Immunotoxins for targeted cancer therapy

Kreitman, Robert J.; Pastan, Ira

doi:10.1016/s0169-409x(97)00094-x

Cited by 142 publications

(82 citation statements)

References 325 publications

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“…The toxic payload is usually a  protein toxin, either plant or bacterial. Immunotoxin commonly contains toxins such as diphtheria toxin and pseudomonas exotoxin [2] . Immunotoxins targeting hematological malignancies and solid tumors have been additionally demonstrated with excellent clinical activity [3] , representing a second revolution in antibodymediated cancer therapy [4] B cell-activating factor (BAFF), also known as Blymphocyte stimulator (BLyS), TNF-and APOL-related leukocyte expressed ligand 1 (TALL-1), or TNF homolog that activates apoptosis, NKFB, and JNK (THANK), is a member of tumor necrosis factor (TNF) superfamily .…”

Section: Discussionmentioning

confidence: 99%

“…Then the purified recombinant protein and diphtheria toxin of various concentrations (0.0 ng/ml as the non-drug group; 0.4 ng/ml, 0.8 ng/ml, 1.2 ng/ml, 1.6 ng/ml, 2.0 ng/ml and 2.4 ng/ml as the drug groups) were added to triplicate wells. Cells were cultured at 37°C in 5% CO 2 All data were expressed as x±s. Differences of the mRNA expression levels of human BAFF receptors (BAFF-R, TACI and BCMA) in BALL-1, Hmy2.CIR and U937 cell lines were evaluated by analysis of variance (ANOVA).…”

Section: Cytotoxicity Experimentsmentioning

confidence: 99%

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Diphtheria toxin/human B-Cell activating factor fusion protein kills human acute lymphoblastic leukemia BALL-1 cells: An experimental study

Gao

Liu²,

Jiao

et al. 2012

Chin. J. Cancer Res.

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Objective: This study aimed to express a fusion protein of diphtheria toxin and human B cell-activating factor (DT388sBAFF) in Escherichia coli (E. coli) and investigate its activity in human B-lineage acute lymphoblastic leukemia 1 cells (BALL-1).Methods: A fragment of DT388sBAFF fusion gene was separated from plasmid pUC57-DT388sBAFF digested with Nde I and Xho I, and inserted into the expression vector pcold II digested with the same enzymes. Recombinants were screened by the colony polymerase chain reaction (PCR) and restriction map. The recombinant expression vector was transformed into BL21 and its expression was induced by isopropyl β-D-1-thiogalactopyranoside (IPTG). The recombinant protein was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot, and then purified by Ni 2+

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Section: Discussionmentioning

confidence: 99%

Section: Cytotoxicity Experimentsmentioning

confidence: 99%

Diphtheria toxin/human B-Cell activating factor fusion protein kills human acute lymphoblastic leukemia BALL-1 cells: An experimental study

Gao

Liu²,

Jiao

et al. 2012

Chin. J. Cancer Res.

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“…A wide variety of immunotoxins have been tested against a wide variety of malignancies in cell culture, in animal models, and in patients. The most useful of these agents appear to be the relatively small recombinant fusion toxins that contain either growth factor or Fv fragments as ligands (Kreitman, 2006). At present, immunotoxins, which contain human interleukin-2 and truncated diphtheria toxin, are approved for use in cutaneous T-cell lymphoma (Wood, 2014).…”

Section: Antitumor Activity Of Bacterial Toxinsmentioning

confidence: 99%

Biotoxins for Cancer Therapy

Liu

Yang²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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In recent times, a number of studies have provided evidence that biotoxins present great potential as antitumor agents, such as snake venom, bee venom, some bacteria toxins and plant toxins, and thus could be used as chemotherapeutic agents against tumors. The biodiversity of venoms and toxins make them a unique source from which novel anticancer agent may be developed. Biotoxins, also known as natural toxins, include toxic substances produced by plants, animals and microorganisms. Here, we systematically list representative biological toxins that have antitumor properties, involving animal toxins, plant toxins, mycotoxins as well as bacterial toxins. In this review, we summarize the current knowledge involving biotoxins and the active compounds that have anti-cancer activity to induce cytotoxic, antitumor, immunomodulatory, and apoptotic effects in different tumor cells in vivo or in vitro. We also show insights into the molecular and functional evolution of biotoxins.

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“…However, common toxicities included transaminase evaluation. The therapeutic window for this class of constructs may be optimized by various design changes to lower the efficacious dose, improve specificity by reducing off-target effects, thereby allowing an increase in the maximal tolerated dose (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

Cao

Marks

Huang

et al. 2012

Molecular Cancer Therapeutics

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Recombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10 À8 to 10 À11 mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity.

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Immunotoxins for targeted cancer therapy

Cited by 142 publications

References 325 publications

Diphtheria toxin/human B-Cell activating factor fusion protein kills human acute lymphoblastic leukemia BALL-1 cells: An experimental study

Diphtheria toxin/human B-Cell activating factor fusion protein kills human acute lymphoblastic leukemia BALL-1 cells: An experimental study

Biotoxins for Cancer Therapy

Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity

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