This PDF is the current document as it appeared on Public Inspection on 09/12/2016 at 08:45 am.
National Institutes of Health, HHS.
The invention listed below is owned by an agency of the U.S. Government and is available for licensing and/or co-development in the U.S. in accordance with 35 U.S.C. 209 and 37 CFR part 404 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing and/or co-development.
Invention Development and Marketing Unit, Technology Transfer Center, National Cancer Institute, 9609 Medical Center Drive, Mail Stop 9702, Rockville, MD, 20850-9702.Start Further Info
FOR FURTHER INFORMATION CONTACT:
Information on licensing and co-development research collaborations, and copies of the U.S. patent applications listed below may be obtained by contacting: Attn. Invention Development and Marketing Unit, Technology Transfer Center, National Cancer Institute, 9609 Medical Center Drive, Mail Stop 9702, Rockville, MD, 20850-9702, Tel. 240-276-5515 or Email firstname.lastname@example.org. A signed Confidential Disclosure Agreement may be required to receive copies of the patent applications.End Further Info End Preamble Start Supplemental Information
Technology description follows.
Title of invention: Immunotoxins with Increased Stability for Cancer Therapy.
Keywords: Recombinant Immunotoxin, RIT, Antibody, Mesothelin, Mesothelioma.
Description of Technology
Recombinant immunotoxins (RITs) are fusions of an antibody-based targeting moiety and a toxin. Pseudomonas exotoxin A (PE) is a bacterial toxin that has been used in several RITs evaluated in clinical trials.[1 2] Once the Fv portion of the immunotoxin binds to its target receptor, the immunotoxin is internalized by endocytosis. Following internalization, Furin cleavage is critically important for proper cytosolic shuttling of the immunotoxin. Early PE-containing RITs were effective, but also had issues of off-target toxicity.
To mitigate off-target toxicity of PE, the inventors removed specific sequences of domain II, and connected the Fv domain to domain III (PE24) by a furin linker peptide. These PE24-RITs are very active and better tolerated by mice. However, the PE24-containing RITs could potentially be cleaved and inactivated before internalization by cell surface furin or other proteases in the bloodstream or the tumor microenvironment, due to the absence of a key disulfide bond (lost after removal of domain II sequences).
Researchers at the National Cancer Institute's Laboratory of Molecular Biology (NCI LMB) developed and isolated several de-immunized, low toxicity, PE24-based RITs with a longer serum half-life. This was enabled by using a disulfide bond to protect the furin cleavage sequence (FCS). Collectively, the new RITs are designated “DS-PE24” immunotoxins. The goal of the disulfide bond is to protect the RIT from cleavage-based deactivation before internalization. The most active of these new RITs has longer serum half-life than an RIT without the disulfide bond, has the same anti-tumor activity, while remaining less cytotoxic in vitro. Currently, the inventors are working with mouse models to further develop the DS-PE24 RITs towards developing an anti-mesothelin RIT for treatment of mesothelin-expressing cancers, such as mesothelioma.
Potential Commercial Applications
- A more stable cancer therapeutic for currently used PE-coupled RITs, for example, anti-mesothelin PE-based immunotoxins.
- Protection of the FCS by a disulfide bond results in more stable RIT, which can lead to fewer off-target effects.
Development Stage: In-vivo.
Inventor(s): Ira Pastan M.D. (NCI), et al.
Intellectual Property: United States Provisional Patent Application 62/323,668 (NIH Reference E-157-2016/0-US-01), entitled “New, More Stable Start Printed Page 62917Immunotoxin Variants with a Disulfide Bond Protecting the Furin Cleavage Site.”
- NIH Reference E-262-2005, entitled “Mutated Pseudomonas Exotoxins with Reduced Antigenicity”
- NIH Reference E-292-2007, entitled “Deletions in Domain II of Pseudomonas Exotoxin A that Reduce Non-Specific Toxicity”
- NIH Reference E-174-2011, entitled “Pseudomonas Exotoxin A with Less Immunogenic T-Cell and/or B-Cell Epitopes”
- NIH Reference E-263-2011, entitled “Pseudomonas Exotoxin A with Less Immunogenic B-Cell Epitopes”
Collaboration Opportunity: Researchers at the NCI seek parties interested in licensing DS-PE24 RITs.
Contact Information: Requests for copies of the patent application or inquiries about licensing, research collaborations, and co-development opportunities should be sent to John D. Hewes, Ph.D., email: email@example.com.Start Signature
Dated: September 5, 2016.
John D. Hewes,
Technology Transfer Specialist, Technology Transfer Center, National Cancer Institute.
1. Fitzgerald DJ, Kreitman R, et al. Int J Med Microbiol. 2004;293:577-582.
2. Sampson JH, Akabani G, Archer GE, et al. J Neurooncol. 2003;65(1):27-35.Back to Citation
[FR Doc. 2016-21906 Filed 9-12-16; 8:45 am]
BILLING CODE 4140-01-P