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Enhanced Function of Gene Modified T-Cells: Identification of T-Cell Receptors (TCR) with Altered Amino Acid Sequence

Posted May 10 2009 5:00pm

Description of Invention:
A major limitation of the current chemotherapy-based therapeutics is the cytotoxic side-effects associated with them. Thus there is a dire need to develop new therapeutic strategies with fewer side-effects. Immunotherapy has taken a lead among the new cancer therapeutic approaches. Adoptive immunotherapy is one of the most promising new therapeutic approaches that enhance the innate immunity of an individual to fight against a certain disease.

T cell receptors (TCR) are the proteins responsible for the T cell's ability to recognize infected or transformed cells. TCR consists of two domains, one variable domain that recognizes the antigen and one constant region that helps the TCR anchor to the membrane and transmit the recognition signal by interacting with other proteins.

This invention is directed to substitutions in gene sequences that code for T cell receptors, specifically the inventors found that one to two amino acid substitutions in the TCRs that recognize 1G4 XY-ESO-1 and MART-1 resulted in a marked increase of these modified TCRs to recognize tumor cell targets. These mutated sequences are currently being evaluated as candidates for clinical development. The inventors also consider the invention as providing a "general paradigm" that will allow the generation of TCR directed against a variety of antigens that can enhance the function of gene modified T cells.

Applications:
  • Improved ability of modified TCRs to recognize tumor cell targets.
  • High affinity TR can be generated that recognizes a variety of antigens that can be potentially used for the diagnosis and treatment of patients with a variety of conditions that include cancer, infectious diseases and autoimmunity.
  • Mutant high affinity TR can also be used to transduce T cells in order to generate cells reactive with tumor antigens as well as viral antigens.


Development Status:
Pre-clinical work has been completed and clinical work is undergoing.

Inventors:
Paul F Robbins (NCI)
Steven A Rosenberg (NCI)
Richard A Morgan (NCI)


Patent Status:
HHS, Reference No. E-304-2006/0
PCT, Application No. PCT/US2007/079487 filed 26 Sep 2007 , which published as WO 2008/039818 on 03 Apr 2008
US, Application No. 12/443,111 filed 26 Mar 2009


Relevant Publication:
  1. PF Robbins, et al. Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol. 2008 May 1;180(9):6116-31. [ PubMed abs ]


Licensing Status:
This technology is available for licensing under an exclusive or non-exclusive patent license.

Collaborative Research Opportunity:
The NIH Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize adoptive immunotherapy. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


Portfolios:
Cancer
Cancer - Diagnostics
Cancer - Therapeutics



For Additional Information Please Contact:
Samuel Bish Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: bishse@mail.nih.gov
Phone: 301-435-5282
Fax: 301-402-0220


Ref No: 1512

Updated: 05/2009

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