A chimeric protein comprised of IL-4 and Pseudomonas exotoxin is cytotoxic for activated human lymphocytes.

Puri, Raj K.; Mehrotra, P T; Leland, Pamela; Kreitman, R. J.; Siegel, Jay P.; Pastan, Ira

doi:10.4049/jimmunol.152.7.3693

Cited by 16 publications

(2 citation statements)

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“…To harness hIL‐4's cancer‐specificity for therapeutic purposes, a fusion protein of hIL‐4 and Pseudomonas exotoxin A (PE) was engineered to create an anticancer agent (Figure 3B). The initial fusion protein exhibited cytotoxicity on a variety of cancer cell lines, but had 15–20 fold weaker affinity compared to unfused hIL‐4 226–228 . Because the C‐terminus of hIL‐4 is implicated in binding to IL‐4Rα, it was hypothesized that the fused toxin was interfering with receptor engagement.…”

Section: Cytokine Engineering In the Il‐4/il‐13 Axismentioning

confidence: 99%

“…The initial fusion protein exhibited cytotoxicity on a variety of cancer cell lines, but had 15-20 fold weaker affinity compared to unfused hIL-4. [226][227][228] Because the C-terminus of hIL-4 is implicated in binding to IL-4Rα, it was hypothesized that the fused toxin was interfering with receptor engagement. To further engineer these fusion proteins for improved receptor affinity, the hIL-4 sequence was circularly permuted to allow a new terminus for PE toxin fusion.…”

Section: Il-4andil-13toxinfusionproteinsfor Cancer Therapymentioning

confidence: 99%

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Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Bernstein

Shenoy

Chen

et al. 2023

Immunological Reviews

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SummaryThe structurally and functionally related interleukin‐4 (IL‐4) and IL‐13 cytokines play pivotal roles in shaping immune activity. The IL‐4/IL‐13 axis is best known for its critical role in T helper 2 (Th2) cell‐mediated Type 2 inflammation, which protects the host from large multicellular pathogens, such as parasitic helminth worms, and regulates immune responses to allergens. In addition, IL‐4 and IL‐13 stimulate a wide range of innate and adaptive immune cells, as well as non‐hematopoietic cells, to coordinate various functions, including immune regulation, antibody production, and fibrosis. Due to its importance for a broad spectrum of physiological activities, the IL‐4/IL‐13 network has been targeted through a variety of molecular engineering and synthetic biology approaches to modulate immune behavior and develop novel therapeutics. Here, we review ongoing efforts to manipulate the IL‐4/IL‐13 axis, including cytokine engineering strategies, formulation of fusion proteins, antagonist development, cell engineering approaches, and biosensor design. We discuss how these strategies have been employed to dissect IL‐4 and IL‐13 pathways, as well as to discover new immunotherapies targeting allergy, autoimmune diseases, and cancer. Looking ahead, emerging bioengineering tools promise to continue advancing fundamental understanding of IL‐4/IL‐13 biology and enabling researchers to exploit these insights to develop effective interventions.

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Section: Cytokine Engineering In the Il‐4/il‐13 Axismentioning

confidence: 99%

Section: Il-4andil-13toxinfusionproteinsfor Cancer Therapymentioning

confidence: 99%

Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Bernstein

Shenoy

Chen

et al. 2023

Immunological Reviews

View full text Add to dashboard Cite

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Potent in vitro and in vivo antitumor activity of interleukin‐4‐conjugated Pseudomonas exotoxin against human biliary tract carcinoma

Ishige

Shoda

Kawamoto

et al. 2008

Intl Journal of Cancer

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Targeting cytotoxins or immunotoxins to tumor cell surface receptors represents a new approach for the treatment of cancers. We tested the antitumor activity of a cytotoxin (IL-4-PE) composed of an interleukin-4 (IL-4) targeting moiety and a truncated form of Pseudomonas exotoxin A against human biliary tract carcinoma (BTC). Immunohistochemical analysis showed that cultured BTC cell lines and cancerous epithelia in BTC tissue (e.g., gallbladder carcinoma, extraheaptic cholangiocarcinoma, and intrahepatic cholangiocarcinoma) expressed receptors for IL-4 in situ at high densities. However, normal epithelial cells in gallbladder and bile duct tissues did not express these IL-4 receptors. Eight BTC cell lines expressed IL-4R on the cell surface as determined by radiolabeled ligand binding assays. When these cells were treated with IL-4-PE, significant cytotoxicity was observed as determined by the inhibition of protein synthesis. The concentration of agent causing 50% inhibition of protein synthesis (IC 50 ) was found to be less than 10 ng/mL in 4 of the 8 BTC cell lines studied. The antitumor activity of IL-4-PE was assessed for human BTC cells implanted subcutaneously in immunodeficient mice. By intratumoral injection of IL-4-PE, complete disappearance of the established tumors was observed in 40% of animals. Intraperitoneal administration of IL-4-PE at tolerated doses to animals with peritoneally disseminated BTC exhibited significantly prolonged survival compared to untreated animals (>14 weeks vs. 5 weeks in treated and untreated mice, respectively). These results indicate that IL-4 receptor-targeted cytotoxin is a potent agent that may provide a new therapeutic option for BTC.

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Human neurological cancer cells express interleukin‐4 (IL‐4) receptors which are targets for the toxic effects of IL4‐pseudomonas exotoxin chimeric protein

Puri

Leland

Kreitman

et al. 1994

Intl Journal of Cancer

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Glioblastoma, glioma or neuroblastoma cells were examined for the expression of IL-4 receptors (IL-4R) by flow cytometric analysis and 125I-IL-4 binding. These cancer cell lines expressed IL-4R which were of high affinity (KD = 700 x 10(-12) M) on glioblastoma cells. To investigate the function of these receptors and to target potent cytotoxic antitumor agents to human neurological cancers, we utilized IL4-PE4E, which is composed of IL-4 and mutant Pseudomonas exotoxin (IL4-PE4E). This chimeric molecule was cytotoxic toward human glioblastoma, neuroblastoma and glioma tumor cells in a dose-dependent manner. The cytotoxicity of IL4-PE4E was specific, since it was neutralized by excess IL-4, and by an anti-IL-4 monoclonal antibody in all types of brain tumor tested. IL2-PE4E and IL6-PE4E were not cytotoxic, nor was an IL4-PE4E mutant lacking ADP-ribosylating activity, indicating the IL4-PE4E-mediated cytotoxicity of the brain tumor cells required both IL-4R binding and enzymatic toxin activity. These data indicate that human neurological cancer cells express IL-4R which are targets for the cytotoxic effects of IL4-toxin. In addition, our data also suggest that IL4-PE4E should be studied further as a potential treatment for human neurological cancers.

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A chimeric protein comprised of IL-4 and Pseudomonas exotoxin is cytotoxic for activated human lymphocytes.

Cited by 16 publications

References 0 publications

Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Potent in vitro and in vivo antitumor activity of interleukin‐4‐conjugated Pseudomonas exotoxin against human biliary tract carcinoma

Human neurological cancer cells express interleukin‐4 (IL‐4) receptors which are targets for the toxic effects of IL4‐pseudomonas exotoxin chimeric protein

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