Methods and compositions for the treatment and/or prophylaxis of Clostridium difficile associated disease
Inventors
Lyras, Dena • HUTTON, Melanie • CUNNINGHAM, Bliss • Li, Lucy • Carter, Glen • Rood, Julian
Assignees
Publication Number
US-10144775-B2
Publication Date
2018-12-04
Expiration Date
2034-04-17
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Abstract
The present invention relates to methods and compositions for the treatment and/or prophylaxis of Clostridium difficile associated disease (CD AD). In particular, the invention relates to antibodies that bind to C. difficile antigens and are capable of inhibiting C. difficile infection, at least one symptom of C. difficile associated disease, shedding of C. difficile, and C. difficile associated mortality. The compositions of the present application comprise: mammalian or avian antibodies which bind to a C. difficile Toxin B; and mammalian or avian antibodies that bind to a C. difficile vegetative cell antigen and/or a C. difficile endospore antigen.
Core Innovation
The invention relates to methods and compositions for treating and preventing Clostridium difficile associated disease (CDAD). In particular, it involves mammalian or avian antibodies that bind specifically to C. difficile antigens, including Toxin B, vegetative cell antigens, and endospore antigens. These antibodies are capable of inhibiting C. difficile infection, symptoms of CDAD, shedding of C. difficile, and mortality associated with the disease.
The problem addressed by the invention arises from the significant morbidity, mortality, and increasing prevalence of CDAD, especially due to hypervirulent strains resistant to antibiotics and causing epidemics worldwide. Current treatments have notable failures and high recurrence rates. There remains a need for effective prophylaxis and treatment against a broad range of C. difficile strains and associated symptoms.
The invention provides compositions comprising hyperimmune colostrum containing antibodies that specifically bind to C. difficile Toxin B and to at least one of either vegetative cell or endospore antigens. These antibodies are raised against vaccines made from purified toxins, vegetative cells, endospores, or their respective antigenic components such as the S-layer protein SlpA and exosporium proteins. The antibodies have cross-reactivity against different C. difficile strains and toxinotypes and demonstrate neutralizing activity in vitro and protective efficacy in vivo in animal models. The compositions may be formulated for oral administration and used prophylactically or therapeutically.
Claims Coverage
The claims cover a composition and methods involving mammalian hyperimmune colostrum containing specific antibodies and their use in treating or preventing symptoms of C. difficile associated disease. The main inventive features involve antibodies targeting key C. difficile antigens, their preparation, and specific compositions.
Composition comprising antibodies binding C. difficile Toxin B and vegetative cell/endospore antigens
A composition comprising mammalian hyperimmune colostrum including antibodies that bind to C. difficile Toxin B, and antibodies that bind to at least one vegetative cell antigen and/or one endospore antigen, wherein the vegetative cell antibodies are raised against vaccines comprising vegetative cells or S-layer preparations of a first strain, and the endospore antibodies are raised against vaccines comprising endospores of a first strain.
Antibodies raised against specific C. difficile strains and cross-reactivity
Antibodies binding to C. difficile Toxin B are raised against a vaccine comprising Toxin B from a first strain, such as strain 630, and also bind to Toxin B from a second strain. Similarly, antibodies binding vegetative cell and endospore antigens may bind to corresponding antigens from different strains.
Antibodies binding to specific C. difficile proteins
Antibodies bind to specific proteins such as S-layer protein A (SlpA) in vegetative cells and exosporium proteins in endospores.
Compositions comprising antibodies in defined ratios
The composition contains antibodies binding Toxin B, vegetative cell antigens, and endospore antigens in specific ratios such as 1:1:1, 2:1:1, 3:1:1, or up to 8:1:1.
Hyperimmune colostrum as source of antibodies and preparation method
The antibodies are derived from bovine hyperimmune colostrum prepared by vaccinating separate lots of one or more mammals with vaccines comprising C. difficile Toxin B, vegetative cells, and endospores, followed by blending the hyperimmune colostrum from these lots.
Formulation and dosing for oral administration
The composition is formulated for oral administration and may be prepared at doses ranging from about 30 mg to about 15,000 mg, preferably about 1800 mg per dose.
Methods for treatment and prophylaxis using the composition
Methods of treating or preventing at least one symptom of CDAD in a subject by administering a therapeutically effective amount of the described composition are claimed, including specific antigen targeting, dosing, composition ratios, and preparation from hyperimmune colostrum.
The claims define a composition of mammalian hyperimmune colostrum comprising polyclonal antibodies targeting C. difficile Toxin B, vegetative cell antigens, and/or endospore antigens prepared from vaccinated animals, formulated for oral administration in defined antibody ratios, and methods of using such compositions for treating or preventing symptoms of C. difficile associated disease.
Stated Advantages
Antibodies that bind to C. difficile Toxin B neutralise toxin cytotoxicity in vitro and inhibit disease progression in vivo, including prevention of weight loss, mortality, and gastrointestinal damage associated with C. difficile infection.
Antibodies that bind to C. difficile vegetative cell antigens and endospore antigens reduce bacterial colonisation, shedding of infectious spores, and inhibit transmission, thereby addressing infection and its spread.
Compositions comprising combinations of antibodies binding multiple C. difficile antigens demonstrate synergistic protective effects, improving survival and reducing disease severity compared to single antibody treatments.
The use of hyperimmune colostrum as a source of antibodies enables provision of stable, orally administrable immunotherapeutics resistant to gastrointestinal degradation.
The antibodies show cross-reactivity and neutralising activity against multiple C. difficile strains and toxinotypes, making the therapy broadly effective across diverse clinical isolates.
Documented Applications
Treatment and prophylaxis of at least one symptom of Clostridium difficile associated disease (CDAD) including diarrhoea, abdominal pain, fever, loss of appetite, pseudomembranous colitis, toxic megacolon, colonisation, weight loss, cytotoxicity, gastrointestinal damage, histopathologic changes, faecal shedding of spores, and mortality.
Use in prevention and treatment of infection and colonisation by diverse strains of C. difficile, including hypervirulent and Toxin A-negative, Toxin B-positive strains.
Reduction of C. difficile shedding and transmission in infected subjects, thus contributing to infection control.
Therapeutic administration post-infection and prophylactic administration prior to increased risk circumstances such as hospital or nursing home admission.
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