WO2023094628A1 - Antibodies for use as therapeutics against bacterial infections - Google Patents

Antibodies for use as therapeutics against bacterial infections Download PDF

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Publication number
WO2023094628A1
WO2023094628A1 PCT/EP2022/083353 EP2022083353W WO2023094628A1 WO 2023094628 A1 WO2023094628 A1 WO 2023094628A1 EP 2022083353 W EP2022083353 W EP 2022083353W WO 2023094628 A1 WO2023094628 A1 WO 2023094628A1
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seq
antibody
sequence
domain
domain comprises
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English (en)
French (fr)
Inventor
Stephen Reece
Aisha KRISHNA
Siobhan O'leary
Josefin BARTHOLDSON SCOTT
Simon Watson
Stephen Baker
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Kymab Ltd
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Kymab Ltd
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Priority to JP2024531252A priority Critical patent/JP2024543911A/ja
Priority to US18/713,540 priority patent/US20250026816A1/en
Priority to CN202280089066.5A priority patent/CN118922440A/zh
Priority to EP22822905.0A priority patent/EP4436994A1/en
Publication of WO2023094628A1 publication Critical patent/WO2023094628A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1203—Gram-negative bacteria
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1203—Gram-negative bacteria
    • C07K16/1218—Acinetobacter (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity

Definitions

  • the present invention relates to antibodies that bind Acinetobacter baumannii, and their use in the diagnosis of, and the prevention and treatment of, bacterial infection caused by Acinetobacter baumannii.
  • Acinetobacter genus consists of 26 named species and nine genomic species.
  • Acinetobacter baumannii is a bacterial pathogen primarily associated with hospital-acquired infections. It is a gram-negative bacillus.
  • Acinetobacter baumannii specifically targets moist tissues such as mucous membranes or areas of the skin that are exposed. If left untreated, this infection can lead to septicemia and death. Once Acinetobacter baumannii is in a hospital environment, this poses a significant risk, particularly in ICU wards where patients are chronically ill.
  • Carbapenems are beta-lactam antibiotics that are structurally distinct from other commonly used betalactam antibiotics such as penicillin and cephalosporin classes. Carbapenems have proved the drug of choice to treat extended spectrum beta-lactamase (ESBL) producing bacteria, including A. baumannii strains, which are associated with poor clinical outcomes in severe infections in hospital settings such as pneumonia and bacteremia.
  • ESBL extended spectrum beta-lactamase
  • CRAB carbapenem-resistant Acinetobacter baumannii
  • VAP ventilator associated pneumonia
  • Acinetobacter baumannii classifications comprise 3 European clones (ECI-III), 8 Worldwide clones (WWl-8-which have effectively become 8 International clones, IC1-8) and 2 Global clones (GC1 and 2).
  • MLST Multi-locus sequence typing
  • Global clones 1 and 2 which are equal to IC1 and 2 respectively are also supported by full genome phylogenetics (Pathog Dis. 2014 Aug;71(3):292-301. doi: 10.1111/2049- 632X. 12125. Epub 2014 Jan 27 the contents of which are incorporated herein by reference).
  • GC2 is the predominant global lineage associated with carbapenem resistance.
  • the present invention aims to provide monoclonal antibodies for diagnosis and treatment of bacterial infection caused by Acinetobacter baumannii. 3. SUMMARY OF THE INVENTION
  • the present invention provides monoclonal antibodies suitable for diagnosis, prevention and treatment of bacterial infection caused by Acinetobacter baumannii.
  • the present invention provides monoclonal antibodies that specifically bind at the bacterial wall of Acinetobacter baumannii bacteria, such as on, e.g., living bacteria.
  • the present invention provides monoclonal antibodies that specifically bind at the bacterial wall of Acinetobacter baumannii bacteria and induce complement activation (e.g. as measured by flow cytometry-based assay).
  • the present invention identifies novel antibody targets at the surface of Acinetobacter baumannii bacteria for diagnosis, prevention and treatment of bacterial infection caused by Acinetobacter baumannii.
  • the present invention demonstrates for the first time that the Oxa-23 enzyme is present at the surface of live bacteria and can be targeted by diagnostic and therapeutic antibodies.
