[Federal Register Volume 66, Number 107 (Monday, June 4, 2001)]
[Notices]
[Pages 29977-29979]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-13888]


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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, DHHS.

ACTION: Notice.

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SUMMARY: 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 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 contacting Peter A. 
Soukas, J.D., at the Office of Technology Transfer, National Institutes 
of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 
20852-3804; telephone: 301/496-7056 ext. 268; fax: 301/402-0220; e-
mail: [email protected]. A signed Confidential Disclosure Agreement 
will be required to receive copies of the patent applications.

Identification of New Small RNAs and ORFs

Susan Gottesman (NCI), Gisela Storz (NICHD), Karen Wassarman (NICHD), 
Francis Repoila (NCI), Carsten Rosenow (EM)
DHHS Reference No. E-072-01/0, filed 01 Feb 2001

    The inventors have isolated a number of previously unknown sRNAs 
found in E. coli. Previous scientific publications by the inventors and 
others regarding

[[Page 29978]]

sRNAs have shown these sRNAs to serve important regulatory roles in the 
cell, such as regulators of virulence and survival in host cells. 
Prediction of the presence of genes encoding sRNAs was accomplished by 
combining sequence information from highly conserved intergenic regions 
with information about the expected transcription of neighboring genes. 
Microarray analysis also was used to identify likely candidates. 
Northern blot analyses were then carried out to demonstrate the 
presence of the sRNAs. Three of the sRNAs claimed in the invention 
regulate (candidates 12 and 14, negatively and candidate 31, 
positively) expression of RpoS, a major transcription factor in 
bacteria that is important in many pathogens because it regulates 
(amongst other things) virulence. The inventors' data show that these 
sRNAs are highly conserved among closely related bacterial species, 
including Salmonella and Klebsiella, presenting a unique opportunity to 
develop both specific and broad-based antibiotic therapeutics. The 
invention contemplates a number of uses for the sRNAs, including, but 
not limited to, inhibition by antisense, manipulation of gene 
expression, and possible vaccine candidates.

LL-37 Is an Immunostimulant

Oleg Chertov (NCI), Joost Oppenheim (NCI), De Yang (NCI), Qian Chen 
(NCI), Ji Wang (NCI), Mark Anderson (EM), Joseph Wooters (EM)

Serial No. 60/233,983, filed 21 Sep 2000

    This invention relates to use of an antimicrobial peptide as a 
vaccine adjuvant. LL-37 is the cleaved antimicrobial 37-residue C-
terminal peptide of hCAP18, the only identified member in humans of a 
family of proteins called cathelicidins. LL-37/hCAP18 is produced by 
neutrophils and various epithelial cells. LL-37 is well known as an 
antimicrobial peptide. However, although antimicrobial peptides have 
generally been considered to contribute to host innate antimicrobial 
defense, some of them may also contribute to adaptive immunity against 
microbial infection. The inventors have shown that LL-37 utilizes 
formyl peptide receptor-like 1 (FPLR1) as a receptor to activate human 
neutrophils, monocytes, and T cells. Since leukocytes participate in 
both innate and adaptive immunity, the fact that LL-37 can chemoattract 
human leukocytes may provide one additional mechanism by which LL-37 
can contribute to host defense against microbial invasion, by 
participating in the recruitment of leukocytes to sites of infection. 
The invention claims methods of enhancing immune responses through the 
administration of LL-37 alone, in conjunction with a vaccine, and 
methods of treating autoimmune diseases. The invention is further 
described in Chertov et. al., ``LL-37, the neutrophil granule-and 
epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-
like 1 (FPRL1) as a receptor to chemoattract human peripheral blood 
neutrophils, monocytes, and T cells,'' J Exp. Med. 2000 Oct 
2;192(7):1069-74.

