[Federal Register Volume 76, Number 131 (Friday, July 8, 2011)]
[Notices]
[Pages 40381-40383]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-17228]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 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.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301-496-7057; fax: 301-402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Breakthrough Immunotherapy for Brain Cancer: Epidermal Growth Factor 
Receptor Variant III Chimeric Antigen Receptors

    Description of Technology: Scientists at the National Institutes of 
Health (NIH) have developed chimeric antigen receptors (CARs) with high 
affinity for the epidermal growth factor receptor variant III 
(EGFRvIII) to use as a promising immunotherapy for aggressive brain 
cancer (glioblastoma) as well as several other malignancies. CARs are 
hybrid proteins consisting of the portion of an antibody that 
recognizes a cancer antigen, in this case human monoclonal antibody 139 
which recognizes EGFRvIII, fused to protein signaling domains that 
serve to activate the CAR-expressing cell. Human cells that express 
CARs, most notably T cells, can recognize specific tumor antigens in an 
MHC-unrestricted manner with high reactivity and mediate an immune 
response that promotes robust tumor cell elimination.

Advantages

     EGFRvIII CAR immunotherapy is a breakthrough treatment for 
glioblastomas, a cancer with no other effective treatment option.
     EGFRvIII CARs can cross the blood-brain barrier, are 
expected to target only tumor cells, and thus, generate fewer side 
effects than other brain cancer treatment approaches.
     With the advent of Provenge[supreg], personalized 
immunotherapy is becoming more widely accepted as a viable cancer 
treatment option.

Applications

     Immunotherapeutics to treat and/or prevent the recurrence 
of a variety of cancers that overexpress human EGFRvIII, primarily 
glioblastoma multiforme (GBM). About half of GBM tumor cells express 
the EGFRvIII antigen. Other cancers that overexpress EGFRvIII include 
breast, ovarian, prostate, bladder, colorectal, non-small cell lung 
carcinomas, and head and neck squamous cell carcinomas.
     A personalized cancer treatment strategy for patients 
whose tumor cells express EGFRvIII whereby the patient's own T cells 
are isolated, engineered to express the EGFRvIII specific CAR, and re-
infused into the patient to attack the tumor.
    EGFRvIII is a rare antigen in that is highly expressed by tumor 
cells, but not expressed by other cells in the body. This cancer 
antigen is expressed on nearly 50% of GBM tumor cells and also in other 
tumor types, such as other nervous system cancers and head and neck 
cancers. There exist very few, if any, effective treatments for GBM, so 
the expected clinical benefit of an anti-EGFRvIII CAR to patients is 
expected to be a therapeutic breakthrough for treatment of this cancer. 
These CARs are expected to combine high affinity recognition of 
EGFRvIII provided by the antibody portion with the target cell killing 
activity of cytotoxic T cells. Infusion of these EGFRvIII-specific CARs 
into patients could prove to be a powerful new immunotherapeutic tool 
for treating brain cancers, a type of cancer with a long-felt need for 
breakthrough therapeutics.
    Development Status: This technology could soon be ready for 
clinical development. A clinical protocol to utilize an EGFRvIII CAR to 
treat GBM is currently under review at NIH.
    Inventors: Richard A. Morgan and Steven A. Rosenberg (NCI).
    Patent Status: U.S. Provisional Application No. 61/473,409 filed 
April 8, 2011 (HHS Reference No. E-148-2011/0-US-01).

Related Technologies

     E-269-2010/0--U.S. Provisional Application No. 61/384,931 
filed September 21, 2010.
     E-236-2010/0--U.S. Provisional Application No. 61/405,931 
filed October 22, 2010.
     E-205-2009/0--PCT Application No. PCT/US2010/048701 filed 
September 14, 2010, which published as WO2011/041093 on April 7, 2011.

