Immunogenic compositions against Clostridioides (Clostridium) difficile and methods thereof
Inventors
Anderson, Annaliesa Sybil • Gribenko, Alexey Vyacheslavovitch • Gruber, William Carl • Jansen, Kathrin Ute • Khandke, Lakshmi • Kitchin, Nicholas Randolph Everard • Lawrence, Jody • Peng, Yahong • Pride, Michael William • Webber, Christopher Frederick • Wellnitz, Sabine Susanne • Yi, Zhuobiao
Assignees
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Publication Number
US-12569547-B2
Publication Date
2026-03-10
Expiration Date
Abstract
In one aspect, the invention relates to an immunogenic composition that includes a Clostridium difficile toxoid A and/or a C. difficile toxoid B, and methods of use thereof. In another aspect, the invention relates to a method for eliciting an immune response in a human against a C. difficile infection. The method includes administering to the human an effective dose of a composition, which includes a C. difficile toxoid, wherein the composition is administered at least two times, and wherein the immune response against C. difficile toxin A and/or toxin B is sustained.
Core Innovation
The patent describes antibody or binding fragment compositions that target Clostridioides difficile toxin A (TcdA) using specific heavy chain variable and light chain variable amino acid sequences. In particular, an antibody or binding fragment is defined by a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 938 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 939. The disclosed approach includes binding fragments and defines antigen-binding specificity through toxoid or toxin-derived epitope regions associated with toxoid A.
The patent further defines antibody binding properties in relation to C. difficile toxoid A epitope specificity. The disclosed antibodies bind an epitope of Clostridioides difficile toxoid A in which the epitope includes an amino acid sequence defined by SEQ ID NO: 1044 or SEQ ID NO: 1045. Additional narrowing is provided by specifying binding to a domain of toxoid A, including the glucosyltransferase domain (GTD) of toxoid A, thereby concentrating target binding to defined structural regions of toxoid A.
A quantitative binding-affinity constraint is also described for at least one antibody configuration, including a dissociation constant (Kd) for binding to C. difficile toxin A. The patent positions these sequence-defined antibodies and binding fragments as neutralizing anti-toxin antibody compositions capable of targeting toxin activity across strain diversity, including cross-reactivity among strains and combinations with anti-TcdA and anti-TcdB monoclonals to support neutralization and related therapeutic or preventive outcomes.
Claims Coverage
The provided independent claim covers an antibody or binding fragment with fixed heavy- and light-chain variable region amino acid sequences defined by SEQ ID NO: 938 and SEQ ID NO: 939, and the dependent claims refine binding specificity to toxoid A epitope sequences, the glucosyltransferase domain (GTD), and a quantitative Kd binding threshold.
Sequence-defined antibody variable regions
An antibody or binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 938 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 939.
Epitope-defined toxoid A binding
An antibody or binding fragment that binds to an epitope of Clostridioides difficile toxoid A, where the epitope includes an amino acid sequence defined by SEQ ID NO: 1044 or SEQ ID NO: 1045.
Glucosyltransferase domain targeting on toxoid A
The antibody or binding fragment binds the glucosyltransferase domain (GTD) of toxoid A.
Quantitative binding-affinity constraint to toxin A
An antibody or binding fragment that binds C. difficile toxin A with a dissociation constant (Kd) of 0.06 nM.
Across the independent and dependent claim structure, the inventive coverage is anchored by fixed heavy and light chain variable region sequences (SEQ ID NO: 938 and SEQ ID NO: 939), and is further narrowed by epitope sequence identity on toxoid A (SEQ ID NO: 1044 or SEQ ID NO: 1045), by restricting binding to the glucosyltransferase domain (GTD) of toxoid A, and by specifying a quantitative Kd threshold for binding to C. difficile toxin A.
Stated Advantages
Provides antibody-mediated targeting of C. difficile toxin A through epitope- and domain-defined binding specificity.
Supports neutralization and related anti-toxin outcomes for preventing or treating CDI, including cross-reactivity among strains and synergistic combination effects with anti-TcdA and anti-TcdB monoclonals.
Provides broad neutralization breadth and binding/neutralizing characterization associated with defined toxoid-toxin targeting.
Documented Applications
Preventing or treating Clostridioides difficile infection (CDI) using C. difficile toxin-targeting antibody compositions.
Using immunogenic toxoid-based vaccine components to induce an immune response and elicit neutralizing antibodies, including components associated with genetically modified and chemically inactivated TcdA and TcdB.
Treating, preventing, or reducing incidence or severity of CDI (Clostridioides difficile infection) using the described antibody and/or vaccine immunogenic compositions.
Inducing durable immune responses as part of vaccination or immunization against CDI.
Use of the described human monoclonal antibody panel as replacement antibodies in IVRA, including stability-indicating labile-epitope antibodies.
TNA assay-based neutralization assessment against TcdA and, where data exist, TcdB for the human monoclonal antibodies described in the document.
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