Targeting IL-13Rα2-positive cancer with a novel recombinant immunotoxin composed of a single-chain antibody and mutated <i>Pseudomonas</i> exotoxin

Kioi, Mitomu; Seetharam, Saraswathy; Puri, Raj K.

doi:10.1158/1535-7163.mct-07-2131

Cited by 56 publications

(68 citation statements)

References 23 publications

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“…IL-13-induced activation of STAT-6 occurs through IL-13Ra1 signaling. 64,65 and showed survival benefit in phase 1/2 clinical trials of patients with glioblastoma multiforme at doses that do not produce significant toxicity. 66 Therefore, IL-13Ra2 expression in CTCL might represent a marker of malignancy that can be exploited for targeted therapy of the disease.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

Geskin¹,

Viragova²,

Stolz

et al. 2015

Blood

135

113

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Key Points• IL-13 is an autocrine factor for CTCL.• IL-13 and its receptors represent novel markers of CTCL malignancy and potential therapeutic targets for intervention.Cutaneous T-cell lymphomas (CTCLs) primarily affect skin and are characterized by proliferation of mature CD4 1 T-helper cells. The pattern of cytokine production in the skin and blood is considered to be of major importance for the pathogenesis of CTCLs. Abnormal cytokine expression in CTCLs may be responsible for enhanced proliferation of the malignant cells and/or depression of the antitumor immune response. Here we show that interleukin-13 (IL-13) and its receptors IL-13Ra1 and IL-13Ra2 are highly expressed in the clinically involved skin of CTCL patients. We also show that malignant lymphoma cells, identified by the coexpression of CD4 and TOX (thymus high-mobility group box), in the skin and blood of CTCL patients produce IL-13 and express both receptors. IL-13 induces CTCL cell growth in vitro and signaling through the IL-13Ra1. Furthermore, antibody-mediated neutralization of IL-13 or soluble IL-13Ra2 molecules can lead to inhibition of tumor-cell proliferation, implicating IL-13 as an autocrine factor in CTCL. Importantly, we established that IL-13 synergizes with IL-4 in inhibiting CTCL cell growth and that blocking the IL-4/IL-13 signaling pathway completely reverses tumor-cell proliferation. We conclude that IL-13 and its signaling mediators are novel markers of CTCL malignancy and potential therapeutic targets for intervention. (Blood. 2015;125(18):2798-2805

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Section: Discussionmentioning

confidence: 99%

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

Geskin¹,

Viragova²,

Stolz

et al. 2015

Blood

135

113

View full text Add to dashboard Cite

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“…Husain and colleagues (32) took these properties into consideration to propose an alternative strategy of specifically targeting the IL-13 pathway using a chimeric IL-13-PE. It has been demonstrated that IL-13-PE can successfully eradicate not only IL-13R-positive tumors in vivo and in vitro (32)(33)(34), but also established chronic airway inflammatory and fibrotic responses induced by distinct provocations, such as Aspergillus fumigatus (31), Schistosoma mansoni eggs (35), and bleomycin (36). Given the overexpression of IL-13Ra2 and IL-13 in silicotic mice, we addressed the hypothesis that the therapeutic treatment with IL-13-PE would impact inflammation and fibrosis in these animals.…”

Section: Discussionmentioning

confidence: 99%

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Ferreira

Arantes

Nascimento

et al. 2013

The Journal of Immunology

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Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13–PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13–PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13–PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13–PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13–PE. In addition, IL-13–PE inhibited both IL-13–induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13–PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

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“…Cintredekin besudotox (IL13-PE38QQR), a synthesized cytotoxin combining human IL-13 and mutated Pseudomonas exotoxin PE38, was shown to have a promising antitumor effect in vitro and in vivo (12,13). Anti-IL-13Ra2-PE38, a recombinant immunotoxin composed of a human single-chain Fv antibody specific to IL13Ra2 and PE38, has also been investigated in vitro and in a mouse model (14).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Takenouchi

Hirai²,

Sakuragi³

et al. 2011

Clinical Cancer Research

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Purpose: The interleukin-13 receptor a2 (IL-13Ra2) is expressed by a variety of human malignant cells. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL-13Ra2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor 5-aza-2 0 -deoxycytidine (5-aza-dC) and anti-IL-13Ra2 monoclonal antibody on mesothelioma xenografts.Experimental Design: Cell surface expression of IL-13Ra2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti-IL-13Ra2 and 5-aza-dC were investigated using antibodydependent cellular cytotoxicity and proliferation assays and by monitoring the survival of mesotheliomabearing mice.Results: We found that human malignant mesotheliomas expressed surface IL-13Ra2 on their surface and that it was upregulated by treatment with 5-aza-dC. This augmented expression of IL-13Ra2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13Ra2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by IFN-g that was only detected in the supernatant when effector cells were exposed to 5-aza-dC-treated tumors in the presence of anti-IL-13Ra2. Compared with the control or either regimen alone, in vivo administration of anti-IL-13Ra2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts.Conclusions: These observations indicate a promising role for IL-13Ra2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency.

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Targeting IL-13Rα2-positive cancer with a novel recombinant immunotoxin composed of a single-chain antibody and mutated Pseudomonas exotoxin

Cited by 56 publications

References 23 publications

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

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