DNA encoding chimeric diphtheria toxins

    公开(公告)号:US5677148A

    公开(公告)日:1997-10-14

    申请号:US477418

    申请日:1995-06-07

    Applicant: Diane Williams

    Inventor: Diane Williams

    Abstract: A chimeric toxin comprising protein fragments joined together by peptide bonds, the chimeric toxin comprising, in sequential order, beginning at the amino terminal end of the chimeric toxin, (a) the enzymatically active Fragment A of diphtheria toxin, (b) a first fragment including the cleavage domain 1.sub.1 adjacent the Fragment A of diphtheria toxin, (c) a second fragment comprising at least a portion of the hydrophobic transmembrane region of Fragment B of diphtheria toxin, the second fragment having a deletion of at least 50 diphtheria toxin amino acid residues, the deletion being C-terminal to the portion of the transmembrane region, and the second fragment not including domain 1.sub.2, and (d) a third fragment comprising a portion of a cell-specific polypeptide ligand, the portion including at least a portion of the binding domain of the polypeptide ligand, the portion of the binding domain being effective to cause the chimeric toxin to bind selectively to a predetermined class of cells to be attacked by the enzymatically active Fragment A, the chimeric toxin possessing any of, greater toxicity than that of a toxin comprised of DAB.sub.486 fused to the third fragment, a lower K.sub.d for the sites on cells of the predetermined class to which the chimeric toxin binds than that of a toxin comprised of DAB.sub.486 fused to the third fragment, greater resistance to proteolytic degradation than that exhibited by a toxin comprised of DAB.sub.486 fused to the third fragment, greater resistance to the inhibition of its cytotoxicity by the cell-specific polypeptide ligand than that exhibited by DAB.sub.486 fused to the third fragment, the ability to inhibit protein synthesis to a given degree by a period of exposure that is shorter than the period of exposure required by DAB.sub.489 fused to the third fragment to inhibit protein synthesis to the same degree, or the ability to effect a more rapid onset of the inhibition of protein synthesis than that exhibited by DAB.sub.486 fused to the third fragment.

    Compositions and methods for inhibition of HIV production
    73.
    发明授权
    Compositions and methods for inhibition of HIV production 失效
    抑制艾滋病毒生产的组成和方法

    公开(公告)号:US5554528A

    公开(公告)日:1996-09-10

    申请号:US147829

    申请日:1993-11-04

    Abstract: All lines of mammalian origin which have been stably transformed with a chimeric toxin gene expressed under the regulatory control of HIV cis-acting sequences and HIV trans-acting factors are provided by the present invention. HIV infection of a cell of such a transformed cell line results in the death of that cell due to the specific induction of toxin gene expression within the cell. As specifically exemplified, the toxin gene is the diphtheria toxin fragment A gene or a tox176 fragment A chain gene. Also provided by the present invention are recombinant nucleic acid molecules suitable for the stable transformation of a mammalian cell line to produce a transformed cell which will effectively commit suicide in response to HIV infection due to induction of toxin gene expression.

    Abstract translation: 通过在HIV顺式作用序列和HIV反式作用因子的调节控制下表达的嵌合毒素基因稳定转化的哺乳动物来源的所有系由本发明提供。 由于细胞内毒素基因表达的特异性诱导,这种转化细胞系的细胞的HIV感染导致该细胞的死亡。 如具体示例的,毒素基因是白喉毒素片段A基因或tox176片段A链基因。 本发明还提供了适合于稳定转化哺乳动物细胞系以产生转化细胞的重组核酸分子,其将由于诱导毒素基因表达而响应于HIV感染而有效地自杀。

    Immunotoxins for treatment of intracranial lesions and as adjunct to
chemotherapy
    74.
    发明授权
    Immunotoxins for treatment of intracranial lesions and as adjunct to chemotherapy 失效
    用于治疗颅内损伤和辅助化疗的免疫毒素

    公开(公告)号:US5352447A

    公开(公告)日:1994-10-04

    申请号:US925417

    申请日:1992-08-10

    Abstract: A potent and specific immunotoxin is prepared by coupling a binding-site inactivated diphtheria toxin (CRM 107) to a new binding moiety consisting of transferrin or a monoclonal antibody against the human transferrin receptor. These immunotoxins are tumor specific and lack the nonspecific toxicity produced by the binding activity of the native toxin. The immunotoxin is useful in treating primary brain tumors, metastatic tumors to the brain, CSF-borne tumors, leptomeningeal leukemia and leptomeningeal carcinomatosis.

    Abstract translation: 通过将结合位点灭活的白喉毒素(CRM 107)与由转铁蛋白或针对人转铁蛋白受体的单克隆抗体组成的新结合部分偶联来制备有效和特异性的免疫毒素。 这些免疫毒素是肿瘤特异性的,并且缺乏由天然毒素的结合活性产生的非特异性毒性。 免疫毒素可用于治疗原发性脑肿瘤,转移性脑肿瘤,脑脊液肿瘤,脑膜性白血病和脑膜炎等。

    Methods and compositions based on diphtheria toxin-interleukin-3 conjugates

    公开(公告)号:US12180257B2

    公开(公告)日:2024-12-31

    申请号:US17411947

    申请日:2021-08-25

    Abstract: The present invention provides methods for inhibiting interleukin-3 receptor-expressing cells, and, in particular, inhibiting the growth of such cells by using a diphtheria toxin-human interleukin-3 conjugate (DT-IL3) that is toxic to cells expressing the interleukin-3 receptor. In preferred embodiments, the DT-IL3 conjugate is a fusion protein comprising amino acids 1-388 of diphtheria toxin fused via a peptide linker to full-length, human interleukin-3. In certain embodiments, the methods of the present invention relate to the administration of a DT-IL3 conjugate to inhibit the growth of cancer cells and/or cancer stem cells in humans, which cells express one or more subunits of the interleukin-3 receptor. Exemplary cells include myeloid leukemia cancer stem cells. In other embodiments, the methods of the present invention relate to ex vivo purging of bone marrow or peripheral blood to remove cells that express one or more subunits of the interleukin-3 receptor such that the purged bone marrow or peripheral blood is suitable, e.g., for autologous stem cell transplantation to restore hematopoietic function.

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