Relevant Publications

    1. Weber R, et al. U.S. Patent No. 7,628,986 issued December 8, 
2009 entitled ``Antibodies Directed to the Deletion Mutants of 
Epidermal Growth Factor Receptor and Uses Thereof''.
    2. Carter B.S., et al. U.S. Patent Application No. 12/444,090 filed 
April 2, 2009 entitled ``Chimeric T-Cell Receptors and T-Cells 
Targeting EGFRvIII on Tumors''.
    3. Bullian SS, et al. Genetically engineered T cells to target 
EGFRvIII expressing glioblastoma. J Neurooncol. 2009 Sept;94(3):373-
382. [PMID: 19387557].
    4. Ohno M, et al. Retrovirally engineered T-cell based 
immunotherapy targeting type III variant epidermal growth factor 
receptor, a glioma-associated antigen. Cancer Sci. 2010 
Dec;101(12):2518-2524. [PMID: 20880333].
    Licensing Status: Available for licensing.
    Licensing Contact: Samuel E. Bish, PhD; 301-435-5282; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute, 
Surgery Branch, is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize cell-based immunotherapies targeting 
EGFRvIII expressing cancers. Please contact John Hewes, PhD at 301-435-
3121 or [email protected] for more information.

An Improved Anti-Mesothelin Immunotoxin for Treatment of Mesothelioma, 
Lung Cancer, Ovarian Cancer and Pancreatic Cancer

    Description of Technology: Mesothelin is a cell surface 
glycoprotein that is highly expressed in many cancers (e.g., malignant 
mesothelioma, lung cancer, ovarian cancer, and pancreatic cancer). 
Because of its differential expression, mesothelin is an excellent

[[Page 40382]]

target for the selective killing of cancer cells. For instance, anti-
mesothelin monoclonal antibodies can carry cellular toxins specifically 
to mesothelin-expressing cancer cells, resulting in their selective 
killing while healthy, essential cells remain unharmed.
    A high affinity anti-mesothelin antibody (SS1) was previously 
combined with a functional fragment of Pseudomonas Exotoxin A (PE), 
producing the immunotoxin SS1P. SS1P selectively killed mesothelin-
expressing cancer cells, suggesting it could be an excellent 
therapeutic agent. Unfortunately, PE-based immunotoxins can lose 
therapeutic efficacy following multiple administrations, due to the 
formation of neutralizing antibodies against the PE portion of the 
molecule. As a result, less immunogenic variants of PE have been 
created in order to develop immunotoxins that do not induce the 
formation of neutralizing antibodies.
    Improved PE variants have been created which lack lysosomal 
protease sites, a dominant T-cell epitope (PE-LR), and several major B-
cell epitopes (PE-LR/8M). Although these new PE variants demonstrate 
efficient cell killing activity when used in combination with certain 
antibodies, their activity when using SS1 as the targeting agent (SS1-
LR and SS1-LR/8M) was less impressive. Fortunately, the inventors 
surprisingly discovered that the addition of a small linker peptide 
within these immunotoxins was able to restore their cell killing 
activity to the level of SS1P.
    These new SS1-targeted immunotoxins (e.g., SS1-LR/GGS and SS1-LR/
GGS/8M) have the cell-killing activity of SS1P, but are less likely to 
generate neutralizing antibodies. As a result, these immunotoxins are 
considered to be very promising prospects for treating patients 
suffering from mesothelin-expressing cancers.

Applications

     Treatment of mesothelin expressing cancers, including 
mesothelioma, pancreatic cancer, ovarian cancer and lung 
adenocarcinoma.
     Treatment in combination with standard chemotherapy.
     Diagnostic agent for the detection of mesothelin-
expressing cancers.

