Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2001-07-06
2004-05-18
Navarro, Albert M (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S157100, C424S169100, C424S242100, C424S257100, C514S023000, C514S025000, C536S017200, C536S017900, C536S034000, C536S023100, C536S023700, C536S024100
Reexamination Certificate
active
06737063
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to bacterial adhesin proteins and active fragments thereof for use in vaccine compositions for the prevention, diagnosis and treatment of bacterial induced diseases such as those of the urinary tract, especially to the use of such adhesins as immunogenic agents in humans and animals to stimulate an immune response.
BACKGROUND OF THE INVENTION
Urinary tract infections (herein, “UTI”) present a disease process that is mediated by the attachment of bacteria to cells.
Escherichia coli
is the most common pathogen of the urinary tract, accounting for more than 85% of cases of asymptomatic bacteriuria, acute cystitis and acute pyelonephritis, as well as greater than 60% of recurrent cystitis, and at least 35% of recurrent pyelonephritis infections. Furthermore, approximately 25%-30% of women experience a recurrent
E. coli
urinary tract infection within the first 12 months following an initial infection but after a second or third infection the rate of recurrence increases to 60%-75%. Given the high incidence, continued persistence, and significant expense associated with
E. coli
urinary tract infections, there is a need for a prophylactic vaccine to reduce susceptibility to this disease.
While many factors contribute to the acquisition and progression of
E. coli
urinary tract infections, it is generally accepted that colonization of the urinary epithelium is a required step in the infection process. In a typical course of
E. coli
urinary tract infection, bacteria originate from the bowel, ascend into the bladder, and adhere to the bladder mucosa where they multiply and establish an infection (cystitis) before ascending into the ureters and kidneys. Disruption or prevention of pilus-mediated attachment of
E. coli
to urinary epithelia may prevent or retard the development of urinary tract infections. In this regard, a number of studies have pointed to a role for pili in mediating attachment to host uroepithelial cells.
To initiate infection bacterial pathogens must first be able to colonize an appropriate target tissue of the host. For many pathogens this tissue is located at a mucosal surface. Colonization begins with the attachment of the bacterium to receptors expressed by cells forming the lining of the mucosa. Attachment is mediated via proteins on the bacterium that bind specifically to cellular receptors. These proteins, or adhesins, are expressed either directly on the surface of the bacterium, or more typically, as components of elongated rod-like protein structures called pili, fimbriae or fibrillae.
Type 1 pili are thought to be important in initiating colonization of the bladder and inducing cystitis, whereas P pili are thought to play a role in ascending infections and the ensuing pyelonephritis.
Such pili are heteropolymeric structures that are composed of several different structural proteins required for pilus assembly. Two types of pili are of particular interest: P pili and type 1 pili. P pili-carrying bacteria recognize and bind to the gal-(&agr;1-4)gal moiety present in the globoseries of glycolipids on kidney cells in mammals. Type 1 pili-carrying bacteria recognize and bind to D-mannose in glycolipids and glycoproteins of bladder epithelial cells.
FimH is the D-mannose-binding adhesin that promotes attachment of type 1 piliated bacteria to host cells via mannose-containing glycoproteins on eukaryotic cell surfaces. FimC is its periplasmic chaperone protein.
In this specification, the terms “pili”, “fimbriae,” and “fibrillae” are used to refer to heteropolymeric protein structures located on the extracellular surface of bacteria, most commonly gram-negative bacteria. Typically these structures are anchored in the outer membrane. Throughout this specification the terms pilus, pili, fimbriae, and fibrilla will be used interchangeably.
As used herein, the term “periplasmic chaperone” is defined as a protein localized in the periplasm of bacteria that is capable of forming complexes with a variety of chaperone-binding proteins via recognition of a common binding epitope (or epitopes). Chaperones serve as templates upon which proteins exported from the bacterial cell into the periplasm fold into their native conformations. Association of the chaperone-binding protein with the chaperone also serves to protect the binding proteins from degradation by proteases localized within the periplasm, increases their solubility in aqueous solution, and leads to their sequentially correct incorporation into an assembling pilus.
Chaperone proteins are a class of proteins in gram-negative bacteria that are involved in the assembly of pili by mediating such assembly, but are not incorporated into the structure. FimC is the periplasmic chaperone protein that mediates assembly of type 1 pili in bacteria.
It has recently been reported that such chaperones can direct formation of the appropriate native structure of the corresponding adhesin or pilin by inserting a specific fold of the chaperone protein in place of a missing domain or helical strand of the chaperone or pilin. Thus, FimH proteins tend to have their native structure in the presence of such a chaperone but not in its absence. [see: Choudhury et al, X-ray Structure of the FimC-FimH Chaperone-Adhesin Complex from Uropathogenic
E. coli, Science
285, 1061 (1999); Sauer et al, Structural Basis of Chaperone Function and Pilus Biogenesis,
Science
285, 1058 (1999)] In addition, recent publications have indicated that the required chaperone strand can be inserted into the adhesin or pilin protein, such as FimH, to provide the missing structure and produce the correct native structure; Barnhart, M. M. et al., PapD-like Chaperones Provide the Missing Information for Folding of Pilin Proteins,
Proc. Natl. Acad. Sci
. (
USA
), 10.1073/pnas.130183897 (published online Jun. 20, 2000).
Antibodies directed against purified whole type 1 or P pili protect against cystitis and pyelonephritis, respectively, in both murine and primate models for these diseases. See: Abraham et al.,
Infect Immun.
48:625 (1985), Roberts et al.,
Proc. Natl. Acad. Sci. (USA)
91:11889 (1994), O'Hantey et al.,
J. Clin. Invest.
75: 347 (1985). However, such protection is limited to either homologous
E. coli
strains from which the pili used as immunogens were derived, or to a small subset of serologically cross-reactive heterologous strains. Therefore, vaccines composed predominantly of the major structural proteins of pili (i.e., PapA or FimA) appear to be of limited value because antibodies developed against these highly variable proteins are specific for the strains used for immunization.
Furthermore, antibodies to FimH have been found to be protective. Barnhart, M. M. et al., PapD-like Chaperones Provide the Missing Information for Folding of Pilin Proteins,
Proc. Natl. Acad. Sci
. (
USA
), 10.1073/pnas.130183897 (published online Jun. 20, 2000).
Recently, Sokurenko et al [see:
J. Bacteriol.
177, 3680-86 (1995)] have found that quantitative variations in mannose-sensitive adhesion of
E. coli
are due primarily to structural differences in the FimH adhesin. Further research has shown that the ability of the FimH lectins to interact with monomannosyl residues strongly correlates with their ability to mediate
E. coli
adhesion to uroepithelial cells so that certain phenotypic variants of type 1 fimbriae may contribute more than others to the virulence of
E. coli
in the urinary tract. [Sokurenko et al,
J. Biol. Chem.
272, 17880-17886 (1997)]. Heretofore, random point mutations in FimH genes that increase binding of the adhesin to mono-mannose residues (structures abundant in the oligosaccharide moieties of urothelial glycoproteins) have been found to confer increased virulence in the mouse urinary tract. [See: Sokurenko et al,
Proc. Natl. Acad. Sci. USA
95, 8922-8926 (1998)]
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention relates to immunogenic polypeptides derived from different strains of the bacterium
Escherichia coli
(
E.
Auguste Christine
Burlein Jeanne
Langermann Solomon
Revel Andrew
Baskar Padma
Grant Alan J.
MedImmune, Inc.
Navarro Albert M
Olstein Elliot M.
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