公开(公告)号：US20170216398A1

公开(公告)日：2017-08-03

申请号：US15488898

申请日：2017-04-17

Applicant: The United States of America, as represented by the Secretary, Department of Health and Human Serv

Inventor： Ira H. Pastan ,  Masanori Onda ,  Wenhai Liu

IPC: A61K38/16 ,  C07K16/28 ,  C07K16/12 ,  C07K16/30 ,  C07K14/21

CPC classification number: A61K38/164 ,  A61K38/00 ,  A61K47/48484 ,  C07K14/21 ,  C07K16/1214 ,  C07K16/2851 ,  C07K16/2896 ,  C07K16/30 ,  C07K2317/34 ,  C07K2317/56 ,  C07K2317/622 ,  C07K2319/01 ,  C07K2319/55

Abstract: The invention provides a Pseudomonas exotoxin A (PE) comprising an amino acid sequence having a substitution of one or more of amino acid residues E420, D463, Y481, L516, R563, D581, D589, and K606, wherein the amino acid residues are defined by reference to SEQ ID NO: 1. The invention further provides related chimeric molecules, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and phaxinaceutical compositions. Methods of treating or preventing cancer in a mammal, methods of inhibiting the growth of a target cell, methods of producing the PE, and methods of producing the chimeric molecule are further provided by the invention.

公开(公告)号：US20110195020A1

公开(公告)日：2011-08-11

申请号：US13021302

申请日：2011-02-04

Applicant: Chien-Hsing Chang ,  David M. Goldenberg ,  William J. McBride ,  Edmund A. Rossi

Inventor： Chien-Hsing Chang ,  David M. Goldenberg ,  William J. McBride ,  Edmund A. Rossi

IPC: A61K51/10 ,  A61K39/395 ,  A61K38/17 ,  A61K38/19 ,  A61K38/21 ,  A61K38/18 ,  A61K38/43 ,  A61K51/08 ,  A61K38/20 ,  A61K38/22 ,  A61K38/27 ,  A61K38/29 ,  A61K38/28 ,  A61K38/24 ,  A61P35/00 ,  A61P35/02

CPC classification number: A61K47/48438 ,  A61K31/00 ,  A61K38/00 ,  A61K47/48415 ,  A61K47/48484 ,  A61K47/485 ,  A61K47/48538 ,  A61K47/48546 ,  A61K47/48561 ,  A61K47/48569 ,  A61K47/6811 ,  A61K47/6817 ,  A61K47/6829 ,  A61K47/6833 ,  A61K47/6843 ,  A61K47/6845 ,  A61K47/6849 ,  A61K47/6851 ,  A61K2039/505 ,  B82Y5/00 ,  B82Y10/00 ,  B82Y15/00 ,  C07K14/475 ,  C07K16/18 ,  C07K16/22 ,  C07K16/28 ,  C07K16/2803 ,  C07K16/2833 ,  C07K16/2851 ,  C07K16/2863 ,  C07K16/2881 ,  C07K16/2887 ,  C07K16/2896 ,  C07K16/3007 ,  C07K16/3092 ,  C07K16/32 ,  C07K2317/31 ,  C07K2317/55 ,  C07K2317/76 ,  C07K2319/30 ,  C07K2319/35 ,  C07K2319/70 ,  C07K2319/74 ,  C12N9/12 ,  C12N9/22 ,  C12N9/96 ,  C12Y207/11001 ,  G01N33/54353 ,  G01N33/588 ,  Y02A50/491

Abstract: The present invention concerns methods and compositions for making and using bioactive assemblies of defined compositions, which may have multiple functionalities and/or binding specificities. In particular embodiments, the bioactive assembly is formed using dock-and-lock (DNL) methodology, which takes advantage of the specific binding interaction between dimerization and docking domains (DDD) and anchoring domains (AD) to form the assembly. In various embodiments, one or more effectors may be attached to a DDD or AD sequence. Complementary AD or DDD sequences may be attached to an adaptor module that forms the core of the bioactive assembly, allowing formation of the assembly through the specific DDD/AD binding interactions. Such assemblies may be attached to a wide variety of effector moieties for treatment, detection and/or diagnosis of a disease, pathogen infection or other medical or veterinary condition.

