[Federal Register Volume 67, Number 1 (Wednesday, January 2, 2002)]
[Notices]
[Pages 85-86]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-32170]


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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.

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. 09/960,876 filed 21 Sep 2001

    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.

A Method for Bioconjugation Using Diels-Alder Cycloaddition

Vince Pozsgay (NICHD)
Serial Number 09/919,637 filed 01 Aug 2001

    This invention relates to a new method for the synthesis of 
conjugate vaccines using the Diels-Alder cycloaddition reaction to 
covalently attach a carbohydrate antigen from a pathogen to a protein 
carrier. The Diels-Alder reaction has not been extended to conjugation 
involving biopolymers or other types of polymeric materials. Advantages 
of this method are that cross-linking during conjugation is entirely 
avoided in addition to the mild chemical conditions under which this 
synthesis method proceeds. Diels-Alder reactions commonly take place in 
high-temperature environments; the method contemplated by this 
invention takes place at much lower temperatures. In addition to 
claiming methods of synthesis for conjugate vaccines using the Diels-
Alder cycloaddition, the patent application claims vaccines produced 
utilizing the method, and methods of inducing antibodies which react 
with the polysaccharides contemplated by the invention.

Identification of New Small RNAs and ORFs

Susan Gottesman (NCI), Gisela Storz (NICHD), Karen Wassarman (NICHD), 
Francis Repoila (NCI), Carsten Rosenow (EM)
Serial No. 60/266,402 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 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

[[Page 86]]

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.

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

Roger Kurlander, Elizabeth Chao, Janet Fields (CC)
DHHS Reference No. E-172-99/1 filed 12 Dec 2000 (PCT/US00/33027, 
published as WO 01/40275), with priority to 06 Dec 1999
    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.

Vibrio cholerae O139 Conjugate Vaccines

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

    Dated: December 19, 2001.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 01-32170 Filed 12-31-01; 8:45 am]
BILLING CODE 4140-01-P