Antibody Response to DT–GM, a Novel Fusion Toxin Consisting of a Truncated Diphtheria Toxin (DT) Linked to Human Granulocyte–Macrophage Colony Stimulating Factor (GM), during a Phase I Trial of Patients with Relapsed or Refractory Acute Myeloid Leukemia

Hall, Philip D.; Virella, Gabriel; Willoughby, Tony; Atchley, Daniel H.; Kreitman, Robert J.; Frankel, Arthur E.

doi:10.1006/clim.2001.5066

Cited by 40 publications

(27 citation statements)

References 11 publications

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“…As some other well-demonstrated antitumor immunotoxin (6-8), e23sFv-PEA40 was shown to have potent and selective cytotoxicity to tumors in culture and nude mouse models. However, most of the immunotoxin clinical trials faced the same obstacle that immunotoxin would arouse strong humoral immune responses (9)(10)(11)(12)(13)(14). In most cases, patients with normal immune systems develop neutralizing antibodies against the plant or bacterial-derived toxins (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…In most cases, patients with normal immune systems develop neutralizing antibodies against the plant or bacterial-derived toxins (9,10). Besides, vascular leakage, nonspecific toxicity to vascular endothelial, liver, or renal cells are other side effects of immunotoxin administration (8,(10)(11)(12)(13)(14). In short, clinical trial results suggest that it is the foreign toxin fragments that usually cause humoral immune response and therefore limit the clinical utility of immunotoxins.…”

Section: Introductionmentioning

confidence: 99%

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Recombinant Immunoproapoptotic Proteins with Furin Site Can Translocate and Kill HER2-Positive Cancer Cells

Wang¹,

Zhao²,

Ren

et al. 2007

Cancer Research

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We previously reported the selective killing of HER2-positive tumor cells by a class of immunoproapoptotic proteins containing single-chain antibody, translocation domain of Pseudomonas exotoxin A (domain II; PEA II), and constitutively active human apoptotic molecules. In this study, a novel class of antitumor immunoproapoptotic proteins was explored to mediate tumor-specific apoptosis both in vitro and in vivo. Three furin cleavage sequences, including a synthetic polyarginine tract, and two furin cleavable sequences from PEA and diphtheria toxin were respectively used to replace PEA II in the previously constructed immunoproapoptotic protein. When produced and secreted by the genetically modified Jurkat cells, the novel targeted proapoptotic proteins selectively bound to HER2, which is often overexpressed on tumor cell surface. Followed by receptor-mediated endocytosis and furin cleavage in the endosome, the recombinant proteins could translocate into the cytosol, leading to irreversible cell death. Moreover, delivery of these proteins by either i.m. plasmid injection or i.v. injection of plasmidexpressing Jurkat cells led to tumor regression and prolonged animal survival in a nude mouse xenograft tumor model, indicating in vivo antitumor activity of the recombinant proteins. We conclude that the new class of immunoproapoptotic proteins show comparable activity with PEA II-containing counterpart and provide an attractive therapeutic alternative as they contain much less exogenous fragments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recombinant Immunoproapoptotic Proteins with Furin Site Can Translocate and Kill HER2-Positive Cancer Cells

Wang¹,

Zhao²,

Ren

et al. 2007

Cancer Research

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“…The toxin part of the fusion proteins elicits a high degree of humoral response in humans. In addition, in developed countries, where people have become immunized against diphtheria, the patient's serum will have circulating antibodies against the diphtheria toxin that will result in a neutralization of diphtheria toxin-based immunotoxins (Hall et al, 2001). Both the Pseudomonas exotoxin and the diphtheria toxin are large molecules and are difficult to humanize.…”

Section: Immunotoxinsmentioning

confidence: 99%

E. coli Alpha Hemolysin and Properties

Bakás¹,

Sabina²,

Romina³

et al. 2012

Biochemistry

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“…Decreased immunogenicity has been observed with toxins that are foreign antigens to which patients have not been previously exposed, but antitoxin antibodies appear after a lag of 3-4 weeks. 26 (4) Cytotoxicity of the immunotoxin depends on its intratumor cell internalization and intracellular trafficking. In particular, DT can escape from early endosomes to the cytosol, while PE and ricin toxin only reach the cytosol after passage through the Golgi apparatus and endoplasmic reticulum (see below), and this clearance by intracellular components influences the cytotoxicity of the toxins.…”

Section: Lessons From Immunotoxinsmentioning

confidence: 99%

Protein toxins: intracellular trafficking for targeted therapy

2005

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The immunotoxin approach is based on the use of tumortargeting ligands or antibodies that are linked to the catalytic (toxic) moieties of bacterial or plant protein toxins. In this review, we first discuss the current state of clinical development of immunotoxin approaches describing the results obtained with the two toxins most frequently used: diphtheria and Pseudomonas toxin-derived proteins. In the second part of the review, a novel concept will be presented in which the roles are inverted: nontoxic receptor-binding toxin moieties are used for the targeting of therapeutic and diagnostic compounds to cancer or immune cells. The cell biological basis of these novel types of toxin-based therapeutics will be discussed, and we will summarize ongoing preclinical and clinical testing.

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Antibody Response to DT–GM, a Novel Fusion Toxin Consisting of a Truncated Diphtheria Toxin (DT) Linked to Human Granulocyte–Macrophage Colony Stimulating Factor (GM), during a Phase I Trial of Patients with Relapsed or Refractory Acute Myeloid Leukemia

Cited by 40 publications

References 11 publications

Recombinant Immunoproapoptotic Proteins with Furin Site Can Translocate and Kill HER2-Positive Cancer Cells

Recombinant Immunoproapoptotic Proteins with Furin Site Can Translocate and Kill HER2-Positive Cancer Cells

E. coli Alpha Hemolysin and Properties

Protein toxins: intracellular trafficking for targeted therapy

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