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    Multiple Signaling Pathways Induced by Hexavalent, Monospecific and Bispecific Antibodies for Enhanced Toxicity to B-Cell Lymphomas and Other Diseases
    3.
    发明申请
    Multiple Signaling Pathways Induced by Hexavalent, Monospecific and Bispecific Antibodies for Enhanced Toxicity to B-Cell Lymphomas and Other Diseases 有权
    用于增强B细胞淋巴瘤和其他疾病毒性的六价，单特异性和双特异性抗体诱导的多重信号通路

    公开(公告)号：US20150023870A1

    公开(公告)日：2015-01-22

    申请号：US14491189

    申请日：2014-09-19

    申请人： Chien-Hsing Chang ,  David M. Goldenberg ,  Edmund A. Rossi

    发明人： Chien-Hsing Chang ,  David M. Goldenberg ,  Edmund A. Rossi

    IPC分类号： A61K47/48

    CPC分类号： A61K47/6807 ,  A61K39/3955 ,  A61K47/6811 ,  A61K47/6813 ,  A61K47/6815 ,  A61K47/6849 ,  A61K47/6851 ,  A61K47/6867 ,  A61K47/6885 ,  A61K51/1027 ,  A61K51/1045 ,  C07K14/47 ,  C07K2317/31 ,  C07K2317/732 ,  C07K2317/734 ,  C07K2319/33 ,  C07K2319/70 ,  C07K2319/74

    摘要： Disclosed herein are compositions and methods of use comprising hexavalent DNL complexes. Preferably, the complexes comprise anti-CD20 and/or anti-CD22 antibodies or fragments thereof. More preferably, the anti-CD20 antibody is veltuzumab and the anti-CD22 antibody is epratuzumab. Administration of the subject hexavalent DNL complexes induces apoptosis and cell death of target cells in diseases such as B-cell lymphomas or leukemias, autoimmune disease or immune dysfunction disease. In most preferred embodiments, the DNL complexes increase levels of phosphorylated p38 and PTEN, decrease levels of phosphorylated Lyn, Akt, ERK, IKKα/β and IκBα, increase expression of RKIP and Bax and decrease expression of Mcl-1, Bcl-xL, Bcl-2, and phospho-BAD in target cells. The subject DNL complexes show EC50 values for inhibiting tumor cell growth in the low nanomolar or even sub-nanomolar concentration range.

    摘要翻译： 本文公开了包含六价DNL复合物的组合物和使用方法。 优选地，复合物包含抗CD20和/或抗-CD22抗体或其片段。 更优选地，抗CD20抗体是veltuzumab，抗CD22抗体是依帕珠珠单抗。 主题六价DNL复合物的给药诱导疾病如B细胞淋巴瘤或白血病，自身免疫疾病或免疫功能障碍疾病中靶细胞的凋亡和细胞死亡。 在最优选的实施方案中，DNL复合物增加磷酸化p38和PTEN的水平，降低磷酸化Lyn，Akt，ERK，IKKα/ bgr的水平; 和Bα，增加RKIP和Bax的表达，并降低靶细胞中Mcl-1，Bcl-xL，Bcl-2和phospho-BAD的表达。 受试者DNL复合物显示在低纳摩尔或甚至亚纳摩尔浓度范围内抑制肿瘤细胞生长的EC 50值。

    Dock-and-lock (DNL) complexes for delivery of interference RNA
    5.
    发明授权
    Dock-and-lock (DNL) complexes for delivery of interference RNA 有权
    Dock-and-lock（DNL）复合物用于传递干扰RNA

    公开(公告)号：US08491914B2

    公开(公告)日：2013-07-23

    申请号：US12964021

    申请日：2010-12-09

    申请人： Chien-Hsing Chang ,  David M. Goldenberg

    发明人： Chien-Hsing Chang ,  David M. Goldenberg

    IPC分类号： A61K39/44 ,  C07K16/28 ,  C07K16/46 ,  C07K14/00 ,  C07H21/02

    CPC分类号： A61K47/484 ,  A61K47/48561 ,  A61K47/48576 ,  A61K47/48723 ,  A61K47/6849 ,  A61K47/6853 ,  A61K47/6891 ,  B82Y5/00 ,  C07K16/2803 ,  C07K16/2887 ,  C07K16/3007 ,  C07K16/468 ,  C07K2317/31 ,  C07K2317/55 ,  C07K2317/77 ,  C07K2317/92 ,  C07K2318/10 ,  C07K2319/00 ,  C07K2319/30

    摘要： Described herein are compositions and methods of use of targeted delivery complexes for delivery of siRNA to a disease-associated cell, tissue or pathogen. The targeted delivery complex comprises a targeting molecule, such as an antibody or fragment thereof, conjugated to one or more siRNA carriers. In preferred embodiments the siRNA carrier is a dendrimer or protamine and the targeting molecule is an anti-cancer antibody, such as hRS7. More preferably, the antibody or fragment is rapidly internalized into the target cell to facilitate uptake of the siRNA. Most preferably, the targeted delivery complex is made by the DNL technique. The compositions and methods are of use to treat a variety of disease states, such as cancer, autoimmune disease, immune dysfunction, cardiac disease, neurologic disease, inflammatory disease or infectious disease.

