Clostridium difficile (C. difficile) is a gram-positive anaerobic bacillus. Disease is associated with C. difficile infection.
Antibiotic associated pseudomembranous colitis results from the use of broad-spectrum antibiotic agents such as clindamycin. These antibiotics cause diarrhea in about 10% of treated patients and pseudomembranous colitis in about 1%. C. difficile causes antibiotic associated diarrhea and almost all cases of pseudomembranous colitis.
Pseudomembranous colitis results from the production of C. difficile toxin A (MW, 308,000) and toxin B (MW, 270,000) in the colon (Barroso et al., Nucleic Acids Res., 18:4004; Dove et al., Infect. Immun., 58:480-488; Lyerly et al., Clin. Microbiol. Rev., 1:1-18). Toxin A probably causes most of the gastrointestinal symptoms because of its enterotoxic activity (Lyerly et al., Infect. Immun., 35:1147-1150; Lyerly et al., Infect. Immun., 47:349-352). The toxins may act synergistically and the initial pathology caused by toxin A allows toxin B to manifest its toxicity (Lyerly et al., Infect. Immun., 47:349-352).
Most patients with C. difficile associated disease are treated effectively with vancomycin or metronidazole. Other treatment modalities include tolevemer, a toxin binding polymer (T. J. Louie et al., Clin. Infect. Dis. 2006; 43:411), and an antiparasitic medication, nitazoxanide (Med. Letter Drugs Ther. 2006; 48:89). Current treatments for C. difficile associated disease use antibiotics such as metronidazole and vancomycin. These drugs result in further disruption of the intestinal flora and are associated with a 20-25% incidence of disease relapse. Therefore, there is still a need for additional treatments of Clostridium difficile associated disease in humans.
Immunological treatment is valuable against C. difficile. Vaccination against toxins A and B stimulates active immunity against C. difficile disease in animals (Libby et al., Infect. Immun., 36:822-829).
Passive immunization is another immunological treatment against C. difficile. Serum antibodies against C. difficile have been shown to protect hamsters against C. difficile disease after oral administration. Passive immunization with bovine antibodies has been proposed as a treatment for other infectious diseases of the gastrointestinal tract, such as diseases caused by rotavirus, enteropathogenic and enterotoxigenic Escherichia coli, Vibrio cholerae, and Cryptosporidium parvum. Preliminary studies indicate that such passive immunization provides protection (Boesman-Finkelstein et al., Infect. Immun., 57:1227-1234; Brussow et al., J. Clin. Microbiol., 25:982-986; Fayer et al., Infect. Immun., 58:2962-2965; Hilpert et al., J. Infect. Dis., 156:158-166; Mietens et al., Eur. J. Pediatr., 132:239-252; Tacket et al., N. Engl. J. Med., 318:1240-1243; Yoshiyama et al., Immunology, 61:543-547).
It has been reported that bovine immunoglobulin G (IgG) concentrate from the colostrum of cows vaccinated with C. difficile toxoid protects hamsters against antibiotic associated cecitis. The hamsters were protected when treated before the onset of diarrhea but not after diarrhea began (Lyerly et al., Infection and Immunity, Vol. 59, No. 6, pages 2215-2218 (1991)). IgG directed against toxins A and B of C. difficile are present in the general population (Bacon and Fekety, Diagn. Microbiol. Infect. Dis., 1994; 18:205-209). Human intravenous immunoglobulin derived from plasma donors has facilitated treatment in some patients, especially patients who lack circulating antibodies to the C. difficile toxins (Leung D. Y. et al., J. Pediatr. 1991 April; 118(4 (Pt 1)):633-7; Salcedo J. et al., Gut 1997; 41:366-370; Wilcox M. H., J. Antimicrob. Chemoth. 2004; 53:882-884; McPherson S. et al., Dis. Colon Rectum 2006; 49:640-645; Cone L. A. et al., Infect. Dis. Clin. Pract. 2006; 14:217-220).
In vitro experiments have demonstrated that polymeric IgA is superior to monomeric IgA and IgG in preventing C. difficile toxin damage to intestinal epithelial cell monolayers (Stubbe H. et al., J. Immunol. 2000; 164:1952-1960). Selective neutralization of C. difficile toxin by serum IgA has also been demonstrated (Johnson S. et al., Infect. Immun. 1995; 63:3166-3173).
Administration of an immunoglobulin product containing specific antibodies to C. difficile results in the elimination of C. difficile toxins and also killing of the bacteria within the colon as detailed in U.S. Pat. No. 5,773,000. Such passive immunization therefore provides an effective approach for the treatment of C. difficile associated diseases such as colitis, pseudomembranous colitis and antibiotic associated diarrhea. This is especially important for patients experiencing multiple relapses.
Oral human immunoglobulin treatment has shown efficacy in treating acute C. difficile infections. Monomeric IgA admixed with IgG (2:1) was derived from plasma (IgAbulin, Immuno, Vienna) (100 mg/mL); four mL administered orally 3 times daily for 3 weeks to a three and one-half year old child with antibiotic-associated diarrhea and C. difficile toxin A in his stools proved effective in the context of concurrent vancomycin administration. The child improved on this treatment (Tjellstrom B. et al., Lancet 1993; 341:701702). This report demonstrates the efficacy of passive immunization with IgA derived from the general population.
The isolation of secretory forms of immunoglobulins is more difficult that securing forms of a respective immunoglobulin that circulate in the blood and lack secretory component.
Thus, there exists a need for IgA and IgM therapeutics that are resistant to gastrointestinal tract degradation. There also exists a need to provide such a therapeutic in a dosing form well suited for treating an infected subject. Human plasma derived IgA and IgM has been successfully combined with recombinant secretory component to produce secretory IgA and secretory IgM with biological activity (Longet et al 2013).
USPTO Backgrounds
USPTO Backgrounds