[Federal Register Volume 73, Number 206 (Thursday, October 23, 2008)]
[Notices]
[Pages 63161-63165]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-25210]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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.
Development of Mutations Useful for Attenuating Dengue Viruses and
Chimeric Dengue Viruses
Description of Technology: Although flaviviruses cause a great deal
of human suffering and economic loss, there is a shortage of effective
vaccines. This invention relates to dengue virus mutations that may
contribute to the development of improved dengue vaccines. Site
directed and random mutagenesis techniques were used to introduce
mutations into the dengue virus genome and to assemble a collection of
useful mutations for incorporation in recombinant live attenuated
dengue virus vaccines. The resulting mutant viruses were screened for
several valuable phenotypes, including temperature sensitivity in Vero
cells or human liver cells, host cell restriction in mosquito cells or
human liver cells, host cell adaptation for improved replication in
Vero cells, and attenuation in mice or in mosquitoes. The genetic basis
for each observed phenotype was determined by direct sequence analysis
of the genome of the mutant virus. Mutations identified through these
sequencing efforts have been further evaluated by re-introduction of
the identified mutations, singly, or in combination, into recombinant
dengue virus and characterization of the resulting recombinant virus
for phenotypes. In this manner, a menu of attenuating and growth
promoting mutations was developed that is useful in fine-tuning the
attenuation and growth characteristics of dengue virus vaccine
candidates. The mutations promoting growth in Vero cells have
usefulness for the production of live or inactivated dengue virus
vaccines.
Inventors: Stephen S. Whitehead, Brian R. Murphy, Kathryn A.
Hanley, Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent No. 7,226,602 issued 05 Jun 2007 (HHS
Reference No. E-120-2001/0-US-04); U.S. Patent Application No. 11/
446,050 filed 02 Jun 2006 (HHS Reference No. E-120-2001/0-US-10).
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or
[email protected] for more information.
Dengue Tetravalent Vaccine Containing a Common 30 Nucleotide Deletion
in the 3'-UTR of Dengue Types 1, 2, 3, and 4
Description of Technology: The invention relates to a dengue virus
[[Page 63162]]
tetravalent vaccine containing a common 30-nucleotide deletion
(Delta30) in the 3'-untranslated region (UTR) of the genome of dengue
virus serotypes 1, 2, 3, and 4. The previously identified Delta30
attenuating mutation, created in dengue virus type 4 (DEN4) by the
removal of 30 nucleotides from the 3'-UTR, is also capable of
attenuating a wild-type strain of dengue virus type 1 (DEN1). Removal
of 30 nucleotides from the DEN1 3'-UTR in a highly conserved region
homologous to the DEN4 region encompassing the Delta30 mutation yielded
a recombinant virus attenuated in rhesus monkeys to a level similar to
recombinant virus DEN4Delta30. This established the transportability of
the Delta30 mutation and its attenuation phenotype to a dengue virus
type other than DEN4. The effective transferability of the Delta30
mutation establishes the usefulness of the Delta30 mutation to
attenuate and improve the safety of commercializable dengue virus
vaccines of any serotype.
A tetravalent dengue virus vaccine containing dengue virus types 1,
2, 3, and 4 each attenuated by the Delta30 mutation is being developed.
The presence of the Delta30 attenuating mutation in each virus
component precludes the reversion to a wild-type virus by intertypic
recombination. In addition, because of the inherent genetic stability
of deletion mutations, the Delta30 mutation represents an excellent
alternative for use as a common mutation shared among each component of
a tetravalent vaccine.
Inventors: Stephen S. Whitehead (NIAID), Brian R. Murphy (NIAID),
Lewis Markoff (FDA), Barry Falgout (FDA), Kathryn A. Hanley (NIAID),
Joseph E. Blaney (NIAID).
Patent Status: U.S. Patent Application No. 10/970,640 filed 21 Oct
2004, claiming priority to 03 May 2002 (HHS Reference No. E-089-2002/1-
US-02)
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or
[email protected] for more information.
Live Attenuated Vaccine to Prevent Disease Caused by West Nile Virus
Description of Technology: WNV has recently emerged in the U.S. and
is considered a significant emerging disease that has embedded itself
over a considerable region of the U.S. WNV infections have been
recorded in humans as well as in different animals. To date, WNV has
killed 294 people in the U.S. and caused severe disease in more than
4222 others. This project is part of NIAID's comprehensive emerging
infectious disease program, which supports research on bacterial,
viral, and other types of disease-causing microbes.