  • the present invention demonstrates for the first time that the lipooligosaccharide (LOS) type OC 1 at the surface of live bacteria and can be targeted by diagnostic and therapeutic antibodies.
  • LOS lipooligosaccharide
  • the present invention demonstrates for the first time that the KL49 carbohydrate capsular antigen at the surface of live bacteria can be targeted by diagnostic and therapeutic antibodies.
  • Acinetobacter baumannii bacteria provides an important advancement in the diagnosis, prevention and treatment of bacterial infection caused by Acinetobacter baumannii.
  • the present invention provides a particularly important advancement for the diagnosis, prevention and treatment of bacterial infection caused by carbapenem-resistant Acinetobacter baumannii (CRAB), where the existing carbapenem treatment will be ineffective.
  • CRAB is particularly associated with the G2 lineage of Acinetobacter baumannii.
  • the present invention further provides novel monoclonal antibodies that bind Oxa-23 at the surface of Acinetobacter baumannii bacteria. Such antibodies find particular use in the diagnosis of Acinetobacter baumannii.
  • the present invention further provides novel antibodies that bind Oxa-23 at the surface of Acinetobacter baumannii bacteria and induce complement activation, thereby killing the bacteria. Such antibodies find particular use in the prevention and treatment of bacterial infection caused by Acinetobacter baumannii.
  • the present invention further provides novel monoclonal antibodies that bind OC1 LOS at the surface of Acinetobacter baumannii bacteria. Such antibodies find particular use in the diagnosis of Acinetobacter baumannii.
  • the present invention further provides novel antibodies that bind OC1 LOS at the surface of Acinetobacter baumannii bacteria and induce complement activation, thereby killing the bacteria. Such antibodies find particular use in the prevention and treatment of bacterial infection caused by Acinetobacter baumannii.
  • the present invention further provides novel monoclonal antibodies that bind KL49 at the surface of Acinetobacter baumannii bacteria. Such antibodies find particular use in the diagnosis of Acinetobacter baumannii.
  • the present invention further provides novel antibodies that bind KL49 at the surface of Acinetobacter baumannii bacteria and induce complement activation, thereby killing the bacteria. Such antibodies find particular use in the prevention and treatment of bacterial infection caused by Acinetobacter baumannii.
  • Antibody sequences are referred to herein by reference to the internal reference number of the relevant antibody, as well as by SEQ ID NOs. Any disclosure herein reciting antibody reference numbers is intended to include disclosure with the corresponding nucleic acid or amino acid sequence number (SEQ ID NO), as presented in Tables 1 and 2.
  • Antibodies are provided herein which specifically bind Oxa-23.
  • antibodies 1348, 1349, 1540, 1 48, and 1550 as exemplified herein have been found to specifically bind to Oxa-23 on outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria.
  • OMVs outer membrane vesicles
  • the present invention provides an antibody that specifically binds to Oxa-23 at the surface of Acinetobacter baumannii bacteria, such as on, e.g., living bacteria
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria as measured by an indirect whole bacterial cell ELISA. Due to high correlation between outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria and live Acinetobacter baumannii bacteria, such antibodies have been found to also specifically bind to Oxa-23 on outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria.
  • OMVs outer membrane vesicles
  • the antibody induces complement activation (e.g. as measured by flow cytometrybased assay).
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and HCDR3 is the HCDR3 of antibody 1348, 1349, 1540, 1548, or 1550 .
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody 1348, 1349, 1540, 1548, or 1550 .
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • HCDR3 is the HCDR3 of antibody 1348.
  • HCDR3 is the HCDR3 of antibody 1349.
  • HCDR3 is the HCDR3 of antibody 1540.
  • HCDR3 is the HCDR3 of antibody 1548.
  • HCDR3 is the HCDR3 of antibody 1550.
  • the present invention provides an anti-Oxa-23 antibody, wherein the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the 6 CDRs are those of antibody 1348, 1349, 1540, 1548, or 1550 .
  • VH variable heavy
  • CDRs complementarity determining regions
  • LCDR1, LCDR2 and LCDR3 variable light domain sequence
  • the present invention provides an anti-Oxa-23 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the 6 CDRs are those of antibody 1348, 1349, 1540, 1548, or 1550 .
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • the antibody has the 6 CDRs of antibody 1348.