Abstract translation: 本发明涉及用于制备和使用具有多种功能和/或结合特异性的限定组合物的生物活性组合物的方法和组合物。 在特定的实施方案中，生物活性组件使用对接和锁定（DNL）方法形成，其利用二聚化和对接结构域（DDD）和锚定结构域（AD）之间的特异性结合相互作用形成组件。 在各种实施方案中，一个或多个效应物可以连接到DDD或AD序列。 互补AD或DDD序列可以连接到形成生物活性组件核心的适配器模块，从而允许通过特定的DDD / AD结合相互作用形成组装体。 这些组合物可以连接到各种各样的效应部分，用于治疗，检测和/或诊断疾病，病原体感染或其他医学或兽医病症。

公开(公告)号：US07906121B2

公开(公告)日：2011-03-15

申请号：US12417917

申请日：2009-04-03

Applicant: Chien-Hsing Chang ,  David M. Goldenberg ,  William J. McBride ,  Edmund A. Rossi

Inventor： Chien-Hsing Chang ,  David M. Goldenberg ,  William J. McBride ,  Edmund A. Rossi

IPC: A61K39/44 ,  A61K38/19 ,  A61K38/38 ,  A61K38/21 ,  A61K38/17 ,  A61K39/385 ,  A61K51/12 ,  A61K49/00

CPC classification number: A61K47/48438 ,  A61K31/00 ,  A61K38/00 ,  A61K47/48415 ,  A61K47/48484 ,  A61K47/485 ,  A61K47/48538 ,  A61K47/48546 ,  A61K47/48561 ,  A61K47/48569 ,  A61K47/6811 ,  A61K47/6817 ,  A61K47/6829 ,  A61K47/6833 ,  A61K47/6843 ,  A61K47/6845 ,  A61K47/6849 ,  A61K47/6851 ,  A61K2039/505 ,  B82Y5/00 ,  B82Y10/00 ,  B82Y15/00 ,  C07K14/475 ,  C07K16/18 ,  C07K16/22 ,  C07K16/28 ,  C07K16/2803 ,  C07K16/2833 ,  C07K16/2851 ,  C07K16/2863 ,  C07K16/2881 ,  C07K16/2887 ,  C07K16/2896 ,  C07K16/3007 ,  C07K16/3092 ,  C07K16/32 ,  C07K2317/31 ,  C07K2317/55 ,  C07K2317/76 ,  C07K2319/30 ,  C07K2319/35 ,  C07K2319/70 ,  C07K2319/74 ,  C12N9/12 ,  C12N9/22 ,  C12N9/96 ,  C12Y207/11001 ,  G01N33/54353 ,  G01N33/588 ,  Y02A50/491

Abstract: The present invention concerns methods and compositions for making and using bioactive assemblies of defined compositions, which may have multiple functionalities and/or binding specificities. In particular embodiments, the bioactive assembly is formed using dock-and-lock (DNL) methodology, which takes advantage of the specific binding interaction between dimerization and docking domains (DDD) and anchoring domains (AD) to form the assembly. In various embodiments, one or more effectors may be attached to a DDD or AD sequence. Complementary AD or DDD sequences may be attached to an adaptor module that forms the core of the bioactive assembly, allowing formation of the assembly through the specific DDD/AD binding interactions. Such assemblies may be attached to a wide variety of effector moieties for treatment, detection and/or diagnosis of a disease, pathogen infection or other medical or veterinary condition.

Abstract translation: 本发明涉及用于制备和使用具有多种功能和/或结合特异性的限定组合物的生物活性组合物的方法和组合物。 在特定的实施方案中，生物活性组件使用对接和锁定（DNL）方法形成，其利用二聚化和对接结构域（DDD）和锚定结构域（AD）之间的特异性结合相互作用形成组件。 在各种实施方案中，一个或多个效应物可以连接到DDD或AD序列。 互补AD或DDD序列可以连接到形成生物活性组件核心的适配器模块，从而允许通过特定的DDD / AD结合相互作用形成组装体。 这些组合物可以连接到各种各样的效应部分，用于治疗，检测和/或诊断疾病，病原体感染或其他医学或兽医病症。

公开(公告)号：US6103235A

公开(公告)日：2000-08-15

申请号：US843409

申请日：1997-04-15

Applicant: David M. Neville ,  Stuart Knechtle

Inventor： David M. Neville ,  Stuart Knechtle

IPC: A61K47/48 ,  C07K16/28 ,  A61K39/395 ,  A61K39/00

CPC classification number: A61K47/48484 ,  A61K47/48561 ,  C07K16/2809 ,  A61K2039/505 ,  C07K2317/77

