Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Anti-idiotypic
Reexamination Certificate
2001-05-10
2003-10-14
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Anti-idiotypic
C424S141100, C424S422000, C424S423000, C424S426000, C424S184100, C424S204100, C424S206100, C424S259100, C424S274100, C424S239100, C530S387100, C530S387200, C435S007100
Reexamination Certificate
active
06632431
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to an anti-idiotypic antibody and a composition containing same, such as an immunizing composition.
2. Description of the Related Art
Urinary tract infection (UTI) is one of the most common infectious diseases that primarily affect women of all ages. Nearly as many as 50% of all women experience at least one infection in the urinary tract during their lifetimes. Although as prevalent as the common cold, UTI causes far more discomfort and sends 10 million people annually in the United States alone to seek medical attention. Approximately 1.5 million of these visits are diagnosed as pyelonephritis (kidney infection), which is often so serious that hospitalization is required. In addition, approximately 20% of women experience frequent infections (on the order of three to six per year) after the initial episode of UTI, resulting in additional morbidity and lost productivity. It is estimated that five billion healthcare dollars are spent each year to treat UTIs.
Over 85% of all UTIs are caused by the enterobacteria
Escherichia coli
, and an overwhelming majority of these
E. coli
bacteria express surface filamentous organelles called Type I fimbriae. Experimental and epidemiological studies have established that Type I fimbriae are the major virulence factor of uropathogenic
E. coli
, where these fimbriae function as an adhesive apparatus that allows
E. coli
to bind to the epithelial lining, urothelium, of the urinary tract. Such a binding between the invading
E. coli
and the host urothelial surface is a pivotal step in the establishment of
E. coli
colonization within the urinary tract.
Type I fimbriae are hairlike structures which emanate from the surface of
E. coli
and nearly all members of the Enterobacteriaceae family (Brinton, 1965). The major component of Type I fimbriae is repeating subunits of FimA arranged in a right-handed helix to form a filament approximately 1 &mgr;m in length and 7 nm in diameter with a central axial hole (Brinton, 1965). Along with FimA as the major subunit, the fimbrial filament also contains FimF, FimG and FimH as minor protein subunits (Maurer et al, 1987; Abraham et al, 1987; Russel et al, 1992). The minor protein subunit FimH is a mannan-binding adhesin that promotes adherence of Type I-fimbriated bacteria to mannose-containing glycoproteins on eukaryotic cell surfaces and represents a family of proteins which bind to various targets, including mannan and fibronectin (Abraham et al, 1987; Ofek et al, 1977; Sokurenko et al, 1994). Immune electron microscopy studies have revealed that FimH is strategically placed at the distal tips of Type I fimbriae where it appears to be complexed with FimG, forming a flexible fibrillum structure (Abraham et al, 1987 and 1988; Jones et al, 1995), and is also placed longitudinally at various intervals along the filament (Abraham, 1987 and 1988).
While prophylaxis with antibiotics offers quick relief against most UTIs, it is not free from serious drawbacks. For most patients suffering from uncomplicated UTIs, a three-day regimen of trimethoprim/sulfamethozole or a seven-day course of nitrofurandantoin usually stops the infection. However, for some patients, they soon develop side effects, such as vaginitis, gastrointestinal upset and rashes, from the antibiotic, conditions which then require further medical attention. One in five women who experience one infection will experience another infection within weeks. For these patients, a low dose but much longer course (six months to two years) of antibiotics is prescribed to reduce the frequency of reinfections. Although the efficacy of antibiotic prophylaxis for recurrent UTIs has been recently demonstrated, major problems persist in the areas of patient compliance, adverse effects of antibiotics, emergence of bacterial resistance, along with the associated costs of long-term medication. Recent studies show that antibiotic prophylaxis results in a dramatic change in the population of uropathogens reinfecting the host (Reid, 1997). Infections caused by these new strains are generally more difficult to control. Recurrent UTIs not only present a challenge to clinical management, but also significantly increase the risk of kidney involvement, such as pyelonephritis, and complicated UTIs that often require hospitalization and initial parenteral antibiotic therapy. In this situation, a newer generation of antibiotics (e.g., quinolones) or a combination of several antibiotics is usually indicated. However, resistance has been now reported even for these newer generation of antibiotics.
The prevalence of UTIs and the emergence of antibiotic-resistant microorganisms call for novel preventative and therapeutic strategies. One effective approach is the development of vaccines against causative agents of UTIs. The overwhelming majority of UTIs (>85%) are caused by
E. coli
, most of which are Type I-fimbriated. Type I fimbriae serve as an adhesive apparatus, via their tip FimH adhesins, for enabling the bacteria to attach to the urothelial surface.
Past efforts in developing a UTI vaccine have been met with limited success. For example, an injectable cocktail containing heat-killed uropathogenic
E. coli
called Urovac has been available in Europe since the 1980s. However, the efficacy of this vaccine is questionable as it provides limited protection against UTIs. Not only is the protection short-lived, but also the toxins in intact
E. coli
cause significant side effects, including painful inflammation around the injection sites. To circumvent these problems, a group in Wisconsin tested an alternative delivery method (vaginal suppository) using the same vaccine. Preliminary clinical trials have shown short-term protection against recurrence as UTI-prone patients are less prone to be reinfected. Again, the protection appears to be short-lived. The major drawback of using the entire
E. coli
as a vaccine also lies in the fact that the FimH adhesin, which is a minor protein in
E. coli
, is under-presented as an antigen and, thus, unlikely to elicit a sufficient immune response that would target the process of
E. coli
adherence to the urothelial surface.
A new strategy that was recently tested by a group in St. Louis utilizes recombinant FimH adhesin as a UTI vaccine (Langermann et al, 1997). Immunization of mice with this putative FimH vaccine reduced in vivo colonization of the bladder mucosa by more than 99% in a mouse cystitis model. Immunoglobulin G to FimH was detected in the urine of protected mice. These studies suggest that an anti-FimH approach can be effective in preventing urinary colonization by uropathogenic
E. coli
(Langermann et al, 1997; Service, 1997). However, there are two major limitations with this approach which, if unresolved, can prevent the FimH-based vaccine from clinical use. First, it is difficult to produce large amounts of FimH protein. FimH expressed alone in
E. coli
using the recombinant approach is easily degraded. When co-expressed with a chaperone protein (FimD), FimH is somewhat stabilized, but remains at a very low level (Langermann et al, 1997). This can limit the use of FimH as a vaccine. Second, the current putative FimH preparation does not discriminate FimH-carrying uropathogenic
E. coli
and FimH-carrying intestinal
E. coli
, the latter of which are beneficial flora. Host immune response targeted against FimH vaccine will likely suppress intestinal
E. coli
, which could lead to serious side effects (Service, 1997).
Idiotypes have been intensively studied following Jerne's immune network theory in 1974. One of his major proposals is the self-regulation of the immune system through a network of idiotype-anti-idiotype interactions (Jerne, 1974). It was suggested that the idiotopes on a single antibody molecule can mimic and be the “internal image” of any foreign or self epitope at the molecular level. Internal image determinants have been proposed for use in vaccines (Nisonoff et al, 1981). By means of Mab technology, a protective
Browdy and Neimark
New York University
Portner Ginny Allen
Smith Lynette R. F.
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