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Platform Technology Using Ubiquitin to Improve the Delivery and Efficacy of Cytosolic Targeted Toxins
Case ID:
TAB-2323
Web Published:
12/6/2022
Description:
Targeted toxins (TT) are hybrid protein drugs consisting of ligands that bind to the surface of cancer cells and deliver polypeptide toxins that kill malignant cells by inactivating cytosolic protein synthesis and inducing cell death. A major challenge in the construction of targeted toxins is reducing the nonspecific binding of the toxin moiety to normal tissues and increasing the cytotoxicity of the treatment.
To address these issues, the NIH inventors have identified that the protein ubiquitin, a small protein in eukaryotic cells that plays a role in protein recycling, can separate the targeting moiety and the catalytic moiety of a TT in the cytosol of cells. By decoupling the two moieties, the cytotoxicity of the TT treatment can be greatly increased since the catalytic domain remains longer in the cytosol. This technology would be highly useful for all TT and immunotoxins that access the cytosol to either affect cytosolic targets or traffic to further sites of action. To validate this approach, the inventors have tested ubiquitin variants within a TT consisting of anthrax toxin lethal factor N-terminus (LFn) and Pseudomonas exotoxin A catalytic domain (PEIII). Here, they show that the intracellular release of the PEIII (catalytic moiety) is achievable and that ubiquitination of the TT controls the persistence of the TTs in the cytosol and thus controls the observed cytotoxicity.
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Direct Link:
https://nih.technologypublisher.com/tech/Platform_Technology_Using_Ubiquitin_ to_Improve_the_Delivery_and_Efficacy_of_Cytosolic_Targeted_Toxins
Category(s):
Licensing
Therapeutics
Oncology
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For Information, Contact:
Wade Green
NIH Technology Transfer
wade.green@nih.gov
Inventors:
Stephen Leppla
Shihui Liu
Thomas Morley
Christopher Bachran
Keywords:
ACTING
CBXXXX
CXXXXX
Cytosolic
EFFICACY
FUSIONS
IMPROVING
Targeted
TOXINS
Ubiquitin
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