Abstract: Provided is a method of treating an immune system disorder not involving T cell proliferation, comprising administering to the animal an immunotoxin comprising a mutant diphtheria toxin moiety linked to an antibody moiety which routes by the anti-CD3 pathway, or derivatives thereof under conditions such that the disorder is treated. Thus, the present method can treat graft-versus-host disease. Also provided is a method of inhibiting a rejection response by inducing immune tolerance in a recipient to a foreign mammalian donor tissue or cells, comprising the steps of: a) exposing the recipient to an immunotoxin so as to reduce the recipients's peripheral blood T-cell lymphocyte population by at least 80%, wherein the immunotoxin is anti-CD3 antibody linked to a diphtheria protein toxin, wherein the protein has a binding site mutation; and b) transplanting the donor cells into the recipient, whereby a rejection response by the recipient to the donor organ cell is inhibited, and the host is tolerized to the donor cell.

Abstract translation: 提供了一种治疗不涉及T细胞增殖的免疫系统疾病的方法，包括对动物施用免疫毒素，所述免疫毒素包含与通过抗CD3途径途径的抗体部分连接的突变白喉毒素部分或其衍生物， 该疾病得到治疗。 因此，本方法可以治疗移植物抗宿主病。 还提供了通过在外来哺乳动物供体组织或细胞的受体中诱导免疫耐受来抑制排斥反应的方法，包括以下步骤：a）将受体暴露于免疫毒素以便减少受体的外周血T细胞 淋巴细胞群体至少80％，其中所述免疫毒素是与白喉蛋白毒素连接的抗CD3抗体，其中所述蛋白质具有结合位点突变; 和b）将供体细胞移植到受体中，由此受体对供体器官细胞的排斥反应被抑制，并且宿主对供体细胞是耐受的。

公开(公告)号：US5980895A

公开(公告)日：1999-11-09

申请号：US809668

申请日：1997-08-21

Applicant: Ira Pastan ,  Chien-Tsun Kuan

Inventor： Ira Pastan ,  Chien-Tsun Kuan

IPC: A61K31/00 ,  A61K38/00 ,  A61K39/395 ,  A61K47/48 ,  A61P31/04 ,  A61P35/00 ,  A61P37/02 ,  C07K16/30 ,  C07K16/32 ,  C07K16/00

CPC classification number: A61K47/48569 ,  A61K47/48369 ,  A61K47/48484 ,  C07K16/30 ,  C07K16/32 ,  A61K2039/505 ,  A61K38/00 ,  C07K2317/624 ,  C07K2319/00

Abstract: This invention provides for immunotoxins comprising a Pseudomonas exotoxin (PE) that does not require proteolytic activation for cytotoxic activity attached to an Fv antibody fragment having a variable heavy chain region bound through at least one disulfide bond to a variable light chain region. The combination of a "disulfide-stabilized" binding agent fused to a PE that does not require proteolytic activation provides an immunotoxin having surprising cytotoxic activity.

Abstract translation: PCT No.PCT / US96 / 16327 Sec。 371日期1997年8月21日 102（e）日期1997年8月21日PCT提交1996年10月11日PCT公布。 第WO97 / 13529号公报 日期1997年04月17日本发明提供了包含假单胞菌外毒素（PE）的免疫毒素，其不需要蛋白水解活化，附着于具有通过至少一个二硫键结合至可变轻链的可变重链区的Fv抗体片段的细胞毒活性 地区。 与不需要蛋白水解活化的PE融合的“二硫键稳定”结合剂的组合提供具有惊人的细胞毒活性的免疫毒素。

公开(公告)号：US5912322A

公开(公告)日：1999-06-15

申请号：US839425

申请日：1997-04-14

Applicant: Mark W. Riemen ,  Steven M. Stirdivant

Inventor： Mark W. Riemen ,  Steven M. Stirdivant

IPC: A61K47/48 ,  C07K14/21 ,  C07K14/485 ,  C07K14/495 ,  C07K14/00 ,  C12N15/00

CPC classification number: B82Y5/00 ,  A61K47/48353 ,  A61K47/48484 ,  C07K14/21 ,  C07K14/485 ,  C07K14/495 ,  C07K2319/00

Abstract: Psuedomonas exotoxin 40 is modified by deleting or substituting one or more cysteine residues. Such a modified protein may be incorporated into a fusion protein with TGF.alpha.. The resulting fusion protein exhibits altered biological activities from unmodified TGF.alpha.-PE.sub.40, including decreased cell killing activity and increase receptor-binding activity.