  • the antibody has the 6 CDRs of antibody 1349.
  • the antibody has the 6 CDRs of antibody 1540.
  • the antibody has the 6 CDRs of antibody 1548.
  • the antibody has the 6 CDRs of antibody 1550.
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 , optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 , optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1348, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1348, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1349, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1349, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1540, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1 40, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1548, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1548, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1550, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1550, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 , provided that the antibody has the CDRs of antibody 1348, 1349, 1540, 1548, or 1550 , respectively.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 provided that the antibody has the CDRs of antibody 1348, 1349, 1540, 1548, or 1550 , respectively.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1348 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1348, provided that the antibody has the CDRs of antibody 1348.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1349 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1349, provided that the antibody has the CDRs of antibody 1349.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1540 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1540, provided that the antibody has the CDRs of antibody 1540.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1548 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1548, provided that the antibody has the CDRs of antibody 1548.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1550 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1550, provided that the antibody has the CDRs of antibody 1550.
  • the present invention provides an antibody that specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 .
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1348.
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1349.
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1540. In one embodiment, the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1548.
  • the antibody specifically binds Oxa-23 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1550.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 .
  • the antibody comprises the VH and VL domain sequences of antibody 1348.
  • the antibody comprises the VH and VL domain sequences of antibody 1349.
  • the antibody comprises the VH and VL domain sequences of antibody 1540.
  • the antibody comprises the VH and VL domain sequences of antibody 1 48.
  • the antibody comprises the VH and VL domain sequences of antibody 1550.
  • the antibody is selected from the group consisting of antibodies 1348, 1349, 1540, 1548, or 1550.
  • the antibody is antibody 1348.
  • the antibody is antibody 1349.
  • the antibody is antibody 1540.
  • the antibody is antibody 1548.
  • the antibody is antibody 1550.
  • Antibodies are provided which bind to the same epitope on Oxa-23 as an antibody described anywhere herein.
  • An antibody which binds to the same epitope as antibody 1348, 1349, 1540, 1548, or 1550 , e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1348, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1349, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1540, e.g. as defined by its VH and VL sequences. In one embodiment, an antibody is provided which binds to the same epitope as antibody 1548, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1550, e.g. as defined by its VH and VL sequences.
  • An antibody may contact Oxa-23 with a footprint that fully or partly overlaps with that of an antibody disclosed anywhere herein.
  • competition between antibodies may be determined, for example using SPR, and antibodies are provided which compete for binding to Oxa-23 (compete for binding to their epitope) with an IgG antibody as described anywhere herein.
  • An antibody of the present invention may be one which competes for binding to Oxa-23 with any anti- Oxa-23 antibody described herein, such as antibodies 1348, 1349, 1540, 1548, and 1550 , e.g. as defined by their respective VH and VL sequences.
  • An antibody of the present invention may be one which competes for binding to Oxa-23 with antibody
  • An antibody of the present invention may be one which competes for binding to Oxa-23 with antibody
  • An antibody of the present invention may be one which competes for binding to Oxa-23 with antibody 1540.
  • An antibody of the present invention may be one which competes for binding to Oxa-23 with antibody 1548.
  • An antibody of the present invention may be one which competes for binding to Oxa-23 with antibody 1550.
  • a nucleic acid sequence provided by the invention may comprise a sequence that encodes a VH domain and/or an VL domain of an anti-Oxa-23 antibody as defined anywhere herein.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1540.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1548.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1550.
  • Antibodies are provided herein which specifically bind OC1 lipooligosaccharide (LOS).
  • LOS OC1 lipooligosaccharide
  • antibodies 1042, 1043, 1403, 1405, 1407, 1408, and 1413 as exemplified herein have been found to specifically bind to OC1 LOS at the surface of Acinetobacter baumannii bacteria.
  • the present invention provides an antibody that specifically binds to OC1 LOS at the surface of Acinetobacter baumannii bacteria, such as on, e.g., living bacteria
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria as measured by an indirect whole bacterial cell ELISA. Due to high correlation between outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria and live Acinetobacter baumannii bacteria, such antibodies have been found to also specifically bind to OC1 LOS on outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria.
  • OMVs outer membrane vesicles
  • the antibody induces complement activation (e.g. as measured by flow cytometrybased assay).
