Transferrin toxin but not transferrin receptor immunotoxin is influenced by free transferrin and iron saturation

Gosselaar, Peter H.; van-Dijk, A J G; Degast, Gc; Polito, Letizia; Bolognesi, Andrea; Vooijs, Wim C.; Verheul, A. F. M.; Krouwer, Hendrikus G. J.; Marx, Joannes J.M.

doi:10.1046/j.1365-2362.2002.0320s1061.x

Cited by 17 publications

(10 citation statements)

References 43 publications

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“…The efficacy of an anti-TfR murine mAb conjugated to saporin-S6 was compared to transferrin/saporin-S6 conjugates. Both conjugates were found to be equally effective with IC 50 in 0.1 nM range, but the transferrin/saporin-S6 conjugate, although presenting a minor risk with regard to immunogenicity, was influenced in vivo in its efficacy by free transferrin and iron saturation, whereas the anti-TfR/saporin-S6 IT was not as subdued by these influences [75]. The in vivo efficacy of an anti-receptor protein tyrosine phosphatase β mAb conjugated to saporin-S6 was evaluated in athymic nude mice bearing the U87 glioblastoma cells.…”

Section: Immunotoxinsmentioning

confidence: 99%

Saporin-S6: A Useful Tool in Cancer Therapy

Polito

Bortolotti

Mercatelli

et al. 2013

Toxins

113

115

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Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials.

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Section: Immunotoxinsmentioning

confidence: 99%

Saporin-S6: A Useful Tool in Cancer Therapy

Polito

Bortolotti

Mercatelli

et al. 2013

Toxins

113

115

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“…60 Another antibody, the murine IgA anti-human TfR antibody 42/6 is cytotoxic to RPMI 8226 human MM cells invitro . 61 This antibody inhibits binding of Tf to its receptor and additionally induces down-regulation of the receptor on the cell surface. 62 The 42/6 therapeutic has been studied in a prior phase I clinical trial.…”

Section: Therapeutic Induction Of Iron Deprivation For the Treatmentioning

confidence: 99%

Iron in Multiple Myeloma

VanderWall¹,

Daniels‐Wells²,

Penichet³

et al. 2013

Crit Rev Oncog

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Multiple myeloma is a non-curable B cell malignancy in which iron metabolism plays an important role. Patients with this disorder almost universally suffer from a clinically significant anemia, which is often symptomatic, and which is due to impaired iron utilization. Recent studies indicate that the proximal cause of dysregulated iron metabolism and anemia in these patients is cytokine-induced upregulation of hepcidin expression. Malignant myeloma cells are dependent on an increased influx of iron and therapeutic efforts are being made to target this requirement. The studies detailing the characteristics and biochemical abnormalities in iron metabolism causing anemia and the initial attempts to target iron therapeutically are described in this review.

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“…15). Immunotoxins targeting the hTfR, via chemical conjugation with transferrin (16) or an anti-hTfR antibody (17), have also shown in vitro cytotoxic effects in malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of an anti–transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells

Daniels¹,

Delgado³

et al. 2007

Molecular Cancer Therapeutics

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We have previously developed an antibody fusion protein composed of a mouse/human chimeric IgG3 specific for the human transferrin receptor genetically fused to avidin (anti-hTfR IgG3-Av) as a universal delivery system for cancer therapy. This fusion protein efficiently delivers biotinylated FITC into cancer cells via TfR-mediated endocytosis. In addition, anti-hTfR IgG3-Av alone exhibits intrinsic cytotoxic activity and interferes with hTfR recycling, leading to the rapid degradation of the TfR and lethal iron deprivation in certain malignant B-cell lines. We now report on the cytotoxic effects of a conjugate composed of anti-hTfR IgG3-Av and biotinylated saporin 6 (b-SO6), a toxin derived from the plant Saponaria officinalis that inhibits protein synthesis. Conjugation of anti-hTfR IgG3-Av with b-SO6 enhances the cytotoxic effect of the fusion protein in sensitive cells and also overcomes the resistance of malignant cells that show low sensitivity to the fusion protein alone. Our results show for the first time that loading anti-hTfR IgG3-Av with a biotinylated toxin enhances the cytotoxicity of the fusion protein alone. These results suggest that anti-hTfR IgG3-Av has great potential as a therapeutic agent for a wide range of applications due to its intrinsic cytotoxic activity plus its ability to deliver biotinylated molecules into cancer cells.

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Transferrin toxin but not transferrin receptor immunotoxin is influenced by free transferrin and iron saturation

Abstract: Transferrin-based toxin conjugates are strongly influenced by the presence of free transferrin and the iron saturation state. The corresponding alpha-transferrin receptor-immunotoxin does not show these disadvantages, has similar efficacy and should be preferred for further experiments.

Cited by 17 publications

References 43 publications

Saporin-S6: A Useful Tool in Cancer Therapy

Saporin-S6: A Useful Tool in Cancer Therapy

Iron in Multiple Myeloma

Conjugation of an anti–transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells

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