[Federal Register Volume 59, Number 228 (Tuesday, November 29, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-29314]
[[Page Unknown]]
[Federal Register: November 29, 1994]
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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, HHS.
ACTION: Notice.
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The inventions listed below are owned by agencies 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 U.S. companies and may also be available for licensing.
ADDRESS: Licensing information and copies of the U.S. patent
applications listed below may be obtained by contacting Daniel R.
Passeri, Technology Licensing Specialist, Office of Technology
Transfer, National Institutes of Health, 6011 Executive Boulevard,
Suite 325, Rockville, Maryland 20852-3804 (telephone 301/496-7735 ext.
244; fax 301/402-0220). A signed Confidential Disclosure Agreement will
be required to receive copies of the patent applications. Issued
patents may be obtained from the Commissioner of Patents, U.S. Patent
and Trademark Office, Washington, DC 20231.
Method for Reducing the Immunogenicity of Antibody Variable Domains
Padlan, E.A., Mark, G.E., Daugherty, B.L. (NIDDK)
Filed 17 May 91
Serial No. 07/702,217
The therapeutic use of antibodies derived either completely or
partially from rodents generally produces an immune response toward the
antibody, thus limiting the duration and effectiveness of the therapy.
This invention attempts to overcome this problem by identifying the
amino acid residues responsible for the species specificity or the
immunogenicity on the surface of the mAb and then replacing or coating
(``veneering'') the exterior amino acid residues of one species (the
donor species) with those of a second species (the recipient); these
replacements are made only in the framework regions of the heavy and
light chains of the antibody. Such modifications markedly affect
immunogenicity but do not interfere with ligand-binding properties of
the antibody. Production of the altered antibody is achieved via
recombinant methods.
Anthrax Toxin Fusion Proteins and Related Methods
Leppla, S.H., Arora, N., Klimpel, K.R., Singh, Y., Nichols, P.J. (NIDR)
Filed 25 Jun 93
Serial No. 08/082,849 (CIP of 08/021,601)
This invention involves a number of novel fusion proteins that may
be particularly useful as immunotoxins for the treatment of tumors or
virally infected cells. One method of targeting specific cells in the
body for therapeutic treatment has been to make fusion proteins of
toxin and single-chain antibody (sFv); however, such methods have not
been particularly successful because the need to fuse the toxin to the
targeting molecule (i.e., the antibody) often disrupts the toxin
function or the targeting function of the antibody. Such problems have
been overcome by fusing for example, the translocation domain and
lethal factor (LF) binding domain of the native protective antigen (PA)
protein of anthrax toxin with a target ligand (e.g., cell-specific
sFv). Administration of such a protein, which binds to the target cell,
is then followed by another fusion protein that contains, for example,
the PA binding domain of the LF anthrax protein fused to the cytotoxic
part of a non-LF protein. Once the second fusion protein binds to the
first, it is immediately internalized, and cell death occurs. Because
of the high efficiency of this system, the second fusion can be added
at concentrations of 1 picomole per liter. Thus, in this invention, the
toxin does not need to be directly fused to the cell-specific ligand as
in earlier immunotherapies. This invention--which includes the nucleic
acid sequences for such fusion proteins--may be applicable to treating
HIV-infected cells as well as delivering a variety of therapeutic
agents to specific subsets of cells.
E6-Associated Protein and Methods of Use
Huibregtse, J.M., Scheffner, M., Howley, P.M. (NCI)
Filed 30 Jul 93
Serial No. 08/100,692
Compositions and methods have been developed for screening viruses
for their potential to cause cancer as well as for screening compounds
that can block the ability of certain viruses to transform cells from
normal cells to tumor cells. The malignant transformation of cells has
been linked to the expression of proteins encoded by oncogenes as well
as to the inactivation of proteins encoded by tumor suppressor genes.
Human protein p53 is one of these tumor suppressor gene products. The
E6 oncoproteins of the cancer-associated or ``high risk'' human
papillomaviruses (HPVs) have been shown to complex with p53, leading to
the degradation of the latter. This suggests that E6 deregulates normal
cell growth by eliminating the p53 tumor suppressor protein. An
additional cellular factor, designated E6-Associated Protein (E6-AP),
is necessary for E6-p53 complex formation. Previously, there has been
no acceptable method for inhibiting E6-p53 complex formation or for
determining which viruses have the potential for inactivating p53 in
normal cells and inducing cancer. This invention addresses both of
those problems by providing DNA constructs encoding E6-AP--or
polypeptide fragments derived from it--that can be used for detecting
HPVs associated with a high risk of malignancy. This invention also
provides compounds that inhibit binding of E6 to p53 and provides
methods for further identifying compounds that inhibit the formation of
this complex.