Vibrio cholerae O139 Conjugate Vaccines

Shousun Szu, Zuzana Kossaczka, John Robbins (NICHD)
DHHS Reference No. E-274-00/0; PCT/US00/24119, filed 01 Sep 2000

    Cholera remains an important public health problem. Epidemic 
cholera is caused by two Vibrio cholerae serotypes O1 and O139. The 
disease is spread through contaminated water. According to information 
reported to the World Health Organization in 1999, nearly 8,500 people 
died and another 223,000 were sickened with cholera worldwide. This 
invention is a polysaccharide-protein conjugate vaccine to prevent and 
treat infection by Vibrio cholerae O139 comprising the capsular 
polysaccharide (CPS) of V. cholerae O139 conjugated through a 
dicarboxylic acid dihydrazide linker to a mutant diphtheria toxin 
carrier. In addition to the conjugation methods, also claimed in the 
invention are methods of immunization against V. cholerae O139 using 
the conjugates of the invention. The inventors have shown that the 
conjugates of the invention elicited in mice high levels of serum 
antibodies to CPS, a surface antigen of Vibrio cholerae O139, that have 
vibriocidal activity. Clinical trials of the two most immunogenic 
conjugates have been planned by the inventors. This invention is 
further described in Infection and Immunity 68(9), 5037-5043, Sept. 
2000.

A Novel Chimeric Protein for Prevention and Treatment of HIV 
Infection

Edward A. Berger (NIAID), Christie M. Del Castillo
Serial No. 60/124,681, filed 16 Mar 1999 and PCT/US00/06946, filed 16 
Mar 2000

    This invention relates to bispecific fusion proteins effective in 
viral neutralization. Specifically, the invention is a genetically 
engineered chimeric protein containing a soluble extracellular region 
of human CD4 attached via a flexible polypeptide linker to a single 
chain human monoclonal antibody directed against a CD4-induced, highly 
conserved HIV gp120 determinant involved in coreceptor interaction. 
Binding of the sCD4 moiety to gp120 induces a conformational change 
that enables the antibody moiety to bind, thereby blocking Env function 
and virus entry. This novel bispecific protein displays neutralizing 
activity against genetically diverse primary HIV-1 isolates, with 
potency at least 10-fold greater than the best described HIV-1 
neutralizing monoclonal antibodies. The agent has considerable 
potential for prevention of HIV-1 infection, both as a topical 
microbicide and as a systemic agent to protect during and after acute 
exposure (e.g. vertical transmission, post-exposure prophylaxis). It 
also has potential utility for treatment of chronic infection. Such 
proteins, nucleic acid molecules encoding them, and their production 
and use in preventing or treating viral infections are claimed.

Beta2-Microglobulin Fusion Proteins and High Affinity Variants

RK Ribaudo, M Shields (NCI)
Serial No. 09/719,243, filed 07 Dec 2000 (with priority back to Serial 
No. 60/088,813, filed 10 Jun 1998) and European Patent Application 
Number 99928376.5

    This invention concerns fusion proteins comprising b2-microglobulin 
(b2M), a component of the MHC-1 complex, and immunologically active 
proteins such as the co-stimulatory molecule B7. The fusion proteins, 
and nucleic acids encoding them, have broad utility activating 
Cytotoxic T Lymphocytes (CTLs) against viruses and tumors. The fusion 
proteins locate to the surface of MHC-1 expressing cells. They may be 
used as adjuvants to enhance the efficacy of MHC-1 binding peptides, 
from viruses or cancer antigens, as vaccines. The fusion proteins can 
be used, in vivo or ex vivo, to enhance the immunogenicity of cancer 
cells to cause their destruction by the immune system. B7-b2M is as 
effective at co-stimulating T-cells in comparison to anti-CD28 
monoclonal antibodies, whereas wild-type b2M is ineffective at co-
stimulating T-cells. In addition, B7-b2M induces better recognition and 
killing of tumor cell lines compared to wild-type b2M. Another aspect 
of the invention is a mutant human b2M that binds MHC-1 with higher 
affinity than wild-type b2M. It can be used in place of wild-type b2M, 
including in the fusion proteins, to greater effect.

