Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds bacterium or component thereof or substance produced...
Reexamination Certificate
1999-06-16
2003-11-25
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds bacterium or component thereof or substance produced...
C424S150100, C424S130100, C436S547000
Reexamination Certificate
active
06652857
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to antitoxin therapy and prevention of disease due to
Escherichia coli
verotoxin in humans and other animals, and diagnostic assays to detect toxins. In particular, the present invention relates to the isolation of polypeptides derived from
Escherichia coli
verotoxins, and the use thereof as immunogens for the production of vaccines, including multivalent vaccines, and antitoxins.
BACKGROUND OF THE INVENTION
A.
Escherichia coli
as a Pathogenic Organism
Escherichia coli
is the organism most commonly isolated in clinical microbiology laboratories, as it is usually present as normal flora in the intestines of humans and other animals. However, it is an important cause of intestinal, as well as extraintestinal infections. For example, in a 1984 survey of nosocomial infections in the United States,
E. coli
was associated with 30.7% of the urinary tract infections, 11.5% of the surgical wound infections, 6.4% of the lower respiratory tract infections, 10.5% of the primary bacteremia cases, 7.0% of the cutaneous infections, and 7.4% of the other infections (J. J. Farmer and M. T. Kelly, “Enterobacteriaceae,” in
Manual of Clinical Microbiology,
Balows et al.(eds), American Society for Microbiology, [1991], p. 365). Surveillance reports from England, Wales and Ireland for 1986 indicate that
E. coli
was responsible for 5,473 cases of bacteremia (including blood, bone marrow, spleen and heart specimens); of these, 568 were fatal. For spinal fluid specimens, there were 58 cases, with 10 fatalities (J. J. Farmer and M. T. Kelly, “Enterobacteriaceae,” in
Manual of Clinical Microbiology,
Balows et al.(eds), American Society for Microbiology, [1991], p. 366). There are no similar data for United States, as these are not reportable diseases in this country.
Studies in various countries have identified certain serotypes (based on both the O and H antigens) that are associated with the four major groups of
E. coli
recognized as enteric pathogens. Table 1 lists common serotypes included within these groups. The first group includes the classical enteropathogenic serotypes (“EPEC”); the next group includes those that produce heat-labile or heat-stable enterotoxins (“ETEC”); the third group includes the enteroinvasive strains (“EIEC”) that mimic Shigella strains in their ability to invade and multiply within intestinal epithelial cells; and the fourth group includes strains and serotypes that cause hemorrhagic colitis or produce Shiga-like toxins (or verotoxins) (“VTEC” or “EHEC” [enterohemmorrhagic
E. coli
]).
TABLE 1
Pathogenic
E. coli
Serotypes
Group
Associated Serotypes
Entero-
O6:H16; O8:NM; O8:H9; O11:H27; O15:H11; O20:NM;
toxigenic
O25:NM; O25:H42; O27:H7; O27:H20; O63:H12; O78:H11;
(ETEC)
O78:H12; O85:H7; O114:H21; O115:H21; O126:H9;
O128ac:H7; O128ac:H12; O128ac:H21; O148:H28; O149:H4;
O159:H4; O159:H20; O166:H27; and O167:H5
Entero-
O26:NM; O26:H11; O55:NM; O55:H6; O86:NM; O86:H2;
pathogenic
O86:H34; O111ab:NM; O111ab:H2; O111ab:H12;
(EPEC)
O111ab:H21; O114:H2; O119:H6; O125ac:H21; O127:NM;
O127:H6; O127:H9; O127:H21; O128ab:H2; O142:H6;
and O158:H23
Entero-
O28ac:NM; O29:NM; O112ac:NM; O115:NM; O124:NM;
invasive
O124:H7; O124:H30; O135:NM; O136:NM; O143:NM;
(EIEC)
O144:NM; O152:NM; O164:NM; and O167:NM
Verotoxin-
O1:NM; O2:H5; O2:H7; O4:NM; O4:H10; O5:NM; O5:H16;
Producing
O6:H1; O18:NM; O18:H7; O25:NM; O26:NM; O26:H11;
(VTEC))
O26:H32; O38:H21; O39:H4; O45:H2; O50:H7; O55:H7;
O55:H10; O82:H8; O84:H2; O91:NM; O91:H21; O103:H2;
O111:NM; O111:H8; O111:H30; O111:H34; O113:H7;
O113:H21; O114:H48; O115:H10; O117:H4; O118:H12;
O118:H30; O121:NM; O121:H19; O125:NM; O125:H8;
O126:NM; O126:H8; O128:NM; O128:H2; O128:H8;
O128:H12; O128:H25; O145:NM; O125:H25; O146:H21;
O153:H25; O157:NM; O157:H7; O163:H19; O165:NM;
O165:19; and O165:H25
B. Verotoxin Producing Strains of
E. coli
Although all of these disease-associated serotypes cause potentially life-threatening disease,
E. coli
O157:H7 and other verotoxin-producing strains have recently gained widespread public attention in the United States due to their recently recognized association with two serious extraintestinal diseases, hemolytic uremic syndrome (“HUS”) and thrombotic thrombocytopenic purpura (“TTP”). Worldwide,
E. coli
O157:H7 and other verotoxin-producing
E. coli
(VTEC) are an increasingly important human health problem. First identified as a cause of human illness in early 1982 following two outbreaks of food-related hemorrhagic colitis in Oregon and Michigan (M. A. Karmali, “Infection by Verocytotoxin-Producing
Escherichia coli
,” Clin. Microbiol. Rev., 2:15-38 [1989]; and L. W. Riley, et al. “Hemorrhagic colitis associated with a rare
Escherichia coli
serotype,” New Eng. J. Med., 308: 681-685 [1983]), the reported incidence of VTEC-associated disease has risen steadily, with outbreaks occurring in the U.S., Canada, and Europe.