Method of Inhibiting Kaposi's Sarcoma
Vogel, T., Gallo, R.C., Browning, P.J., Roberts, D.D., Panet, A. (NCI)
Filed 12 Aug 93
Serial No. 08/105,900
A recombinant protein has been developed that offers a more
effective and potentially less toxic treatment for AIDS-related
Kaposi's sarcoma. Kaposi's sarcoma (KS) is a malignant, neoplastic,
vascular proliferation that occurs in immune-compromised individuals
and, especially, in AIDS patients.Effective treatments for AIDS-
associated KS include low-dose combinations of doxorubicin, bleomycin,
vincristine, or -IFN; however, HIV-1 infected patients with KS
are unable to tolerate aggressive chemotherapy due to hematologic and
immunologic complications secondary to HIV-1 infection. Therefore,
there is a need to develop less toxic therapies to treat this
condition. This novel recombinant apolipoprotein E-3 (Apo E-3) has been
shown to block cell proliferation and chemotaxis of AIDS-KS-derived
spindle cells in vitro and in vivo. It appears to be relatively
nontoxic.
Method and Composition for Primer-Specific Solid-Phase Detection of PCR
Products
Fields, H.A., Khudyakov, Y.E. (CDC)
Filed 3 Sep 93
Serial No. 08/116,344
A method and reagents for the detection of polymerase chain
reaction (PCR) products have been developed that offer to significantly
facilitate the use of this powerful gene amplification tool in
diagnostic laboratory procedures. PCR gene amplification products can
be visualized by gel electrophoresis and staining; however, this method
is quite subjective. Colorimetric quantitation of PCR products has been
limited by the availability of a suitable sequence-specific capture
method. The most effective means for detecting PCR products is by
hybridization with a sequence-specific probe attached to a solid phase
(microtiter well); however, this method is not very efficient due to
its dependence on DNA denaturing conditions (i.e., high temperature or
alkali conditions). This newly developed method overcomes such
limitations by amplifying DNA with a primer with a known nucleotide
that can be selectively digested in its double-stranded form. A second
primer with a marker molecule (e.g., biotin) is used to form a double-
stranded product with the known nucleotide sequence on one strand and
the marker molecule on the other. The known nucleotide sequence on the
one strand is then digested to expose a single-stranded sequence, which
is hybridized to a complementary nucleic acid sequence bound to a solid
support. A colorimetric method is then used to detect the marker
molecule.
Method for Detection of Cornifin Expression in Mammalian Tissue
Jetten, A.M. (NIEHS)
Filed 15 Nov 93
Serial No. 08/151,995
Licensing Contact: Dan Passeri
A unique method for detecting the expression of the squamous cell
protein, cornifin, offers to improve the detection and treatment of a
variety of squamous-cell related diseases. Squamous cells are flat,
epithelial cells resulting from squamous differentiation and are seen
in many different tissues including epidermis (skin), esophagus, and
tongue. Currently, the practical methods for the detection of squamous
cell-related diseases largely relate to morphologic and histologic
approaches. Unfortunately, however, these methods detect such
conditions only in their later stages of development, when treatment is
much more difficult. Thus, present treatment regimens are limited by
their specificity and adverse side effects. This new detection method
specifically tests for cornifin, which is a precursor marker for many
squamous cell-related disorders. Thus, the ability to monitor the
expression of cornifins in normal and disease tissues is a valuable
tool in the diagnosis of psoriasis and possibly for other squamous
cell-related diseases such as squamous cell carcinoma, vitamin A
deficiency, and chronic retinoic acid effects. Diagnosis is based on
the levels of cornifin message or cornifin polypeptides in afflicted
tissues.