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and HCDR3 is the HCDR3 of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • HCDR3 is the HCDR3 of antibody 1042.
  • HCDR3 is the HCDR3 of antibody 1043.
  • HCDR3 is the HCDR3 of antibody 1403.
  • HCDR3 is the HCDR3 of antibody 1405.
  • HCDR3 is the HCDR3 of antibody 1407.
  • HCDR3 is the HCDR3 of antibody 1408.
  • HCDR3 is the HCDR3 of antibody 1413.
  • the present invention provides an anti-OCl LOS antibody, wherein the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the 6 CDRs are those of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • VH variable heavy
  • CDRs complementarity determining regions
  • the present invention provides an anti-OCl LOS antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the 6 CDRs are those of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • the antibody has the 6 CDRs of antibody 1042.
  • the antibody has the 6 CDRs of antibody 1043.
  • the antibody has the 6 CDRs of antibody 1403.
  • the antibody has the 6 CDRs of antibody 1405.
  • the antibody has the 6 CDRs of antibody 1407.
  • the antibody has the 6 CDRs of antibody 1408.
  • the antibody has the 6 CDRs of antibody 1413.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1042, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1042, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1043, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1043, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1403, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1403, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1405, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1405, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1407, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1407, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1408, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1408, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1413, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1413, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii and induces complement activation (e.g. as measured by flow cytometry-based assay), and the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, provided that the antibody has the 6 CDRs of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, respectively.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413 provided that the antibody has the 6 CDRs of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, respectively.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1042 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1042, provided that the antibody has the 6 CDRs of antibody 1042.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1043 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1043, provided that the antibody has the 6 CDRs of antibody 1043.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1403 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1403, provided that the antibody has the 6 CDRs of antibody 1403.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1405 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1405, provided that the antibody has the 6 CDRs of antibody 1405.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1407 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1407, provided that the antibody has the 6 CDRs of antibody 1407.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1408 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1408, provided that the antibody has the 6 CDRs of antibody 1408.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1413 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1413, provided that the antibody has the 6 CDRs of antibody 1413.
  • the present invention provides an antibody that specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1042.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1043.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1403.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1405.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1407.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1408.
  • the antibody specifically binds OC1 LOS at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1413.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413. In one embodiment, the antibody comprises the VH and VL domain sequences of antibody 1042.
  • the antibody comprises the VH and VL domain sequences of antibody 1043.
  • the antibody comprises the VH and VL domain sequences of antibody 1403.
  • the antibody comprises the VH and VL domain sequences of antibody 1405.
  • the antibody comprises the VH and VL domain sequences of antibody 1407.
  • the antibody comprises the VH and VL domain sequences of antibody 1408.
  • the antibody comprises the VH and VL domain sequences of antibody 1413.
  • the antibody is selected from the group consisting of antibodies 1042, 1043, 1403, 1405, 1407, 1408, and 1413.
  • the antibody is antibody 1042.
  • the antibody is antibody 1043.
  • the antibody is antibody 1403.
  • the antibody is antibody 1405.
  • the antibody is antibody 1407.
  • the antibody is antibody 1408.
  • the antibody is antibody 1413.
  • Antibodies are provided which bind to the same epitope on OC1 LOS as an antibody described anywhere herein.
  • An antibody is provided which bind to the same epitope as antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1042.
  • an antibody which binds to the same epitope as antibody 1043.
  • an antibody which binds to the same epitope as antibody 1403.
  • an antibody which binds to the same epitope as antibody 1405.
  • an antibody which binds to the same epitope as antibody 1407.
  • an antibody which binds to the same epitope as antibody 1408.
  • an antibody which binds to the same epitope as antibody 1413.
  • An antibody may contact OC1 LOS with a footprint that fully or partly overlaps with that of an antibody disclosed anywhere herein.
  • competition between antibodies may be determined, for example using SPR, and antibodies are provided which compete for binding to OC1 LOS (compete for binding to their epitope) with an IgG antibody as described anywhere herein.
  • An antibody of the present invention may be one which competes for binding to OC1 LOS at the surface of Acinetobacter baumannii bacteria with any anti-OCl LOS antibody described herein, such as antibodies 1042, 1043, 1403, 1405, 1407, 1408, and 1413, e.g. as defined by its VH and VL sequences.
