Loading patent…
AssigneeWyeth
InventorsKathrin Ute Jansen, Annaliesa Sybil Anderson, Robert G. K. Donald, Maninder K. Sidhu, Narender Kumar Kalyan, Justin Keith Moran, Mark Edward Ruppen, Michael James Flint
Estimating the term…
In one aspect, the invention relates to an immunogenic composition that includes a mutant Clostridium difficile toxin A and/or a mutant Clostridium difficile toxin B. Each mutant toxin includes a glucosyltransferase domain having at least one mutation and a cysteine protease domain having at least one mutation, relative to the corresponding wild-type C. difficile toxin. The mutant toxins may further include at least one amino acid that is chemically crosslinked. In another aspect, the invention relates to antibodies or binding fragments thereof that binds to said immunogenic compositions. In further aspects, the invention relates to isolated nucleotide sequences that encode any of the foregoing, and methods of use of any of the foregoing compositions.
A method for eliciting an immune response against Clostridium difficile in a mammal, said method comprising administering to the mammal an effective dose of a composition, which comprises a modified C. difficile toxin that is produced by contacting a wild-type C. difficile toxin with 1-Ethyl-3-(3-Dimethylaminopropyl)-Carbodiimide (EDC) and N-hydroxysuccinimide (NHS);
Dependencies are inferred from the claim text.
From the US filing history. Foreign family members aren’t listed.
From bacteria: from Clostridium
Bacterial antigens: clostridium, e.g. Clostridium tetani
Drugs for disorders of the alimentary tract or the digestive system
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
About 5 years 8 months of term left · ends 1 Jul 2032 (estimated)
The present invention is directed to compositions concerning mutant Clostridium difficile toxins and methods thereof.
Clostridium difficile (C. difficile) is a Gram-positive anaerobic bacterium that is associated with gastrointestinal disease in humans. Colonization of C. difficile usually occurs in the colon if the natural gut flora is diminished by treatment with antibiotics. An infection can lead to antibiotic-associated diarrhea and sometimes pseudomembranous colitis through the secretion of the glucosylating toxins, toxin A and toxin B (308 and 270 kDa, respectively), which are the primary virulence factors of C. difficile.
Toxin A and toxin B are encoded within the 19 kb pathogenicity locus (PaLoc) by the genes tcdA and tcdB, respectively. Nonpathogenic strains of C. difficile have this locus replaced by an alternative 115 base pair sequence.
FIG. 1A-H: Sequence alignment of wild-type C. difficile toxin A from strains 630, VP110463, R20291, CD196, and mutant toxin A having SEQ ID NO: 4, using CLUSTALW alignment, default parameters.
FIG. 2A-F: Sequence alignment of wild-type C. difficile toxin B from strains 630, VP110463, R20291, CD196, and mutant toxin B having SEQ ID NO: 6, using CLUSTALW alignment, default parameters.
FIG. 3: Graph showing identification of wild-type toxin-negative C. difficile strains. Culture media of 13 C. difficile strains were tested by ELISA for toxin A. As illustrated, seven strains expressed toxin A and 6 strains did not (strains 1351, 3232, 7322, 5036, 4811 and VPI 11186).
SEQ ID NO: 1 sets forth the amino acid sequence for wild-type C. difficile 630 toxin A (TcdA).
SEQ ID NO: 2 sets forth the amino acid sequence for wild-type C. difficile 630 toxin B (TcdB).
SEQ ID NO: 3 sets forth the amino acid sequence for a mutant TcdA having a mutation at positions 285 and 287, as compared to SEQ ID NO: 1.