Advantages

     Immunotoxins are highly selective for cancer cells, 
reducing side-effects due to the non-specific killing of essential, 
healthy cells.
     Less immunogenic PE variants increase the efficacy of the 
immunotoxin by reducing the formation and action of neutralizing 
antibodies.
     PE variants include the removal of both B-cell and T-cell 
epitopes.
     Use of a small linker peptide offers an unexpected 
advantage of strong cell-killing activity with reduced immunogenicity.
    Development Status: Preclinical stage of development for anti-
mesothelin immunotoxins; immunotoxins directed to other targets have 
some clinical data to demonstrate proof-of-concept
    Inventors: Ira Pastan (NCI) et al.

Patent Status

     U.S. provisional patent application 61/483,531 (HHS 
technology E-117-2011/0-US-01).
     U.S. provisional patent application 61/495,085 (HHS 
technology E-174-2011/0-US-01).

For More Information

     U.S. Patent 7,081,518 (HHS technology E-139-1999/0-US-07).
     U.S. Patent Publication US 20090142341 A1 (HHS technology 
E-262-2005/0-US-06).
     U.S. Patent Publication US 20100215656 A1 (HHS technology 
E-292-2007/0-US-06).
     PCT Publication WO 2011/032022 (HHS technology E-269-2009/
0-PCT-02).
    Licensing Status: Available for licensing.
    Licensing Contact: David A. Lambertson, PhD; 301-435-4632; 
[email protected].

Efficient Production of Functional Recombinant Human Neonatal Receptor 
(FcRn) Proteins

    Description of Technology: Human monoclonal antibodies are becoming 
common therapeutics for numerous diseases, including rheumatoid 
arthritis, multiple sclerosis, and several different types of cancers. 
To improve their half-life, antibodies are engineered to have a high 
affinity to the Fc receptor (FcRn). This requires a reliable method to 
produce high yields of functional FcRn which comprises a 1:1 molar 
ratio of the alpha to the beta chain. Unfortunately, current methods 
can be difficult to implement and are not very efficient in producing 
functional FcRns with the 1:1 molar ratio of the alpha to the beta 
chain. Thus, there is a strong need for quick and economical methods of 
producing functional FcRn to aid in antibody development and the 
improvement of existing antibody therapeutics.
    This technology describes a new and efficient method for producing 
functional human FcRn at a 1:1 molar ratio of the alpha to the beta 
chain. The uniqueness of this invention is that the expression of both 
the beta and the alpha chains is under the control of a single promoter 
and the correct 1:1 molar folding of the two chains is facilitated by 
the intermediate flexible linker. The method is easy to scale up for 
producing large quantities of highly pure FcRn. Further, the inventors 
have recently developed a stable cell line for large scale production.
    Benefits: Improving the half-life of existing monoclonal antibodies 
as well as monoclonal antibodies still in development.

Advantages

     Efficient method of producing high yields of functional 
human FcRn at a 1:1 molar ratio of the alpha to the beta chain.
     Stable cell line also available.
    Market: The monoclonal antibodies market generated over $40 billion 
in sales for therapeutic uses last year and is expected to grow 
significantly over the next several years.
    Publications: Feng Y, Gong R, Dimitrov D.S. Design, expression and 
characterization of a soluble single-chain functional human neonatal Fc 
receptor. Protein Expr Purif. 2011 Mar 29, E-pub ahead of print. [PMID: 
21453773]
    Inventors: Dimiter S. Dimitrov and Yang Feng (NCI).
    Patent Status: HHS Reference No. E-296-2010/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: Available for licensing.
    Licensing Contact: Whitney A. Hastings; 301-451-7337; 
[email protected].