1,2-Dihydroellipticines With Activity Against CNS-Specific Cancer Cell
Lines
Haugwitz, R.D., Cushman, M., Narayanan, V.L., Jarayj, J. (NCI)
Filed 21 Dec 93
Serial No. 08/171,234 (DIV of 07/956,903; patent 5,272,146 issued 21
Dec 93)
A new class of derivatives of the compound 1,2-dihydroellipticine
are particularly useful in treating cancers of the central nervous
system (CNS). Many of the drugs that have been developed to treat human
cancers have limited applicability in treating CNS cancers because they
can not effectively penetrate the blood-brain barrier (BBB) or the
blood-cerebrospinal fluid (CSF) barrier. These barriers prevent large
molecular substances from passing from the blood to the interstitial
fluids of the brain and CSF; however, these barriers are generally
highly permeable to water, carbon dioxide, oxygen, and lipid-soluble
substances and slightly permeable to electrolytes. It is also known
that the BBB is relatively impermeable to ionized forms of drugs and
other molecules. This new class of ellipticine-derived compounds--which
have potent antitumor activity--have been converted to neutral,
uncharged species and thus can easily penetrated the BBB and CSF
barriers. Once these compounds enter through the BBB, they are often
oxidized to an ionic form that is eliminated from the brain 10 times
slower than from the rest of the body. Therefore, they are highly
specific for CNS cancers.
Protein Tyrosine Kinase A6
Beeler, J.F., LaRochelle, W., Aaronson, S.A. (NCI)
Filed 12 Jan 94
Serial No. 08/184,252
A gene has been identified that encodes a novel protein tyrosine
kinase that is highly divergent from any of the previously described
protein tyrosine kinases. Protein kinases--enzymes that phosphorylate
proteins--are important to a number of physiologic events ranging from
normal cell growth and differentiation to malignant transformation of
normal cells into cancer cells. This newly discovered kinase may be
important in the regulation of cellular growth control pathways, and
the DNA sequence encoding the protein may be useful as a probe for
determining the distribution of this enzyme in various tissues.
Antibodies to the protein also can be used for determining its levels
in both normal and neoplastic tissue to correspond its activity with
cell proliferation.
Fusion Proteins That Include Antibody and Nonantibody Portions
LaRochelle, W.J., Aaronson, S.A., Dirsch, O. (NCI)
Filed 1 Feb 94
Serial No. 08/189,552
A new class of antibody/nonantibody fusion proteins have been
developed that are valuable for a number of conventional applications
associated with monoclonal antibodies. There have been a number of
attempts to develop tissue- or cell-specific therapeutics by fusing
regions of antibodies--IgG in particular--with other molecules with
bioactivity. However, practical applications of such fusion, or
chimeric, molecules have been slow to emerge, primarily because the H
and L chains of IgG are poorly secreted and rapidly degraded in the
absence of their partner H and L chains. These new IgG/non-IgG fusion
proteins, however, are potently secreted in stable form when
transfected in mammalian cells and display effector properties
characteristic of both the antibody and nonantibody predecessor
molecules, respectively. These fusion proteins may be useful for flow
cytometry, immunohistochemistry, and immunoprecipitation as well as for
diagnostic and therapeutic purposes.
Method of Inhibiting Transformed Cells
Rabinovitz, M., Fisher, J. (NCI)
Filed 18 Feb 94
Serial No. 08/198,953
Novel compounds have been developed for selectively inhibiting
transformed cells that offer to significantly improve the treatment of
a number of cancers. Transformation is a process where normal cells
lose their ability for controlled growth and begin to proliferate in
excess. Types of transformed cells include tumor and cancer cells.
Previously developed agents for inhibiting the growth of or killing
transformed cells have had limited utility because they are also toxic
to normal cells. These new compounds, which are derivatives of the
compound phenanthroline, are highly effective in inhibiting transformed
cells and have shown surprisingly low toxicity in normal cells in
animal studies. They have been shown to inhibit the growth rate of a
wide variety of transformed cells from such tissues as lung, colon,
ovary, skin, blood, central nervous system, and kidney.
Novel, Broad-Spectrum, Human Lung Fibroblast-Derived Mitogen
Rubin, J.S., Chan, A., Aaronson, S.A. (NCI)
Filed 5 May 94
Serial No. 08/238,752 (DIV of 07/582,063)
A fibroblast-derived mitogen, now termed hepatocyte growth factor/
scatter factor (HGF/SF), was shown to have specificity for melanocytes,
endothelial cells, and a variety of epithelial cells. Based on its
activity on these many different cell types, this protein should have
utility in promoting the repair of many tissues as well as angiogenesis
in appropriate settings. It can also be used to develop anti-growth
factor agents which could prove useful in the treatment of
proliferative disorders involving HGF/SF expression.
Dated: November 16, 1994.
Barbara M. McGarey,
Deputy Director, Office of Technology Transfer.
[FR Doc. 94-29314 Filed 11-28-94; 8:45 am]
BILLING CODE 4140-01-P