Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-10-21
2002-10-08
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S200100, C424S190100, C424S185100, C424S184100, C536S023100, C536S023700, C536S024300, C536S024320, C435S069100, C435S069300, C435S069700, C435S252300, C435S320100, C435S325000
Reexamination Certificate
active
06461618
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an approximately 74,000 Dalton (74 kD) outer membrane protein purified from
Moraxella catarrhalis.
BACKGROUND OF THE INVENTION
Moraxella
(Branhamella)
catarrhalis
is one of the major bacterial pathogens causing otitis media in children (Bibliography entries 1,2,3,4). It also causes sinusitis, laryngitis, tracheitis, pneumonia, and other respiratory diseases in children and adults (5,6,7). A prophylactic vaccine is clearly needed because nearly all clinical isolates are resistant to &bgr;-lactam antibiotics (8,9).
The outer membrane proteins (OMPs) of
M. catarrhalis
are being investigated as potential vaccine candidates because they are readily accessible to antibodies. Indeed, antibodies elicited in mice towards certain OMP's including UspA and the CopB have already been shown to have biological activity, such as bactericidal activity, adhesion blocking activity and enhanced pulmonary clearance of the bacteria in an animal model (10,11,12,13). Serology data from humans who have suffered a recent
M. catarrhalis
infection indicates that humans develop antibodies towards OMP's following natural infection (14,15,16,17,18). This suggests that OMP's are the targets of the host's defense mechanisms. UspA-specific antibodies are present in normal human serum and these antibodies have bactericidal activity. There are also high levels of antibodies towards OMPs of approximately 80 kD in sera from both healthy humans and patients recovering from recent
M. catarrhalis
infections (16). Several proteins from
M. catarrhalis
migrate within this size range. Among them are CopB (12), the B1 protein (18), a transferrin binding protein (TbpB) and a lactoferrin binding protein (LbpB) (19) Whether these proteins are the same or different from one another has yet to be determined. None of them, however, has been evaluated in a purified form for vaccine use.
An efficacious vaccine to protect against diseases caused by
M. catarrhalis
should confer protection at all stages of disease. These stages include bacterial colonization on mucosal surfaces, bacterial multiplication, spread and invasion, and the development of inflammatory response. Multiple bacterial components may be required to formulate an efficacious vaccine. Although there is pre-clinical data to suggest that some surface components of
M. catarrhalis
are potential vaccine antigens, it is as yet unclear if these components will confer sufficient protective immunity in humans. Thus, it is important to identify and evaluate new bacterial antigens for vaccine use.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to isolate, purify and characterize an additional protein from
M. catarrhalis
. It is a further object of this invention to test whether this protein is a viable vaccine candidate in appropriate model systems.
These and other objects of the invention as discussed below are achieved by the isolation and purification of a protein from
M. catarrhalis
which is designated the 74 kD protein, based on approximate molecular weight as measured by mass spectrometry, as well as peptides of the 74 kD protein comprising an epitope or epitopes thereof. The isolated and purified 74 kD protein from
M. catarrhalis
has an amino-terminal amino acid sequence which is conserved among various strains of
M. catarrhalis
. This amino-terminal amino acid sequence comprises the sequence Xaa Gly Gly Ser Gly Gly Ser Asn Pro Pro Ala Pro Thr (SEQ ID NO:1), where the first residue is not identified, or a biologically equivalent amino-terminal amino acid sequence thereof. The protein of this invention has a molecular weight of approximately 74.9 kD as measured on a 10% SDS-PAGE gel, while its molecular weight as measured by mass spectrometry is approximately 74 kD.
In another embodiment of this invention, the isolated and purified 74 kD protein or a peptide of the 74 kD protein comprising an epitope or epitopes thereof, is used to prepare a vaccine composition which elicits a protective immune response in a mammalian host. The vaccine composition may further comprise an adjuvant, diluent or carrier. Examples of such adjuvants include aluminum hydroxide, aluminum phosphate, MPL™, Stimulon™ QS-21, and IL-12. The vaccine composition is administered to a mammalian host in an immunogenic amount sufficient to protect the host against disease caused by
M. catarrhalis.
REFERENCES:
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patent: 5972657 (1999-10-01), Murphy et al.
patent: 6004562 (1999-12-01), Campagnari et al.