The methods and compositions of this invention provide a means for
prevention of WNV infection by immunization with attenuated,
immunogenic viral vaccines against WNV. The invention involves a
chimeric virus form consisting of parts of WNV and Dengue virus.
Construction of the hybrids and their properties are described in
detail in AG Pletnev et al., PNAS 2002; 99(5): 3036-3041.
The WNV chimeric vaccine does not target the central nervous
system, which would be the case in an infection with wild type WNV. The
vaccine stimulates strong anti-WNV immune responses, even following a
single dose of the vaccine. When injected into mice, the vaccine
protected all of the immunized animals from subsequent exposure to the
New York WNV strain. The vaccine was also effective in primates.
The WNV vaccine may be used to protect the human population,
particularly the elderly people, and domestic animals from WNV
infection in the affected regions of the U.S. as well as worldwide.
Inventors: Alexander G. Pletnev et al. (NIAID).
Patent Status: U.S. Patent Application No. 10/871,775 filed 18 Jun
2004 (HHS Reference No. E-357-2001/1-US-02).
Licensing Status: Available for exclusive or non-exclusive
licensing for developing a vaccine against WNV for humans or veterinary
use in accordance with 35 U.S.C. 207 and 37 CFR Part 404.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases is seeking statements of capability or
interest from parties interested in collaborative research to further
develop, evaluate, and commercialize this technology. Please contact
Percy Pan at 301-451-3523 or [email protected] for more information.
Development of Dengue Virus Type 3 Vaccine Candidates Containing Either
(1) Nucleotide Deletions in the 3'-UTR of the Genome Consisting of More
Than 30 Contiguous Nucleotides in One or Multiple Regions, or (2) a 3'-
UTR Derived From DEN4 and Containing the A30 Nucleotide Deletion
Description of Technology: The disease burden associated with
dengue virus infection has increased over the past several decades in
the tropical and semi-tropical regions of the world, where over 2
billion people live at risk of dengue infection. Annually, there are an
estimated fifty (50) to one hundred (100) million cases of dengue
fever, making development of an effective vaccine a priority. In
addition, there is a need for a ``travelers vaccine'' to protect those
visiting dengue virus endemic areas, similar in scope to other
currently available ``travelers vaccines'', such as hepatitis A
vaccine.
The previously identified [Delta]30 attenuating mutation, created
in each dengue virus serotype by the removal of 30 homologous
nucleotides from the 3'-UTR, is capable of attenuating wild-type
strains of dengue virus type 1 (DEN1), type 4 (DEN4) and to a limited
extent type 2 (DEN2). These DEN1Delta30 and DEN4Delta30 viruses have
been shown to be both safe and immunogenic in humans. However, the
Delta30 mutation failed to have an attenuating effect on dengue virus
type 3 (DEN3). To generate DEN3 vaccine candidates with a clearly
attenuated phenotype, viruses were produced containing 3'-UTR deletions
consisting of extensions of the original Delta30 mutation or additional
mutations which remove stem-loop structures similar to those removed by
Delta30. In addition, the entire 3'-UTR of DEN3 was replaced with the
3'-UTR derived from DEN4 and containing the Delta30 mutation. Studies
in monkeys demonstrated that these newly developed viruses are highly
attenuated, yet sufficiently immunogenic to warrant their further
development for use as live attenuated vaccine candidates. Such viruses
are anticipated to become the DEN3 component of a tetravalent vaccine
formulation designed to immunize against all four dengue virus
serotypes.
Application: Immunization against all four serotypes of Dengue
Virus.
Developmental Status: Vaccine candidates have been synthesized and
preclinical studies have been performed. The vaccine candidates of this
invention are slated to enter Phase I clinical trials in the next year.
[[Page 63163]]
Inventors: Stephen S. Whitehead, Joseph E. Blaney, Brian R. Murphy
(NIAID).
Patent Status: PCT Application No. PCT/US2007/076004 filed 15 Aug
2007, claiming priority to 15 Aug 2006 (HHS Reference No. E-139-2006/0-
PCT-02).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
these vaccines. Please contact Dr. Brian Murphy at 301-594-1616 or
[email protected] for more information.
Live Attenuated Virus Vaccines for La Crosse Virus and Other
Bunyaviridae
Description of Technology: La Crosse virus (LACV), family
Bunyaviridae, is a mosquito-borne pathogen endemic in the United
States. LACV infection results in 70-130 clinical cases a year and is
the major cause of pediatric arboviral encephalitis in North America.
