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Conditionally activated immunotoxins with prolonged half-life can enhance the anti-tumor activity. | LitMetric

Conditionally activated immunotoxins with prolonged half-life can enhance the anti-tumor activity.

Int J Pharm

State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China; Nankai International Advanced Research Institute (SHENZHEN FUTIAN), Shenzhen 518045, PR China. Electronic address:

Published: November 2024

AI Article Synopsis

  • Immunotoxins show promise for cancer therapy but face challenges like short half-life and toxicity to healthy tissues.
  • A new tumor-conditional immunotoxin, Nb-uPA-A1-PE24, was developed to target tumors more effectively while minimizing harm to healthy cells.
  • In animal studies, this immunotoxin demonstrated increased half-life and better tumor targeting, suggesting improved safety and efficacy for cancer treatment.

Article Abstract

Immunotoxin has become a highly promising therapy for treating cancer and has achieved good results in preclinical trials targeting various cancers. However, there are still some issues that limit the development and application of immunotoxins, such as short half-life and toxic side effects on healthy tissues. In this study, we designed a tumor-conditional immunotoxin called Nb-uPA-A1-PE24. Anti-HSA nanobody (Nb) was fused to the N-terminus of A1-PE24 (immunotoxin targeting mesothelin) via a linker cleavable by tumor-associated proteases, urokinase-type plasminogen activator (uPA). Nb binds to HSA (human serum albumin) in the blood circulation, which not only prolongs the half-life of immunotoxins, but also creates a certain spatial barrier between A1 and mesothelin, thereby reducing the toxicity of Nb-uPA-A1-PE24 to healthy tissues expressing mesothelin. Moreover, uPA cleavable element rendered the immunotoxin conditional activation specifically in tumor microenvironment. In animal experiments, the half-life of the newly designed immunotoxins was increased dramatically. Noted, Nb-uPA-A1-PE24 has better enrichment at tumor, and shows robust anti-tumor effects in multiple preclinical models, such as pancreatic cancer and gastric cancer models. The results indicate that this strategy has greater potential and higher safety for application in tumor treatment, providing new ideas and strategies for the development of immunotoxins for cancer patients.

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Source
http://dx.doi.org/10.1016/j.ijpharm.2024.125003DOI Listing

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