Abstract translation: 通过删除或取代一个或多个半胱氨酸残基来修饰Psuedomonas外毒素40。 这种修饰的蛋白质可以掺入到具有TGFα的融合蛋白中。 所得的融合蛋白表现出来自未修饰的TGFα-PE40的生物活性改变，包括降低的细胞杀伤活性和增加受体结合活性。

公开(公告)号：US5869045A

公开(公告)日：1999-02-09

申请号：US459354

申请日：1995-06-02

Applicant: Ingegerg Hellstrom ,  Karl Erik Hellstrom ,  Kim Folger Bruce ,  George J. Schreiber

Inventor： Ingegerg Hellstrom ,  Karl Erik Hellstrom ,  Kim Folger Bruce ,  George J. Schreiber

IPC: A61K38/00 ,  A61K47/48 ,  A61K49/00 ,  A61K51/10 ,  C07K14/415 ,  C07K16/30 ,  C12N15/10 ,  G01N33/574 ,  A61K39/395 ,  C07K16/00

CPC classification number: A61K47/48407 ,  A61K47/48415 ,  A61K47/48484 ,  A61K47/48569 ,  A61K49/0058 ,  A61K51/1045 ,  A61K51/1087 ,  C07K14/415 ,  C07K16/30 ,  C12N15/10 ,  G01N33/57484 ,  A61K2123/00 ,  A61K38/00 ,  C07K2317/24 ,  C07K2317/54 ,  C07K2317/55 ,  C07K2317/56 ,  C07K2317/622 ,  C07K2317/732 ,  C07K2317/734 ,  C07K2317/77 ,  C07K2319/00

Abstract: The present invention relates to novel antibodies, antibody fragments and antibody conjugates and single-chain immunotoxins reactive with human carcinoma cells. More particularly, the antibodies, conjugates and single-chain immunotoxins of the invention include: a murine monoclonal antibody, BR96; a human/murine chimeric antibody, ChiBR96; a F(ab').sub.2 fragment of BR96; ChiBR96-PE, ChiBR96-LysPE40, ChiBR96 F(ab').sub.2 -LysPE40 and ChiBR96 Fab'-LysPE40 conjugates and recombinant BR96 sFv-PE40 immunotoxin. These molecules are reactive with a cell membrane antigen on the surface of human carcinomas. The BR96 antibody and its functional equivalents, displays a high degree of selectivity for carcinoma cells and possess the ability to mediate antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activity. In addition, the antibodies of the invention internalize within the carcinoma cells to which they bind and are therefore particularly useful for therapeutic applications, for example, as the antibody component of antibody-drug or antibody-toxin conjugates. The antibodies also have a unique feature in that they are cytotoxic when used in the unmodified form, at specified concentrations.

Abstract translation: 本发明涉及与人癌细胞反应的新型抗体，抗体片段和抗体缀合物和单链免疫毒素。 更具体地，本发明的抗体，缀合物和单链免疫毒素包括：鼠单克隆抗体BR96; 人/鼠嵌合抗体，ChiBR96; BR96的F（ab'）2片段; ChiBR96-PE，ChiBR96-LysPE40，ChiBR96F（ab'）2-LysPE40和ChiBR96 Fab'-LysPE40缀合物和重组BR96sFv-PE40免疫毒素。 这些分子与人类癌症表面的细胞膜抗原反应。 BR96抗体及其功能等同物对癌细胞显示出高度的选择性，并具有介导抗体依赖性细胞毒性和补体依赖性细胞毒活性的能力。 此外，本发明的抗体内在于它们结合的癌细胞内，因此特别可用于治疗应用，例如作为抗体药物或抗体 - 毒素缀合物的抗体组分。 抗体还具有独特的特征，因为当以指定浓度以未修饰的形式使用时，它们是细胞毒性的。