LACV was first identified as human pathogen in 1960 after its isolation
from a 4 year-old girl from Minnesota who suffered meningoencephalitis
and later died in La Crosse, Wisconsin. The majority of LACV infections
are mild and never reported, however serologic studies estimate annual
infection rates of 10-30/100,000 in endemic areas. LACV is a member of
the California serogroup of viruses in the genus Orthobunyavirus. The
serogroup contains members found on five continents that include human
pathogens such as La Crosse, Snowshoe hare, and Jamestown Canyon
viruses in North America; Guaroa virus in North and South America;
Inkoo and Tahyna viruses in Europe; and Lumbo virus in Africa. Children
who recover from severe La Crosse encephalitis may have significantly
lower IQ scores than expected and a high prevalence (60% of those
tested) of attention-deficit-hyperactivity disorder. Seizure disorders
are also common in survivors. LACV can also cause encephalitis in
immunosuppressed adults. Projected lifelong economic costs associated
with neurologic sequelae range from $48,775-3,090,398 per case. At
present, a vaccine or FDA approved antiviral therapy is not available.
This application principally claims live attenuated LACV vaccine
compositions, but also includes subunit vaccine compositions including
California encephalitis virus (CEV) serogroup immunogens, attenuated
and inactivated CEV serogroup and chimeric Bunyaviridae. Also claimed
are methods of treating or preventing CEV serogroup infection in a
mammalian host, methods of producing a subunit vaccine composition,
isolated polynucleotides comprising a nucleotide sequence encoding a
CEV serogroup immunogen, methods for detecting LACV infection in a
biological sample and infectious chimeric Bunyaviridae.
Application: Immunization against Bunyaviridae.
Developmental Status: Live attenuated vaccine candidates are
currently being developed and preclinical studies in mice and monkeys
are in progress. Suitable vaccine candidates will then be evaluated in
clinical studies.
Inventors: Stephen S. Whitehead, Richard S. Bennett, Brian R.
Murphy (NIAID)
Publication: RS Bennett et al. Genome sequence analysis of La
Crosse virus and in vitro and in vivo phenotypes. Virol J. 2007 May
8;4:41.
Patent Status: PCT Application No. PCT/US2008/056099 filed 06 Mar
2008, claiming priority to 29 Mar 2007 (HHS Reference No. E-158-2007/3-
PCT-01).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
live attenuated virus vaccine candidates for La Crosse virus and other
Bunyaviridae. Please contact Dr. Whitehead at 301-496-7692 for more
information.
Development of Antigenic Chimeric St. Louis Encephalitis Virus/Dengue
Virus Type Four Recombinant Viruses (SLEV/DEN4) as Vaccine Candidates
for the Prevention of Disease Caused by SLEV
Description of Technology: St. Louis Encephalitis Virus (SLEV) is a
mosquito-borne flavivirus that is endemic in the Americas and causes
sporadic outbreaks of disease in humans. SLEV is a member of the
Japanese encephalitis virus serocomplex and is closely related to West
Nile Virus (WNV). St. Louis encephalitis is found throughout North,
Central, and South America, and the Caribbean, but is a major public
health problem mainly in the United States. Prior to the outbreak of
West Nile virus in 1999, St. Louis encephalitis was the most common
human disease caused by mosquitoes in the United States. Since 1964,
there have been about 4,440 confirmed cases of St. Louis encephalitis,
with an average of 130 cases per year. Up to 3,000 cases have been
reported during epidemics in some years. Many more infections occur
without symptoms and go undiagnosed. At present, a vaccine or FDA
approved antiviral therapy is not available.
The inventors have previously developed a WNV/Dengue4Delta30
antigenic chimeric virus as a live attenuated virus vaccine candidate
that contains the WNV premembrane and envelope (prM and E) proteins on
a dengue virus type 4 (DEN4) genetic background with a thirty
nucleotide deletion (Delta30) in the DEN4 3'-UTR. Using a similar
strategy, the inventors have generated an antigenic chimeric virus,
SLE/DEN4Delta30. Preclinical testing results indicate that
chimerization of SLE with DEN4Delta30 decreased neuroinvasiveness in
mice, did not affect neurovirulence in mice, and appeared to
overattenuate the virus for non-human primates. Modifications of the
SLE/DEN4Delta30 vaccine candidate are underway to improve its
immunogenicity.