Immunocompetent Mouse Model for Tracking Cancer Progression

    Description of Technology: The technology is a transgenic mouse 
model tolerized to firefly Luciferase (ffLuc)- and enhanced green 
fluorescent protein (eGFP)-labeled tissue whilst maintaining normal 
immune function. Luc and eGFP are the most frequently used bioimaging 
markers to track cancer progression in pre-clinical mouse models. As 
these markers are immunogenic, their reporter activity becomes 
diminished over time and so their use has largely been limited to 
immunodeficient mice. However, immune function is crucial for tumor 
development and progression, making the use of immunocompetent mice 
more desirable.
    The immunocompetent mouse model described in this invention was

[[Page 40383]]

generated using the rat growth hormone gene promoter (rGH) to target 
ffLuc-eGFP fusion gene expression to the pituitary gland, restricting 
any resulting interfering reporter signal within the head. This allows 
the tracking of cancer progression throughout the body, where the 
reporter activity of introduced ffLuc/eGFP-labeled tumors is 
maintained, despite normal immune function. These immunocompetent rGH-
ffLuc-eGFP transgenic mice can be used as hosts in cancer models, 
allowing long-term in vivo monitoring of the progression of ffLuc/eGFP-
labeled tumor cells in the body, which may lead to more clinically 
relevant insights into cancer progression, metastases and response to 
therapies.

Applications

     In vivo model for studying tumor progression and testing 
anti-cancer therapeutics using ffLuc or eGFP labeling for bioimaging.
     Since rGH-ffLuc-eGFP is also a growth hormone-responsive 
reporter, these rGH-Luc-GFP mice may also be used to screen growth-
hormone stimulating drugs for treating Achondroplasia (dwarf syndrome) 
or as a test for illegal performance-enhancing drugs.

Advantages

     This technology represents a more clinically relevant in 
vivo model of cancer progression for testing anti-cancer therapeutics.
     This immunocompetent mouse model is more desirable as a 
pre-clinical model over the currently used immunodeficient mouse models 
as immune function is crucial for tumor development and progression.

Development Status

     Early-stage.
     Pre-clinical.
     In vitro data available.
     In vivo data available (animal).
    Inventors: Chi-Ping Day and Glenn Merlino (NCI).

Relevant Publications

    1. Day C.P., et al. Preclinical therapeutic response of residual 
metastatic disease is distinct from its primary tumor of origin. Int 
J Cancer. 2011 Feb 10, doi: 10.1002/ijc.25978. [Epub ahead of 
print].
    2. Day C.P., et al. Lentivirus-mediated bifunctional cell 
labeling for in vivo melanoma study. Pigment Cell Melanoma Res. 2009 
Jun;22(3):283-295. [PMID: 19175523].
    3. Luque R.M., et al. Reporter expression, induced by a growth 
hormone promoter-driven Cre recombinase (rGHp-Cre) transgene, 
questions the developmental relationship between somatotropes and 
lactotropes in the adult mouse pituitary gland. Endocrinology. 2007 
May;148(5):1946-1953. [PMID: 17289844].
    4. Latta-Mahieu M., et al. Gene transfer of a chimeric trans-
activator is immunogenic and results in short-lived transgene 
expression. Hum Gene Ther. 2002 Sep 1;13(13):1611-1620. [PMID: 
12228016].
    5. Stripecke R., et al. Immune response to green fluorescent 
protein: implications for gene therapy. Gene Ther. 1999 
Jul;6(7):1305-1312. [PMID: 10455440].
    6. Liao C.P., et al. Mouse models of prostate adenocarcinoma 
with the capacity to monitor spontaneous carcinogenesis by 
bioluminescence or fluorescence. Cancer Res. 2007 Aug 1;67(15):7525-
7533. [PMID: 17671224].

    Patent Status: HHS Reference No. E-173-2010/0--Research Tool. 
Patent protection is not being pursued for this technology.
    Licensing Status: Available for licensing.
    Licensing Contact: Sabarni K. Chatterjee, PhD; 301-435-5587; 
[email protected].
    Collaborative Research Opportunity: The National Cancer Institute 
Center for Cancer Research is seeking statements of capability or 
interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize immunocompetent rGH-ffLuc-eGFP 
transgenic mice. Please contact John Hewes, PhD at 301-435-3121 or 
[email protected] for more information.

    Dated: July 1, 2011.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 2011-17228 Filed 7-7-11; 8:45 am]
BILLING CODE 4140-01-P