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Novel Anti-Mesothelin Nanobodies and Recombinant Immunotoxins with Exotoxin Catalytic Domain for Cancer Therapeutics. | LitMetric

AI Article Synopsis

  • Recombinant immunotoxins (RITs) are engineered fusion proteins that combine a targeting domain with a toxin, allowing for precise cancer therapy aimed at overexpressed proteins like mesothelin found in certain tumors.
  • Researchers developed RITs targeting mesothelin by selecting specific nanobodies and optimizing them for better expression and purification, achieving high solubility and purity in the process.
  • The most effective RIT, Meso(Nb2)-PE24B, demonstrated strong cytotoxicity against gastric cancer cell lines and selective binding to human mesothelin, suggesting it could be a valuable candidate for targeted cancer treatment in future studies.

Article Abstract

Recombinant immunotoxins (RITs) are fusion proteins consisting of a targeting domain linked to a toxin, offering a highly specific therapeutic strategy for cancer treatment. In this study, we engineered and characterized RITs aimed at mesothelin, a cell surface glycoprotein overexpressed in various malignancies. Through an extensive screening of a large nanobody library, four mesothelin-specific nanobodies were selected and genetically fused to a truncated (PE24B). Various optimizations, including the incorporation of furin cleavage sites, maltose-binding protein tags, and tobacco etch virus protease cleavage sites, were implemented to improve protein expression, solubility, and purification. The RITs were successfully overexpressed in , achieving high solubility and purity post-purification. cytotoxicity assays on gastric carcinoma cell lines NCI-N87 and AGS revealed that Meso(Nb2)-PE24B demonstrated the highest cytotoxic efficacy, warranting further characterization. This RIT also displayed selective binding to human and monkey mesothelins but not to mouse mesothelin. The competitive binding assays between different RIT constructs revealed significant alterations in IC values, emphasizing the importance of nanobody specificity. Finally, a modification in the endoplasmic reticulum retention signal at the C-terminus further augmented its cytotoxic activity. Our findings offer valuable insights into the design and optimization of RITs, showcasing the potential of Meso(Nb2)-PE24B as a promising therapeutic candidate for targeted cancer treatment.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10701305PMC
http://dx.doi.org/10.14348/molcells.2023.0155DOI Listing

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