This application claims live attenuated chimeric SLE/DEN4Delta30
vaccine compositions and bivalent WNV/SLE/DEN4Delta30 vaccine
compositions. Also claimed are methods of treating or preventing SLEV
infection in a mammalian host, methods of producing a subunit vaccine
composition, isolated polynucleotides comprising a nucleotide sequence
encoding a SLEV immunogen, methods for detecting SLEV infection in a
biological sample and infectious chimeric SLEV.
Application: Immunization against SLEV or SLEV and WNV.
Development Status: Live attenuated vaccine candidates are
currently being developed and preclinical studies in mice and monkeys
are in progress. Suitable vaccine candidates will then be evaluated in
clinical studies.
Inventors: Stephen S. Whitehead, Joseph Blaney, Alexander Pletnev,
Brian R. Murphy (NIAID).
Patent Status: PCT Application No. PCT/US2008/066445 filed 10 Jun
2008, claiming priority to 14 Jun 2007 (HHS Reference No. E-240-2007/0-
PCT-02).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
[[Page 63164]]
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
live attenuated virus vaccine candidates for St. Louis encephalitis
virus. Please contact Dr. Whitehead at 301-496-7692 for more
information.
Generation of Wild-Type Dengue Viruses for Use in Rhesus Monkey
Infection Studies
Description of Technology: Dengue virus is a positive-sense RNA
virus belonging to the Flavivirus genus of the family Flaviviridae.
Dengue virus is widely distributed throughout the tropical and
semitropical regions of the world and is transmitted to humans by
mosquito vectors. Dengue virus is a leading cause of hospitalization
and death in children in at least eight tropical Asian countries. There
are four serotypes of dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4)
that annually cause an estimated 50-100 million cases of dengue fever
and 500,000 cases of the more severe form of dengue virus infection
known as dengue hemorrhagic fever/dengue shock syndrome (DHFIDSS). This
latter disease is seen predominately in children and adults
experiencing a second dengue virus infection with a serotype different
than that of their first dengue virus infection and in primary
infection of infants who still have circulating dengue-specific
maternal antibody. A vaccine is needed to lessen the disease burden
caused by dengue virus, but none is licensed.
Because of the association of more severe disease with secondary
dengue virus infection, a successful vaccine must induce immunity to
all four serotypes. Immunity is primarily mediated by neutralizing
antibody directed against the envelope (E) glycoprotein, a virion
structural protein. Infection with one serotype induces long-lived
homotypic immunity and a short-lived heterotypic immunity. Therefore,
the goal of immunization is to induce a long-lived neutralizing
antibody response against DEN-1, DEN-2, DEN-3, and DEN-4, which can
best be achieved economically using live attenuated virus vaccines.
This is a reasonable goal since a live attenuated vaccine has already
been developed for the related yellow fever virus, another mosquito-
borne flavivirus present in tropical and semitropical regions of the
world.
The evaluation of live attenuated dengue vaccine candidates in
rhesus monkeys requires wild type control viruses for each of the four
dengue serotypes. These control viruses are used for comparison to the
attenuated strains and post-vaccination challenge to assess vaccine
efficacy. As such, these viruses need to be well characterized and
sufficiently pure to ensure that they will replicate to consistent
levels in rhesus monkeys. Characterization generally includes sequence
analysis, titration, and evaluation in monkeys. The following viruses
have been characterized: (1) DEN1 WP (2) DEN1 Puerto Rico/94 (3) DEN2
NGC prototype (4) DEN2 Tonga/74 (5) DEN3 Sleman/78 and (6) DEN4
Dominica/81.
Application: Dengue/flavivirus vaccine studies, dengue/flavivirus
diagnostics, dengue/flavivirus research tools.
Development Status: Materials are available for transfer.
Inventors: Stephen S. Whitehead and Joseph E. Blaney, Jr. (NIAID).
Publications:
1. AP Durbin, RA Karron, W Sun, DW Vaughn, MJ Reynolds, JR
Perreault, B Thumar, R Men, C-J Lai, WR Elkins, RM Chanock, BR Murphy,
SS Whitehead. A live attenuated dengue virus type 4 vaccine candidate
with a 30 nucleotide deletion in the 3' untranslated region is highly
attenuated and immunogenic in humans. Am J Trop Med Hyg. 2001 Nov;
65(5): 405-413.
2. SS Whitehead, B Falgout, KA Hanley, JE Blaney Jr., L Markoff, BR
Murphy. A live, attenuated dengue virus type 1 vaccine candidate with a
30-nucleotide deletion in the 3' untranslated region is highly
attenuated and immunogenic in monkeys. J Virol. 2003 Jan; 77(2): 1653-
1657.
