Anti-O2 antibodies and uses thereof

Inventors

Wang, Qun • PENNINI, Meghan • Xiao, Xiaodong • Corti, Davide • Cameroni, Elisabetta • Beltramello, Martina • Kaplan, Gilad • DeMarco, Anna • Stover, Charles K.

Assignees

Humabs Biomed SA • MedImmune LLC

Abstract

The present disclosure provides binding proteins (e.g., antibodies or antigen binding fragments thereof) that specifically bind to Klebsiella pneumoniae 02 and induce opsonophagocytic killing of Klebsiella (e.g., Klebsiellapneumoniae) and/or protects mice from a lethal Klebsiella challenge. 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 02 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 Klebsiella pneumoniae O2 antigen and comprise a set of Complementarity-Determining Regions (CDRs): HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3. The CDRs comprise amino acid sequences defined by the listed SEQ ID NOs, with stated variants and corresponding SEQ ID NO assignments. The disclosed binding proteins are used in methods for treating or ameliorating a Klebsiella infection, and for inhibiting the growth of Klebsiella or reducing the number of Klebsiella in a subject infected with Klebsiella.

The disclosure includes humanized and human antibodies, chimeric antibodies, fusion antibodies, and truncated antibody fragments such as Fab, F(ab’)2, Fv, and scFv. It also encompasses variable-region mutagenesis and further development of CDRs for antigen binding, together with embodiments defined by particular VH and VL sequences using stated SEQ ID NOs. The antigen-binding proteins are characterized with respect to O2 LPS, D-galactan I, and binding not to D-Galactan III.

The disclosure further describes functional properties including opsonophagocytic killing (OPK), LPS neutralization, and inhibition of LPS-induced NF-κB activation, with O1 versus O2 selectivity. It also describes in vivo protection of mice against lethal Klebsiella challenge, activity against O2-serotype strains including multidrug-resistant isolates, and compatibility with combination use with antibiotics such as meropenem, carbapenems, and colistin. Pharmacological formulations, pharmaceutical compositions, polynucleotides, and host cells for expressing the antigen-binding proteins are also described.

Claims Coverage

The provided claims include two independent method claims. Both independent claims center on administering an antigen-binding protein that specifically binds Klebsiella pneumoniae O2 antigen and that comprises specified HCDR1/HCDR2/HCDR3 and LCDR1/LCDR2/LCDR3 amino-acid sequences defined by SEQ. ID. NOs.

Across both independent claims, the inventive core is administration of an O2 antigen-specific antigen-binding protein defined by a particular set of HCDR/LCDR amino-acid sequences to treat or ameliorate infection or inhibit growth or reduce number of Klebsiella in an infected subject.

Stated Advantages

Documented Applications