[[Page 29979]]

Virus-Like Particles as Unlinked Adjuvants

John Schiller, Bryce Chackerian, Joseph Lee, Douglas Lowy (NCI)
Serial No. 60/219,763, filed 20 Jul 2000

    This invention claims immunostimulating or vaccine compositions in 
which non-infectious virus-like particles (VLPs) serve as unlinked 
adjuvants. Co-administration of VLPs with an antigen enhances induction 
of high titer IgG antibodies to self or foreign antigens and promotes T 
cell responses to foreign antigens. The VLP-target antigen combination 
can be administered alone or with a traditional adjuvant. The VLPs of 
the current invention are contemplated to comprise capsid protein(s) of 
a virus assembled into a shell resembling a virion, but not containing 
pathogenic viral DNA or RNA. The VLPs are unlinked, rather than 
physically linked to the antigen because this may reduce the 
manufacturing complexity of the vaccine. Unlinked VLP adjuvants, for 
example papillomavirus VLPs, of the invention have a number of 
advantages: (1) They are non-inflammatory in humans, (2) are potent at 
amplifying IgG antibody responses to self antigens, (3) induce a 
pronounced Th1 type of T cell response, and (4) may provide two-fold 
protection, against the virus corresponding to the VLP type, as well as 
against the disease associated with the other component in the VLP-
target antigen combination.

Peptides That Stabilize Protein Antigens and Enhance Presentation 
to CD8+ T Cells

Roger Kurlander, Elizabeth Chao, Janet Fields (CC)
Serial No. 60/169,227, filed 06 Dec 1999 and PCT/US00/33027, filed 12 
Dec 2000

    This invention relates to compositions and methods for stabilizing 
an antigen against proteolytic degradation and enhancing its 
presentation to CD8+ cells. The invention claims ``fusion agents,'' 
isolated molecules comprising a hydrophobic peptide joined to an 
epitope to which a CD8+ T cell response is desired. Also claimed in the 
invention are the nucleic acid sequences that encode the fusion agents. 
Recently, there has been great interest in developing vaccines to 
induce protective CD8+ T cell responses, however, there are practical 
obstacles to this goal. Although purified antigenic peptides are 
effectively presented in vitro, introduced in a purified form they 
often do not stimulate effective T cell responses in vivo because the 
antigens are insufficiently immunogenic and too easily degraded. 
Adjuvants or infectious ``carriers'' often can enhance these immune 
responses, however, these added agents can cause unacceptable local or 
systemic side effects. The present invention increases antigen 
stability and promotes in vivo responses in the absence of an adjuvant 
or active infection.
    The invention describes three variants of lemA, an antigen 
recognized by CD8+ cells in mice infected with Listeria monocytogenes. 
The antigenic and stabilizing properties of lemA can be accounted for 
by the covalent association of the immunogenic aminoterminal 
hexapeptide with the protease resistant scaffolding provided by amino 
acids 7 to 33 of the lemA sequence (lemA(7-33)). Variants t-lemA, and 
s-lemA bearing an antigenic sequence immediately preceding lemA(7-33), 
and lemS containing an immunogenic sequence immediately after lemA(7-
33), each induce a CD8+ T cell response and protect the crucial 
immunogenic oligopeptide from protease degradation. The site of antigen 
insertion relative to lemA(7-33) can influence antigen processing by 
preferentially promoting processing either in the cytoplasm or 
endosomal compartment. Therefore, several embodiments of the invention 
involve the construction of antigen processing protein molecules and 
their methods of use. Alternatively, a DNA sequence coding lemA(7-33) 
may be inserted at an appropriate site to enhance the immunogenicity of 
the antigenic element coded by a DNA vaccine. In sum, this invention is 
an attractive, nontoxic alternative to protein/adjuvant combinations in 
eliciting CD8 responses in vivo and a useful element for enhancing the 
efficiency with which products coded by DNA vaccines are processed and 
presented in vivo. Because lemA(7-33) is particularly effective in 
protecting oligopeptides from proteases, this invention may have 
particular usefulness in enhancing local T cell at sites such as 
mucosal surfaces where there may be high proteolytic activity.
    For more specific information about the invention or to request a 
copy of the patent application, please contact Peter Soukas at the 
telephone number or e-mail listed above. Additionally, please see a 
related article published in the Journal of Immunology at: 
1999;163:6741-6747.

    Dated: May 25, 2001.
Jack Spiegel,
Director, Division of Technology, Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 01-13888 Filed 6-1-01; 8:45 am]
BILLING CODE 4140-01-P