Humanized tetra-specific octavalent antibody against clostridium difficile toxin A and B
Inventors
Feng, Hanping • ZHANG, Yongrong • Yang, Zhiyong • Yu, Hua • Zhang, Yifan
Assignees
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Publication Number
US-12077575-B2
Publication Date
2024-09-03
Expiration Date
Abstract
Novel, antibody-based binding agents derived from camelid VHH and human immunoglobulins are described. These binding agents recognize and bind with specificity to Clostridium difficile toxin A and/or toxin B and in some cases exhibit toxin neutralizing activity. These binding agents can be used to treat or prevent primary and recurrent CDI. The binding agents include humanized VHH peptide monomers, linked groups of humanized VHH peptide monomers, humanized VHH peptide monomers joined to antibody Fc domains, and humanized VHH peptide monomers joined to IgG antibodies.
Core Innovation
The invention relates to tetra-specific, octameric binding agents that target Clostridium difficile toxins TcdA and/or TcdB. The binding agents comprise humanized VHH peptide monomers with independent binding specificity for epitopes of toxin A (TcdA) or toxin B (TcdB), and the humanized VHH peptide monomers are selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3), and hAH3 (SEQ ID NO:4).
In the tetra-specific, octameric format, the binding agent includes two arms, with each arm comprising a heavy chain lacking a variable region and a light chain lacking a variable region. For each arm, linked first and second humanized VHH peptide monomers are joined to the amino terminus of the light chain, and linked third and fourth humanized VHH peptide monomers are joined to the amino terminus of the heavy chain. The first, second, third, and fourth humanized VHH peptide monomers can have specificity for one or a combination of epitopes.
Antibody-based formats are included, including an IgG antibody configuration and an antibody Fc domain configuration that each provide arms with hinge, CH2 and CH3 regions and an amino terminus. The tetra-specific formats link sets of four humanized VHH peptide monomers to the amino terminus of each arm, yielding octameric binding agents, and the document further describes humanized camelid VHH-derived tetra-specific octavalent binding agents, including humanized VH H peptide monomers and linked multimers, with examples such as IgG- or Fc-fusion formats.
Claims Coverage
The independent claims define multiple related binding-agent architectures using humanized VHH peptide monomers with specified epitope binding to Clostridium difficile toxin A (TcdA) and/or toxin B (TcdB). Across the independent claims, the inventive features are organized around a tetra-specific, octameric two-arm format, IgG-based tetrameric and antibody-Fc-based tetrameric formats, and a humanized VHH peptide-only binding agent format.
Tetra-specific, octameric two-arm humanized VHH binding agent with linked monomers
A tetra-specific, octameric binding agent with two arms, each arm including a heavy chain lacking a variable region and a light chain lacking a variable region; linked first and second humanized VHH peptide monomers joined to the amino terminus of the light chain and linked third and fourth humanized VHH peptide monomers joined to the amino terminus of the heavy chain, where the humanized VHH peptide monomers are independently selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3) and hAH3 (SEQ ID NO:4) and each has binding specificity for an epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB).
IgG antibody tetrameric bi-specific or tetra-specific binding agent with four humanized VHH peptide monomers
A bi-specific or tetra-specific, tetrameric binding agent comprising an IgG antibody and first, second, third and fourth humanized VHH peptide monomers; where the IgG antibody comprises two arms with heavy and light chains lacking variable regions, and for a first arm the first monomer is joined to the amino terminus of the light chain while the second monomer is joined to the amino terminus of the heavy chain, and for a second arm the third monomer is joined to the amino terminus of the light chain while the fourth monomer is joined to the amino terminus of the heavy chain; each monomer has binding specificity for an epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB) and is selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3) and hAH3 (SEQ ID NO:4).
Fc domain tetra-specific octameric binding agent with linked humanized VHH peptide monomers
A tetra-specific, octameric binding agent comprising an antibody Fc domain and two sets of linked first, second, third and fourth humanized VHH peptide monomers, where the Fc domain comprises a first and second arm each with hinge, CH2 and CH3 regions and an amino terminus; for each arm, one set of linked first, second, third and fourth humanized VHH peptide monomers is joined to the amino terminus of the arm; the humanized VHH peptide monomers have binding specificity for an epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB) and are selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3) and hAH3 (SEQ ID NO:4).
Fc domain bi-specific tetrameric binding agent with two linked humanized VHH peptide monomers per arm
A bi-specific, tetrameric binding agent comprising an antibody Fc domain and two sets of linked first and second humanized VHH peptide monomers, where the Fc domain comprises a first and second arm each with hinge, CH2 and CH3 regions and an amino terminus; for each arm, one set of linked first and second humanized VHH peptide monomers is joined to the amino terminus of the arm; and the humanized VHH peptide monomers have binding specificity for an epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB) and are selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3) and hAH3 (SEQ ID NO:4).
Humanized VHH peptide binding agent with at least one monomer targeting a unique TcdA or TcdB epitope
A humanized VHH peptide binding agent comprising at least one humanized VHH peptide monomer, where each humanized VHH peptide monomer has binding specificity for a unique epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB), and where the at least one monomer is selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3) and hAH3 (SEQ ID NO:4), with the first, second, third, and fourth humanized VHH peptide monomers having specificity for one or a combination of epitopes and being selected from h5D (SEQ ID NO:1), hE3 (SEQ ID NO:2), hAA6 (SEQ ID NO:3) and hAH3 (SEQ ID NO:4).
Across the independent claims, the coverage is centered on humanized VHH peptide monomers selected from h5D, hE3, hAA6, and hAH3 that bind epitopes of TcdA and/or TcdB. The claims further cover tetra-specific octameric binding agents in a two-arm heavy/light chain architecture, as well as IgG/Fc-based tetrameric or octameric antibody formats, and a humanized VHH peptide-only binding agent option.
Stated Advantages
Neutralization of TcdA and/or TcdB.
Treatment or prevention of primary and recurrent CDI (Clostridioides difficile infection).
Documented Applications
Treat or prevent primary or recurrent CDI (Clostridioides difficile infection).
Neutralize Clostridium difficile toxins TcdA and/or TcdB in a subject infected by C. difficile by administering a therapeutically-effective amount of the binding agent.
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