Health knowledge made personal
Join this community!
› Share page:
Go
Search posts:

Platform Technology Using Ubiquitin to Improve the Delivery and Efficacy of Cytosolic Targeted Toxins

Posted Sep 28 2011 8:00pm

Description of Invention:
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.

Applications:
  • Chimeric or fusion molecules for increasing the efficacy and cytotoxicity of targeted toxins and immunotoxins.
  • Methods for cytosol delivery of targeted toxins to target cells.


Advantages:
  • Broadly applicable to all cytotoxic immunoconjugates.
  • Increased stability and cytotoxicity of the TT without affecting the delivery or specificity of the treatment.
  • Therapeutic access to the cytosol and/or trafficking to further sites of action such as the nucleus.
  • Rapid cytosolic release of the catalytic moiety and degradation of the targeting moiety.


Development Status:
  • Pre-clinical
  • In vitro data available


Inventors:
Stephen H Leppla (NIDCR)
Shi-hui Liu (NIDCR)
Christopher H Bachran (NIAID)
Thomas Morley


Patent Status:
HHS, Reference No. E-150-2011/0
US, Application No. 61/473,450 filed 08 Apr 2011


Related Technologies:
US, Patent No. 7,468,352, Issued 23 Dec 2008, Reference No. E-293-1999/0
US, Application No. 12/288,482 filed 20 Oct 2008, Reference No. E-293-1999/0
US, Application No. 12/519,362 filed 15 Jun 2009, Reference No. E-070-2007/2
US, Patent No. 7,947,289, Issued 24 May 2011, Reference No. E-059-2004/0
US, Application No. 13/088,011 filed 15 Apr 2011, Reference No. E-059-2004/0
US, Application No. 60/155,961 filed 24 Sep 1999, Reference No. E-293-1999/0
US, Application No. 60/543,417 filed 09 Feb 2004, Reference No. E-059-2004/0
PCT, Application No. PCT/US2007/087664 filed 14 Dec 2007, Reference No. E-070-2007/2


Relevant Publication:
  1. Tcherniuk S, et al. [ PMID 15668131 ]
  2. Wang F. [ PMID 20371697 ]
  3. Heisler I. [ PMID 12455044 ]



For Licensing Information Please Contact:
Whitney Hastings
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: hastingw@mail.nih.gov
Phone: 301-451-7337
Fax: 301-402-0220


Ref No: 2323

Updated: 09/2011

Post a comment
Write a comment:

Related Searches