3. SS Whitehead, KA Hanley, JE Blaney Jr., LE Gilmore, WR Elkins,
BR Murphy. Substitution of the structural genes of dengue virus type 4
with those of type 2 results in chimeric vaccine candidates which are
attenuated for mosquitoes, mice, and rhesus monkeys. Vaccine 2003 Oct
1; 21(27-30): 4307-4316.
4. JE Blaney Jr., CT Hanson, KA Hanley, BR Murphy, SS Whitehead.
Vaccine candidates derived from a novel infectious cDNA clone of an
American genotype dengue virus type 2. BMC Infect Dis. 2004 Oct 4;4:39.
5. JE Blaney Jr., CT Hanson, CY Firestone, KA Hanley, BR Murphy, SS
Whitehead. Genetically modified, live attenuated dengue virus type 3
vaccine candidates. Am J Trop Med Hyg. 2004 Dec; 71(6): 811-821.
6. JE Blaney Jr., JM Matro, BR Murphy, SS Whitehead. Recombinant,
live-attenuated tetravalent dengue virus vaccine formulations induce a
balanced, broad, and protective neutralizing antibody response against
each of the four serotypes in rhesus monkeys. J Virol. 2005 May; 79(9):
5516-5528.
7. JE Blaney Jr., NS Sathe, CT Hanson, CY Firestone, BR Murphy, SS
Whitehead. Vaccine candidates for dengue virus type 1 (DEN1) generated
by replacement of the structural genes of rDEN4 and rDEN4Delta30 with
those of DEN1. Virol J. 2007 Feb 28; 4:23.
Patent Status: HHS Reference No. E-042-2008/0--Research Tool.
Patent protection is not being pursued for this technology.
Licensing Status: Available for nonexclusive biological materials
licensing only.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Monoclonal Antibodies Against Dengue and Other Viruses With Deletion in
Fc Region
Description of Technology: The four dengue virus (DENV) serotypes
(DENV-1 to DENV-4) are the most important arthropod-borne flaviviruses
in terms of morbidity and geographic distribution. Up to 100 million
DENV infections occur every year, mostly in tropical and subtropical
areas where vector mosquitoes are abundant. Infection with any of the
DENV serotypes may be asymptomatic or may lead to classic dengue fever
or more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome
(DSS), which are increasingly common in the dengue endemic areas.
Immunity to the same virus serotype (homotypic immunity) is life-long,
whereas immunity to different serotypes (heterotypic immunity) lasts 2-
3 months so that infection with a different serotype virus is possible.
DHF/DSS often occurs in patients with second, heterotypic DENV
infections or in infants with maternally transferred dengue immunity.
Severe dengue is a major cause of hospitalization, and fatality rates
vary from <1% to 5% in children.
Antibody-dependent enhancement (ADE) has been proposed as an
underlying pathogenic mechanism of DHF/DSS. ADE occurs because
preexisting subneutralizing antibodies and the infecting DENV form
complexes that bind to Fc receptor-bearing cells, leading to increased
virus uptake and replication. ADE has been repeatedly demonstrated in
vitro using dengue immune sera or monoclonal antibodies and cells of
monocytic and recently, B
[[Page 63165]]
lymphocytic lineages bearing Fc receptors. ADE of DENV-2 infection has
also been demonstrated in monkeys infused with a human dengue immune
serum.
We have identified chimpanzee-human chimeric IgG1 mAbs capable of
neutralizing or binding to one or more DENV serotypes. Cross-reactive
IgG 1A5 neutralizes DENV-1 and DENV-2 more efficiently than DENV-3 and
DENV-4, and type-specific IgG 5H2 neutralizes DENV-4 at a high titer.
Analysis of antigenic variants has localized the IgG 1A5 binding site
to the conserved fusion peptide in E. Thus, IgG 1A5 shares many
characteristics with the cross-reactive antibodies detected in
flavivirus infections.
This application claims a variant of an antibody comprising a
polypeptide in the Fc region, which binds an Fc gamma receptor
(FcgammaR) with lower affinity than the parent antibody. The variant
polypeptide comprises a deletion of nine amino acids at the N-terminus
of the CH2 domain in the Fc region. Introduction of the Fc
variant abrogates the antibody-mediated dengue virus replication
enhancing activity. This invention has important implications for the
antibody-mediated prevention of dengue virus infection.
