Clostridium difficile toxins a and/or B antigen and epitope antibody, and pharmaceutical uses thereof
Inventors
Gaudreau, Simon • Cloutier, Martin • Fortier, Louis-Charles • Leduc, Frederic • Tremblay, Maxime • Veronneau, Steeve • Gbric, Djorjde • Larrivee, Jean-Francois
Assignees
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Publication Number
US-10533036-B2
Publication Date
2020-01-14
Expiration Date
Abstract
It is described a Clostridium difficile (C-difficile) toxins A and/or B as a target for therapy, including passive immunotherapy, and particularly prevention of C-difficile intoxication in human or other animals. It is also described a polypeptide comprising a portion of C-difficile toxins A and/or B sequence being an epitope for anti-toxins A and/or B antibody. It is also disclosed a method for generating a neutralizing antibody directed against C-difficile toxins A and/or B. It is also provided a novel formulation that combines key toxins A and/or B epitope antibodies, located in three key domains of toxins A and/or B, for neutralizing toxins A and/or B, at any stage of toxins A and/or B intoxication related to C-difficile infection. The novel formulation of toxins A and/or B epitope antibodies are useful in immunotherapy, for therapeutic and/or prophylactic mediation of C-difficile intoxication.
Core Innovation
The invention relates to Clostridium difficile toxins A and B as therapy targets, using isolated toxin A/B epitope polypeptides defined by SEQ ID NOs: 1-4. The approach focuses on epitope polypeptides and antibodies raised against these epitopes, positioned to capture and neutralize toxins during intoxication stages. The content describes immunogenic compositions built around epitope-defined peptides and vaccine carriers conjugated to those peptides.
The invention further describes vaccine or immunogenic compositions that include pharmaceutically acceptable carriers and pharmaceutically acceptable adjuvants, with peptide antigens defined by SEQ ID NOs: 1-4. Neutralizing antibody generation is supported by administering an immunogenic composition to a host, where the host produces neutralizing antibodies against Clostridium difficile toxins A and B. The disclosure additionally references antigen/antibody-based detection using an antigen-antibody complex.
In addition to antibody generation, the disclosure describes formulation concepts combining multiple epitope antibodies directed to key toxin domains, including CROPs domain, delivery pore forming, auto-protease, and glucosyltransferase. Documented examples include combinations of epitope antibodies (IBSCD1-IBSCD4) used to show neutralization of toxin effects on Caco-2 cells and protection of epithelial integrity measured by TEER. The disclosure also reports reduced in vivo CDI burden and mucosal damage in a mouse model.
Claims Coverage
The partial claim set includes one independent immunogenic-composition claim, further refined by dependent claims specifying additional peptide sequences, conjugation to a vaccine carrier, inclusion of a pharmaceutically acceptable adjuvant, and methods of generating neutralizing antibodies in a host.
Immunogenic composition with vaccine carrier conjugated peptide
An immunogenic composition comprising a first peptide consisting of the sequence set forth in SEQ ID NO: 1 and a vaccine carrier conjugated to said first peptide.
Immunogenic composition with additional epitope peptides
An immunogenic composition further including second, third, and fourth peptides consisting of the sequences set forth in SEQ ID NOs: 2, 3, and 4, respectively, wherein said second, third, and fourth peptides are conjugated to a vaccine carrier.
Immunogenic composition including pharmaceutically acceptable adjuvant
An immunogenic composition further including an effective amount of a pharmaceutically acceptable adjuvant.
Method of generating neutralizing antibodies against toxins A and B
A method of generating in a host neutralizing antibodies against Clostridium difficile toxins A and B by administering an effective amount of the immunogenic composition comprising the peptide defined in SEQ ID NO: 1 and a vaccine carrier conjugate.
Host as mammal or bird
The method is performed using a host that is a mammal or a bird.
Host as a bird
The method is characterized in that the host organism is a bird.
Coverage centers on immunogenic compositions formed from epitope-defined peptides (SEQ ID NOs: 1-4) conjugated to a vaccine carrier, optionally with a pharmaceutically acceptable adjuvant, and on administering such compositions to generate neutralizing antibodies targeting Clostridium difficile toxins A and B, with host scope restricted to mammal/bird and further to bird.
Stated Advantages
Neutralization of toxin effects on Caco-2 cells.
Protection of epithelial integrity as measured by TEER.
Reduced in vivo CDI burden.
Reduced mucosal damage.
The document describes use as antigen/antibody-based diagnostic detection using an antigen-antibody complex.
Documented Applications
Immunotherapy/prophylaxis using immunogenic composition to generate neutralizing antibodies against Clostridium difficile toxins A and B.
Antigen/antibody-based diagnostic detection using an antigen-antibody complex.
Cell-based assessment on Caco-2 intestinal cell line showing neutralization and TEER-related epithelial integrity protection.
Mouse model application showing reduced CDI burden and reduced mucosal damage.
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