patent: 6090576 (2000-07-01), Myers
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patent: WO 90/12591 (1990-11-01), None
patent: WO 90/12591 (1990-04-01), None
patent: WO 97/13785 (1997-04-01), None
patent: WO 97/32980 (1997-09-01), None
Bowie et al. Science, vol. 247: 1990; p. 1306; p. 1308.*
Houghten et al. (Vaccines, 1986, Edited by Fred Brown: Cold Spring Harbor Laboratory.*
Yu et al 1993; Microbial pathogenesis, 15; 433-445.*
AEBI, C, et al., “Expression of the CopB Outer Membrane Protein byMoraxella catarrhalisIs Regulated by Iron and Affects Iron Acquisition from Transferrin and Lactoferrin”Infection and Immunity, Jun. 1996, 64:2024-2030.
Bartos, L. C. and T.F. Murphy, “Comparison of the outer membrane proteins of 50 strains of Branhamella catarrhalis”Journal of Infectious Diseases, Oct. 1988, 158(4):761-765.
Bonnah, R. A., et al., Biochemical analysis of lactoferrin receptors in the Neisseriaceae: identification of a second bacterial lactoferrin receptor protein,Microbial Pathogenesis1995, 19:285-297
Campagnari, A. A, et al. “Growth ofMoraxella catarrhaliswith Human Transferrin and Lactoferrin: Expression of Iron-Repressible Proteins without Siderophore Production”Infection and Immunity, Nov. 1994, 62:4909-4914.
Campagnari, A. A., et al. “Outer Membrane Protein B1, an Iron-Repressible Protein Conserved in the Outer Membrane ofMoraxella(Branhamella)catarrhalis, Binds Human Transferrin”Infection and Immunity, Sep. 1996, 64:3920-3924.
Chen, D., et al., “Antibodies to the UspA Outer Membrane Protein ofMoraxella catarrhalisBlock Bacterial Attachment in vitro and Are Protective in a Murine Pulmonary Challenge Model”Abstracts of the 95thGeneral Meeting of the American Society for Microbiology 1995, 290.
Chen, D., et al., “Evaluation of Purified UspA fromMoraxella catarrhalisas a Vaccine in a Murine Model after Active Immunization”Infection and Immunity, Jun. 1996, 64:1900-1905.
Danve, B., et al. “Transferrin-binding proteins isolated fromNeisseria meningitidiselicit protective and bactericidal antibodies in laboratory animals” VACCINE, 11:1214-1220, 1993.
Gerlach, G.F. et al. “Characterization of Two Genes Encoding Distinct Transferrin-Binding Proteins in DifferentActinobacillus pleuropneumoniaeIsolates”Infection and Immunity, Aug. 1992, 60:3253-3261.
Gary-Owen, S.D. and Schryvers, A. B. “Bacterial transferrin and lactoferrin receptors”Trends in Microbiology, May 1996, 187(4):185-191.
Helminen M. E., et al., “A Large, Antigenically Conserved Protein on the Surface ofMoraxella catarrhalisIs a Target for Protective Antibodies”The Journal of Infectious Diseases1994, 170:867-72.
Helminen M. E., et al., “A Major Outer Membrane Protein ofMoraxella catarrhalisIs a Target for Antibodies That Enhance Pulmonary Clearance of the Pathogen in an Animal Model”Infection and Immunity, May 1993, 61:2003-2010.
Helminen M. E., et al., “Human Immune Response against Outer Membrane Proteins ofMoraxella(Branhamella)catarrhalisDetermined By Immunoblotting and Enzyme Immunoassay”Clinical and Diagnostic Laboratory Immunology, Jan. 1995, 2:35-39.
Lissolo, L. et al., “Evaluation of Transferrin-Binding Protein 2 within the Transferrin-Binding Protein Complex as a Potential Antigen for Future Meningococcal Vaccines”Infection and Immunity, Mar. 1995, 63:884-890.
Maciver, I, et al. “Effect of Immunization on Pulmonary Clearance ofMoraxella catarrhalisin an Animal Model”The Journal of Infectious Diseases1993, 168:469-72.
Mathers, K. E., et al.,
Barniak Vicki L.
Chen Dexiang
McMichael John C.
VanDerMeid Karl R.
American Cyanamid Company
Baskar Padmavathi
Brazil Bill T.
Gordon Alan M.
Smith Lynette R. F.
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