Application: Immunization against Dengue and/or flaviviruses.
Developmental Status: Antibody candidates have been synthesized and
preclinical studies have been performed.
Inventors: Ana Goncalvez, Robert Purcell, C.J. Lai (NIAID).
Publication: AP Goncalvez et. al. Monoclonal antibody-mediated
enhancement of dengue virus infection in vitro and in vivo and
strategies for prevention. Proc Natl Acad Sci USA. 2007 May 29;
104(22): 9422-9427.
Patent Status: PCT Application No. PCT/US2008/059313 filed 03 Apr
2008, claiming priority to 04 Apr 2007 (HHS Reference No. E-159-2007/3-
PCT-01).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Monoclonal Antibodies That Bind or Neutralize Dengue Virus
Description of Technology: Among the arthropod-borne flaviviruses,
the four dengue virus serotypes, dengue type 1 virus (DENV-1), dengue
type 2 virus (DENV-2), dengue type 3 virus (DENV-3), and dengue type 4
virus (DENV-4 are most important in terms of human morbidity and
geographic distribution. Dengue viruses cause dengue outbreaks and
major epidemics in most tropical and subtropical areas where Aedes
albopictus and Aedes aegypti mosquitoes are abundant. Dengue infection
produces fever, rash, and joint pain in humans. A more severe and life-
threatening form of dengue, characterized by hemorrhagic fever and
hemorrhagic shock, has occurred with increasing frequency in Southeast
Asia and Central and South America, where all four dengue virus
serotypes circulate. A safe and effective vaccine against dengue is
currently not available. Passive immunization with monoclonal
antibodies from non-human primates or humans represents a possible
alternative to vaccines for prevention of illness caused by dengue
virus.
The application claims monoclonal antibodies that bind or
neutralize dengue type 1, 2, 3, and/or 4 viruses. The application also
claims fragments of such antibodies retaining dengue virus-binding
ability, fully human or humanized antibodies retaining dengue virus-
binding ability, and pharmaceutical compositions including such
antibodies. The application also claims isolated nucleic acids encoding
the antibodies of the invention. Additionally, application claims
prophylactic, therapeutic, and diagnostic methods employing the
antibodies and nucleic acids of the invention.
Application: Prophylaxis against dengue serotypes 1, 2, 3 and 4.
Development Status: Antibodies have been synthesized and
preclinical studies have been performed.
Inventors: Ching-Juh Lai and Robert Purcell (NIAID).
Publications: The antibodies are further described in:
1. R Men et al. Identification of chimpanzee Fab fragments by
repertoire cloning and production of a full-length humanized
immunoglobulin G1 antibody that is highly efficient for neutralization
of dengue type 4 virus. J Virol. 2004 May; 78(9): 4665-4674.
2. AP Goncalvez et al. Chimpanzee Fab fragments and a derived
humanized immunoglobulin G1 antibody that efficiently cross-neutralize
dengue type 1 and type 2 viruses. J Virol. 2004 Dec; 78(23): 12910-
12918.
3. AP Goncalvez et al. Epitope determinants of a chimpanzee Fab
antibody that efficiently cross-neutralizes dengue type 1 and type 2
viruses map to inside and in close proximity to fusion loop of the
dengue type 2 virus envelope glycoprotein. J Virol. 2004 Dec; 78(23):
12919-12928.
4. AP Goncalvez et al. Monoclonal antibody-mediated enhancement of
dengue virus infection in vitro and in vivo and strategies for
prevention. Proc Natl Acad Sci U.S.A. 2007 May 29; 104(22): 9422-9427.
Patent Status: U.S. Patent Application No. 10/582,006 filed 07 Jun
2006 (HHS Reference No. E-066-2003/5-US-02); Canadian Patent
Application No. 2548808 filed 03 Dec 2004 (HHS Reference No. E-066-
2003/5-CA-03).
Licensing Status: Available for exclusive or non-exclusive
licensing.
Licensing Contact: Peter A. Soukas, J.D.; 301-435-4646;
[email protected].
Collaborative Research Opportunity: The National Institute of
Allergy and Infectious Diseases, Laboratory of Infectious Diseases, is
seeking statements of capability or interest from parties interested in
collaborative research to further develop, evaluate, or commercialize
this technology. Please contact Ching-Juh Lai at 301-594-2422 for more
information.
Dated: October 14, 2008.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. E8-25210 Filed 10-22-08; 8:45 am]
BILLING CODE 4140-01-P