Anti-O1 antibodies and uses thereof
Inventors
Wang, Qun • Stover, Charles K. • PENNINI, Meghan • Chang, Chew-Shun • Xiao, Xiaodong • Hilliard, Jamese • Kaplan, Gilad • Corti, Davide • Cameroni, Elisabetta • Beltramello, Martina
Assignees
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Publication Number
US-12018068-B2
Publication Date
2024-06-25
Expiration Date
Abstract
The present disclosure provides binding proteins (e.g., antibodies or antigen binding fragments thereof) that specifically bind to Klebsiella pneumoniae O1 and induce opsonophagocytic killing of Klebsiella (e.g., Klebsiella pneumoniae). The present disclosure also provides methods of reducing Klebsiella (e.g., Klebsiella pneumoniae) or treating or preventing Klebsiella (e.g., Klebsiella pneumoniae) infection in a subject comprising administering the Klebsiella pneumoniae O1 binding proteins, (e.g., antibodies or antigen-binding fragments thereof) to the subject.
Core Innovation
The invention relates to antigen binding proteins that specifically bind to Klebsiella pneumoniae O1 antigen and comprise Complementarity-Determining Regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3. The CDRs comprise amino acid sequences defined by SEQ ID NO sets, including SEQ ID NOs 1, 2, 3, 4, 5, and 7; SEQ ID NOs 1, 2, 3, 4, 6, and 7; or SEQ ID NOs 1, 2, 3, 4, 5, and 11.
Methods are provided for treating or ameliorating a Klebsiella infection in a subject in need thereof by administering an effective amount of the antigen binding protein that specifically binds to Klebsiella pneumoniae O1 antigen. The same defined CDR-containing antigen binding protein is used in a method for protecting against Klebsiella infection by administering an effective amount to a subject in need thereof.
The disclosed antigen binding protein is also applied in treatment or amelioration of Klebsiella pneumoniae and Staphylococcus aureus co-infection in a subject in need thereof. The approach further includes described characterization and performance of anti-O1 antibodies in binding and functional assays, and reported protection outcomes supported by in vivo efficacy testing in pneumonia, bacteremia, co-infection, endotoxemia, and synergy studies.
Claims Coverage
The independent claims cover three therapeutic/protective method categories. Across these independent claims, the defining inventive emphasis is on an antigen binding protein with defined CDR regions corresponding to specific SEQ ID NO sets.
Treating or ameliorating Klebsiella infection via defined O1 CDR-binding antigen binding protein
A method for treating or ameliorating a Klebsiella infection in a subject in need thereof comprising administering an effective amount of an antigen binding protein that specifically binds to Klebsiella pneumoniae O1 antigen, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise amino acid sequences of SEQ ID NOs 1, 2, 3, 4, 5, and 7 respectively; or SEQ ID NOs 1, 2, 3, 4, 6, and 7 respectively; or SEQ ID NOs 1, 2, 3, 4, 5, and 11 respectively.
Protecting against Klebsiella infection via defined O1 CDR-binding antigen binding protein
A method for protecting against a Klebsiella infection in a subject in need thereof comprising administering an effective amount of antigen binding protein that specifically binds to Klebsiella pneumoniae O1 antigen, wherein the antigen binding protein comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID NOs 1, 2, 3, 4, 5, and 7 respectively; or SEQ ID NOs 1, 2, 3, 4, 6, and 7 respectively; or SEQ ID NOs 1, 2, 3, 4, 5, and 11 respectively.
Treating or ameliorating Klebsiella pneumoniae and Staphylococcus aureus co-infection via defined O1 CDR-binding antigen binding protein
A method for treating or ameliorating a Klebsiella pneumoniae and Staphylococcus aureus co-infection in a subject in need thereof comprising administering an effective amount of an antigen binding protein that specifically binds to Klebsiella pneumoniae O1 antigen, wherein the antigen binding protein comprises a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs 1, 2, 3, 4, 5, and 7 respectively; SEQ ID NOs 1, 2, 3, 4, 6, and 7 respectively; or SEQ ID NOs 1, 2, 3, 4, 5, and 11 respectively.
The independent claim set consistently requires administration of an effective amount of a Klebsiella pneumoniae O1-specific antigen binding protein, where the antigen binding protein is defined by CDR regions containing amino acid sequences specified by the permitted SEQ ID NO sets. The therapeutic framing varies across treating or ameliorating infection, protecting against infection, and addressing Klebsiella pneumoniae plus Staphylococcus aureus co-infection.
Stated Advantages
Induces opsonophagocytic killing (OPK) and/or complement-dependent serum bactericidal killing.
Provides reduced lung organ burden in lethal pneumonia models.
Improves survival in lethal pneumonia and bacteremia models, including drug-resistant strains.
Provides protection in Klebsiella–Staphylococcus aureus co-infection.
Provides synergistic protection with meropenem.
Improved therapeutic effect reflected by greater percent survival versus subjects receiving only one of the antigen binding protein or the antibiotic.
Documented Applications
Treating or ameliorating Klebsiella infection in a subject in need thereof.
Protecting against Klebsiella infection in a subject in need thereof.
Treating or ameliorating Klebsiella pneumoniae and Staphylococcus aureus co-infection in a subject in need thereof.
Therapeutic effect described in lethal pneumonia and bacteremia models.
Protective use described for drug-resistant Klebsiella strains.
In vivo efficacy testing in pneumonia, bacteremia, co-infection, endotoxemia, and synergy studies.
Binding and functional characterization of anti-O1 antibodies using ELISA binding and functional assays including OPK and SBA.
Application of antibody/antigen-binding proteins to address protection outcomes associated with dependence on IL-17/γδ T cell recruitment and epitope mapping to the D-Galactan II domain (wbbYZ locus).
Use in studies of co-infection with Staphylococcus aureus SF8300 (USA300) and endotoxemia/sepsis models.
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