With increased surveillance,
E. coli
O157:H7 has been recognized in other areas of the world including Mexico, China, Argentina, Belgium, and Thailand (N. V. Padhye and M. P. Doyle, “
Escherichia coli O
157:H7: Epidemiology, pathogenesis and methods for detection in food,” J. Food. Prot., 55: 555-565 [1992]; and P. M. Griffin and R. V. Tauxe, “The epidemiology of infections caused by
Escherichia coli
O157:H7, other enterohemorrhagic
E. coli
, and the associated hemolytic uremic syndrome,” Epidemiol. Rev., 13: 60 [1991]).
The disease attracted national attention in the U.S. after a major outbreak in the Pacific Northwest that was associated with consumption of undercooked
E. coli
O157:H7-contaminated hamburgers. Over 700 hundred people fell ill (more than 170 were hospitalized) and four young children died (P. Recer, “Experts call for irradiation of meat to protect against food-borne bacteria,” Associated Press, Jul. 12. 1994 [1994]). Several outbreaks since then have underscored the potential severity and multiple mechanisms for transmission of VTEC-associated diseases (M. Bielaszewska et al., “Verotoxigenic (enterohaemorrhagic)
Escherichia coli
in infants and toddlers in Czechoslovakia,” Infection 18: 352-356 [1990]; A. Caprioli et al., “Hemolytic-uremic syndrome and Vero cytotoxin-producing
Escherichia coli
infection in Italy, “J. Infect. Dis., 166: 184-158 [1992]; A. Caprioli, et al., “Community-wide Outbreak of Hemolytic-Uremic Syndrome Associated with Non-O157 Verocytotoxin-Producing
Escherichia coli
,” J. Infect. Dis., 169: 208-211 [1994]; N. Cimolai, “Low frequency of high level Shiga-like toxin production in enteropathogenic
Escherichia coli
serogroups,” Eur. J. Pediatr., 151: 147 [1992]; and R. Voelker., “Panel calls
E. coli
screening inadequate,”
Escherichia coli O
157:H7—Panel sponsored by the American Gastroenterological Association Foundation in July 1994, Medical News & Perspectives, J. Amer. Med. Assoc., 272: 501 [1994]).
While O157:H7 is currently the predominant
E. coli
serotype associated with illness in North America, other serotypes (as shown in Table 1, and in particular O26:H11, O113:H21, O91:H21 and O111:NM) also produce verotoxins which appear to be important in the pathogenesis of gastrointestinal manifestations and the hemolytic uremic syndrome (P. M. Griffin and R. V. Tauxe, “The epidemiology of infections caused by
Escherichia coli O
157:H7, other enterohemorrhagic
E. coli
, and the associated hemolytic uremic syndrome,” Epidemiol. Rev., 13: 60 (1991) M. M. Levine, et al., “Antibodies to Shiga holotoxin and to two synthetic peptides of the B subunit in sera of patients with
Shigella dysenteriae
1 dysentery,” J. Clin. Microbiol., 30: 1636-1641 [1992]; and C. R. Dorn, et al., “Properties of Vero cytotoxin producing
Escherichia coli
of human and animal origin belonging to serotypes other than O157:H7,” Epidemiol. Infect., 103: 83-95 [1989]). Since organisms with these serotypes have been shown to cause illness in humans they may as
Byrne Lisa Marie
Pugh Charles S. G.
Williams James A.
Devi S.
Medlen & Carroll LLP
Promega Corporation
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