[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