Immunotoxins: Hybrid Molecules Combining High Specificity and Potent Cytotoxicity

Jansen, F. K.; Blythman, Hildur E.; Carrière, D.; Casellas, Pierre; Gros, Olivier; Gros, Pierre; Laurent, Jean-Claude; Paolucci, F.; Pau, Bernard; Poncelet, Pascal; Richer, G.; Vidal, Hubert; Voisin, G A

doi:10.1111/j.1600-065x.1982.tb00394.x

Cited by 158 publications

(32 citation statements)

References 39 publications

(38 reference statements)

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“…Since the cytotoxicity of TF-A chain alone is totally blocked by this treatment (2), it appears that ionophore reveals the few molecules that do eventually enter the cell in the presence of excess transferrin. NH4CI included in culture medium at 10 -~ M failed to show effects comparable to those seen with ionophore (data not shown) even though this agent can raise vesicle pH values and influences cytotoxicity in other delivery systems (14). These results indicate that ionophore-assisted TF-A chain toxicity is still receptor mediated and that cells which bind only miniscule amounts of the toxin can be killed when ionophore is present.…”

Section: Resultsmentioning

confidence: 54%

“…An ability to manipulate the intracellular aspects of the intoxication process is therefore important so that the speed of action and potency of these toxins can be controlled. Various agents including N H4CI (14), chloroquine (15), adenovirus (16), and ricin B chain (12,17) have been used to potentiate toxic activity. The carboxylic ionophores examined in this work, however, possess some unique properties and advantages.…”

Section: Resultsmentioning

confidence: 99%

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Carboxylic ionophores enhance the cytotoxic potency of ligand- and antibody-delivered ricin A chain.

Raso¹,

Lawrence²

1984

The Journal of Experimental Medicine

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The highly selective cytotoxicity of site-directed ricin A chain conjugates can be potentiated by membrane-active carboxylic ionophores. The combined use of the two agents results in much faster inactivation of ribosomes and subsequent cell death and lysis. The potency of A chain cytotoxins is correspondingly increased by several orders of magnitude and cells that sparsely express the target antigen or receptor can be killed.

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Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Carboxylic ionophores enhance the cytotoxic potency of ligand- and antibody-delivered ricin A chain.

Raso¹,

Lawrence²

1984

The Journal of Experimental Medicine

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“…When the ligand was a toxin or a toxin conjugate, there was an enhancement of toxicity compared with the addition of toxin alone. To determine if the phenomenon occurred in lymphoid cells, adenovirus (2 ,gg/ml) and PE-anti-TAC were incubated with HUT-102 cells (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Pseudomonas exotoxin-anti-TAC. Cell-specific immunotoxin active against cells expressing the human T cell growth factor receptor.

FitzGerald¹,

Waldmann²,

Pastan³

1984

J. Clin. Invest.

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Abstract. An immunotoxin was constructed with an activity that discriminated between two T cell lines based on the expression of the T cell growth factor (TCGF) receptor on their cell surface. A toxic protein conjugate, designated PE-anti-TAC, was made by chemically coupling pseudomonas exotoxin (PE) to a monoclonal antibody (anti-TAC) that recognizes the human TCGF receptor. This conjugate was toxic to HUT-102 cells, a cell line that expresses the TCGF receptor, but was nontoxic for MOLT-4 cells, a receptor-negative line. The toxicity of PE-anti-TAC was enhanced 50-fold in the presence of human adenovirus type II and was reduced to control levels by adding excess anti-TAC antibody. The toxicity of PE-anti-TAC for HUT-102 cells was compared with PE-anti-transferrin receptor. To compare the route of entry for both anti-TAC and anti-TFR using electron microscopy, protein conjugates were made by coupling horseradish peroxidase (HRP) to each antibody. Anti-TFR-HRP entered HUT-102 cells by concentrative adsorptive endocytosis via coated pits, and the majority of the antibodies bound to the cell surface at 4VC were seen in receptosomes by 10 min after warming to 370C. Anti-TAC-HRP was also found to enter HUT-102 cells via coated pits and receptosomes; but, in contrast to anti-TFR, anti-TAC did not selectively concentrate in coated pits, and therefore the majority of this surface-bound antibody were not internalized in HUT-102 cells by 10 min at 37GC.

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“…Ricin A chain ITs have been shown to be highly effective for the elimination of malignant B cells in vitro and in vivo [1].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Potency of CD22‐Ricin A Depends on Intracellular Routing Rather than on the Number of Internalized Molecules

et al. 1995

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van Horssen PJ, van Oosterhout YJM, de Witte T, Preijers FWMB. Cytotoxic Potency of CD22-Ricin A Depends on Intracellular Routing Rather than on the Number of Internalized Molecules. Scand J Immunol 1995;41:559-65 Cytotoxicity of immunotoxins (ITs) varies considerably depending on factors like the capability of the target antigen to internalize IT molecules, intracellular processing and routing of the IT. We studied factors that may influence cytotoxicity of CD22-ricin A IT to several B cell lines. The antigen density varied from 5.9xlO3 to 6.0xlO4 molecules/cell. The ID 50, determined by protein synthesis inhibition, varied from 2.1xl0-12 to 3 .8 x l0 " n M IT in absence and from 2 .8 x l0 -14 M to 5 .2 x l0 " 12 M IT in presence of the cytotoxicity enhancer N H 4CI (6 mM). In absence as well as in presence of N H 4CI no correlation could be found between antigen density and ID 50. No relation was observed either with the rate of cytotoxicity. Even in cell lines with a low antigen density, such as KM3, protein synthesis was quickly inhibited. In order to investigate whether the cytotoxicity was dependent on the number of internalized molecules the kinetics of internalization and exocytosis of degraded 125I-labelled CD22 molecules were studied. After 24h the number of internalized CD 22 molecules was highest in Ramos (154,500), followed by Daudi (110,300) and KM3 (69,900). However, despite the higher internalization rate of Daudi the rate of cytotoxicity of 10" s M IT was comparable with KM3. N H 4CI did not influence the number of internalized molecules but postponed degradation of CD22. In conclusion, CD22-ricin A is a very potent and fast acting IT even for elimination of target cells that express low numbers of antigen. These results may have implication for treatment of different B cell malignancies with CD22-ricin A.

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Immunotoxins: Hybrid Molecules Combining High Specificity and Potent Cytotoxicity

Cited by 158 publications

References 39 publications

Carboxylic ionophores enhance the cytotoxic potency of ligand- and antibody-delivered ricin A chain.

Carboxylic ionophores enhance the cytotoxic potency of ligand- and antibody-delivered ricin A chain.

Pseudomonas exotoxin-anti-TAC. Cell-specific immunotoxin active against cells expressing the human T cell growth factor receptor.

Cytotoxic Potency of CD22‐Ricin A Depends on Intracellular Routing Rather than on the Number of Internalized Molecules

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