    摘要翻译： 本文描述了使用靶向递送复合物以将siRNA递送至疾病相关细胞，组织或病原体的组合物和方法。 靶向递送复合物包含与一种或多种siRNA载体缀合的靶向分子，例如抗体或其片段。 在优选的实施方案中，siRNA载体是树状聚合物或鱼精蛋白，靶向分子是抗癌抗体，例如hRS7。 更优选地，抗体或片段快速内化到靶细胞中以促进siRNA的摄取。 最优选地，靶向递送复合物通过DNL技术制备。 组合物和方法可用于治疗各种疾病状态，例如癌症，自身免疫疾病，免疫功能障碍，心脏病，神经系统疾病，炎性疾病或感染性疾病。

    Multivalent Immunoglobulin-Based Bioactive Assemblies
    9.
    发明申请
    Multivalent Immunoglobulin-Based Bioactive Assemblies 审中-公开
    基于多价免疫球蛋白的生物活性组件

    公开(公告)号：US20120276608A1

    公开(公告)日：2012-11-01

    申请号：US13483761

    申请日：2012-05-30

    申请人： Chien-Hsing Chang ,  David M. Goldenberg ,  Edmund A. Rossi

    发明人： Chien-Hsing Chang ,  David M. Goldenberg ,  Edmund A. Rossi

    IPC分类号： C12N9/96

    CPC分类号： C07K16/468 ,  A61K47/6897 ,  A61K51/088 ,  B82Y5/00 ,  B82Y10/00 ,  C07K16/2803 ,  C07K16/2887 ,  C07K16/3007 ,  C07K16/3092 ,  C07K2317/31 ,  C07K2317/55 ,  C07K2317/73 ,  C07K2317/732 ,  C07K2317/734 ,  C07K2317/92 ,  C07K2319/00 ,  C07K2319/30 ,  C07K2319/70

    摘要： The present invention concerns methods and compositions for stably tethered structures of defined compositions, which may have multiple functionalities and/or binding specificities. Preferred embodiments concern hexameric stably tethered structures comprising one or more IgG antibody fragments and which may be monospecific or bispecific. The disclosed methods and compositions provide a facile and general way to obtain stably tethered structures of virtually any functionality and/or binding specificity. The stably tethered structures may be administered to subjects for diagnostic and/or therapeutic use, for example for treatment of cancer or autoimmune disease. The stably tethered structures may bind to and/or be conjugated to a variety of known effectors, such as drugs, enzymes, radionuclides, therapeutic agents and/or diagnostic agents.

    摘要翻译： 本发明涉及可以具有多种功能和/或结合特异性的限定组合物的稳定的束缚结构的方法和组合物。 优选的实施方案涉及包含一种或多种IgG抗体片段并且可以是单特异性或双特异性的六聚体稳定的束缚结构。 所公开的方法和组合物提供了实现任何功能和/或结合特异性的稳定的束缚结构的简便和一般的方法。 稳定的束缚结构可以施用于受试者用于诊断和/或治疗用途，例如用于治疗癌症或自身免疫性疾病。 稳定的束缚结构可以结合到各种已知的效应物上，和/或与其结合，例如药物，酶，放射性核素，治疗剂和/或诊断剂。

    Compositions and Methods of Use of Immunotoxins Comprising Ranpirnase (Rap) Show Potent Cytotoxic Activity
    10.
    发明申请
    Compositions and Methods of Use of Immunotoxins Comprising Ranpirnase (Rap) Show Potent Cytotoxic Activity 审中-公开
    组合物和使用含有兰泼瑞酶（Rapp）的免疫毒素的方法显示强效细胞活性

    公开(公告)号：US20120276100A1

    公开(公告)日：2012-11-01

    申请号：US13528077

    申请日：2012-06-20

    申请人： Chien-Hsing Chang ,  David M. Goldenberg ,  Edmund A. Rossi

    发明人： Chien-Hsing Chang ,  David M. Goldenberg ,  Edmund A. Rossi

    IPC分类号： C12N9/96 ,  A61P35/02 ,  A61P37/00 ,  A61P37/06 ,  A61K39/395 ,  A61P35/00

    CPC分类号： C07K16/2803 ,  B82Y5/00 ,  B82Y10/00 ,  C07K16/2833 ,  C07K16/2863 ,  C07K16/2887 ,  C07K16/3007 ,  C07K16/3092 ,  C07K2317/24 ,  C07K2317/55 ,  C07K2317/77 ,  C07K2319/70

    摘要： The present invention concerns methods and compositions for forming immunotoxin complexes having a high efficacy and low systemic toxicity. In preferred embodiments, the toxin moiety is a ranpirnase (Rap), such as Rap(Q). In more preferred embodiments, the immunotoxin is made using dock-and-lock (DNL) technology. The immunotoxin exhibits improved pharmacokinetics, with a longer serum half-life and significantly greater efficacy compared to toxin alone, antibody alone, unconjugated toxin plus antibody or even other types of toxin-antibody constructs. In a most preferred embodiment the construct comprises an anti-Trop-2 or anti-CD22 antibody conjugated to Rap, although other combinations of antibodies, antibody fragments and toxins may be used to form the subject immunotoxins. The immunotoxins are of use to treat a variety of diseases, such as cancer, autoimmune disease or immune dysfunction.

    摘要翻译： 本发明涉及用于形成具有高效力和低全身毒性的免疫毒素复合物的方法和组合物。 在优选的实施方案中，毒素部分是兰普瑞酶（Rap），例如Rap（Q）。 在更优选的实施方案中，免疫毒素使用对接 - 锁（DNL）技术制备。 与单独的毒素，单独的抗体，未缀合的毒素加抗体或甚至其它类型的毒素 - 抗体构建体相比，免疫毒素表现出改进的药代动力学，具有较长的血清半衰期和显着更高的功效。 在最优选的实施方案中，构建体包含与Rap结合的抗Trop-2或抗-CD22抗体，尽管抗体，抗体片段和毒素的其它组合可用于形成受试者免疫毒素。 免疫毒素可用于治疗各种疾病，例如癌症，自身免疫性疾病或免疫功能障碍。