2，IRTA3，IRTA4或IRTA6。抗体可以与效应分子结合，包括可检测标记，放射性核苷酸，毒素和化学治疗剂。还提供了编码这些抗体的核酸分子，表达载体，宿主细胞和用于表达抗体的方法。还提供了用于检测IRTA5或用于检测IRT A3的方法，以及用于治疗各种B细胞恶性肿瘤的方法。公开了评估自身免疫性疾病治疗疗效的方法。

8. 发明申请

WO2006039238A3 IRTA2 ANTIBODIES AND METHODS OF USE 审中-公开
标题翻译： IRTA2抗体和使用方法
公开(公告)号：WO2006039238A3
公开(公告)日：2007-01-25
申请号：PCT/US2005034444
申请日：2005-09-22
申请人： GOVERMENT OF THE US SECRETARY , PASTAN IRA H , ISE TOMOKO , XIANG LAIMAN , NAGATA SATOSHI
发明人： PASTAN IRA H , ISE TOMOKO , XIANG LAIMAN , NAGATA SATOSHI
IPC分类号： A61K39/395 , A61P35/02 , C07K16/28 , C07K19/00 , C12N5/20 , C12N15/13 , G01N33/53
CPC分类号： G01N33/57407 , A61K2039/505 , C07K16/2803 , G01N33/57426
摘要： Antibodies that specifically bind the extracellular domain of IRTA2 are disclosed herein. In one embodiment, these antibodies do not specifically bind IRTA1, IRTA3., IRTA4, or IRTA5. In one example, the antibodies are humanized antibodies. The antibodies can be conjugated to effector molecules, including detectable labels, radionucleotides, toxins and chemotherapeutic agents. The antibodies that specifically bind IRTA2 are of use to detect B cell malignancies, such as hairy cell leukemia and non-Hodgkin's lymphoma. These antibodies that specifically bind IRTA2 are also of use to treat B cell malignancies that express IRTA2, such as hairy cell leukemia and non-Hodgkin's lymphoma.
摘要翻译：本文公开了特异性结合IRTA2细胞外结构域的抗体。在一个实施方案中，这些抗体不特异性结合IRTA1，IRTA3，IRTA4或IRTA5。在一个实例中，抗体是人源化抗体。抗体可以与效应分子结合，包括可检测的标记，放射性核苷酸，毒素和化学治疗剂。特异性结合IRTA2的抗体可用于检测B细胞恶性肿瘤，如毛细胞白血病和非霍奇金淋巴瘤。特异性结合IRTA2的这些抗体也可用于治疗表达IRTA2的B细胞恶性肿瘤，例如毛细胞白血病和非霍奇金淋巴瘤。

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