公开(公告)号：US5863745A

公开(公告)日：1999-01-26

申请号：US461825

申请日：1995-06-05

Applicant: David J. Fitzgerald ,  Vijay Kumar Chaudhary ,  Ira H. Pastan ,  Thomas Alexander Waldmann ,  Cary L. Queen

Inventor： David J. Fitzgerald ,  Vijay Kumar Chaudhary ,  Ira H. Pastan ,  Thomas Alexander Waldmann ,  Cary L. Queen

IPC: A61K38/00 ,  A61K39/00 ,  A61K47/48 ,  C07K14/21 ,  C07K14/495 ,  C07K14/55 ,  C07K16/28 ,  C12N15/62 ,  G01N33/563 ,  C07K16/46

CPC classification number: A61K47/48561 ,  A61K47/48369 ,  A61K47/48484 ,  C07K14/21 ,  C07K14/495 ,  C07K14/55 ,  C07K16/2866 ,  C07K16/2896 ,  C12N15/62 ,  A61K38/00 ,  A61K39/00 ,  C07K2319/00 ,  C07K2319/55

Abstract: The present invention describes recombinant antibody toxin fusion proteins which selectively kill cells bearing appropriate antigens or receptors.

Abstract translation: 本发明描述了选择性地杀死携带合适抗原或受体的细胞的重组抗体毒素融合蛋白。

公开(公告)号：US5837268A

公开(公告)日：1998-11-17

申请号：US694865

申请日：1996-08-09

Applicant: Andrew A. Potter ,  John G. Manns

Inventor： Andrew A. Potter ,  John G. Manns

IPC: C12N15/09 ,  A61K39/00 ,  A61K39/39 ,  A61K47/48 ,  A61P15/18 ,  A61P35/00 ,  C07K5/103 ,  C07K5/11 ,  C07K5/113 ,  C07K5/117 ,  C07K7/23 ,  C07K14/14 ,  C07K14/285 ,  C07K14/575 ,  C07K14/655 ,  C07K16/26 ,  C07K19/00 ,  C12N1/21 ,  C12N15/16 ,  C12P21/02 ,  C12R1/19 ,  A61K38/00 ,  A61K39/02 ,  C07K2/00 ,  C12N15/00

CPC classification number: A61K39/0006 ,  A61K47/48238 ,  A61K47/4833 ,  A61K47/48484 ,  A61K47/485 ,  C07K14/005 ,  C07K14/285 ,  C07K14/655 ,  C07K16/26 ,  C07K5/1008 ,  C07K5/1019 ,  C07K5/1021 ,  C07K5/1024 ,  C07K7/23 ,  A61K2039/6037 ,  A61K39/00 ,  C07K2319/00 ,  C12N2720/12322

Abstract: New immunological carrier systems, DNA encoding the same, and the use of these systems, are disclosed. The carrier systems include chimeric proteins which include a leukotoxin polypeptide fused to one or more selected GnRH multimers which comprise at least one repeating GnRH decapeptide sequence, or at least one repeating unit of a sequence corresponding to at least one epitope of a selected GnRH molecule. Under the invention, the selected GnRH sequences may all be the same, or may correspond to different derivatives, analogues, variants or epitopes of GnRH so long as the GnRH sequences are capable of eliciting an immune response. The leukotoxin functions to increase the immunogenicity of the GnRH multimers fused thereto.

公开(公告)号：US4806494A

公开(公告)日：1989-02-21

申请号：US888960

申请日：1986-07-24

Applicant: Ira Pastan ,  David J. Fitzgerald ,  Mark Willingham

Inventor： Ira Pastan ,  David J. Fitzgerald ,  Mark Willingham

IPC: A61K38/00 ,  A61K47/48 ,  C07K16/30 ,  G01N33/53 ,  A61K39/00 ,  A61K45/02 ,  G01N33/543

CPC classification number: C07K16/30 ,  A61K47/48484 ,  A61K47/48584 ,  A61K38/00

Abstract: Monoclonal antibodies are produced which specifically bind to human ovarian cancer cells. These antibodies are conjugated to Pseudomonas exotoxin in order to produce an immunotoxin suitable for the chemotherapeutic treatment of human ovarian cancer.

Abstract translation: 产生特异性结合人卵巢癌细胞的单克隆抗体。 这些抗体与假单胞菌外毒素结合，以产生适用于人卵巢癌化学治疗的免疫毒素。