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody 1403.
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody 1405.
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody
  • An antibody of the present invention may be one which competes for binding to OC1 LOS with antibody 1413.
  • a nucleic acid sequence provided by the invention may comprise a sequence that encodes a VH domain and/or an VL domain of an anti- OC1 LOS antibody as defined anywhere herein.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1403.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1405.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1413.
  • Antibodies are provided herein which specifically bind KL49.
  • antibodies 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, and 1416 as exemplified herein have been found to specifically bind KL49 at the surface of Acinetobacter baumannii bacteria.
  • the present invention provides an antibody that specifically binds to KL49 at the surface of Acinetobacter baumannii bacteria, such as on, e.g., living bacteria
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria as measured by an indirect whole bacterial cell ELISA. Due to high correlation between outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria and live Acinetobacter baumannii bacteria, such antibodies have been found to also specifically bind to KL49 on outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria.
  • OMVs outer membrane vesicles
  • the antibody induces complement activation (e.g. as measured by flow cytometrybased assay).
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii and induces complement activation (e.g. as measured by flow cytometry-based assay), and HCDR3 is the HCDR3 of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the HCDR3 is the HCDR3 of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • HCDR3 is the HCDR3 of antibody 1345.
  • HCDR3 is the HCDR3 of antibody 1347.
  • HCDR3 is the HCDR3 of antibodyl350.
  • HCDR3 is the HCDR3 of antibody 1351.
  • HCDR3 is the HCDR3 of antibody 1363.
  • HCDR3 is the HCDR3 of antibodyl364.
  • HCDR3 is the HCDR3 of antibodyl397. In one embodiment, HCDR3 is the HCDR3 of antibody 1398.
  • HCDR3 is the HCDR3 of antibodyl400.
  • HCDR3 is the HCDR3 of antibody 1401.
  • HCDR3 is the HCDR3 of antibodyl402.
  • HCDR3 is the HCDR3 of antibodyl404.
  • HCDR3 is the HCDR3 of antibodyl409.
  • HCDR3 is the HCDR3 of antibodyl410.
  • HCDR3 is the HCDR3 of antibodyl412.
  • HCDR3 is the HCDR3 of antibodyl414.
  • HCDR3 is the HCDR3 of antibodyl415.
  • HCDR3 is the HCDR3 of antibodyl416.
  • the present invention provides an anti-KL49 antibody, wherein the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria as and induces complement activation (e.g. as measured by flow cytometry-based assay), and wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the 6 CDRs are those of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • VH variable heavy
  • CDRs complementarity determining regions
  • LCDR1, LCDR2 and LCDR3 variable light domain sequence
  • the 6 CDRs are those of antibody 1345, 1347, 1350, 1351, 1363, 13
  • the present invention provides an anti-KL49 antibody, wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, wherein the 6 CDRs are those of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • VH variable heavy
  • CDRs complementarity determining regions
  • LCDR1, LCDR2 and LCDR3 variable light domain sequence
  • the 6 CDRs are those of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • the antibody has the 6 CDRs of antibodyl345.
  • the antibody has the 6 CDRs of antibody 1347.
  • the antibody has the 6 CDRs of antibody 1350.
  • the antibody has the 6 CDRs of antibody 1351.
  • the antibody has the 6 CDRs of antibody 1363.
  • the antibody has the 6 CDRs of antibody 1364. In one embodiment, the antibody has the 6 CDRs of antibody 1397.
  • the antibody has the 6 CDRs of antibodyl398.
  • the antibody has the 6 CDRs of antibody 1400.
  • the antibody has the 6 CDRs of antibody 1401.
  • the antibody has the 6 CDRs of antibody 1402.
  • the antibody has the 6 CDRs of antibody 1404.
  • the antibody has the 6 CDRs of antibody 1409.
  • the antibody has the 6 CDRs of antibody 1410.
  • the antibody has the 6 CDRs of antibody 1412.
  • the antibody has the 6 CDRs of antibody 1414.
  • the antibody has the 6 CDRs of antibody 1415.
  • the antibody has the 6 CDRs of antibody 1416.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1345, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1345, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1347, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1347, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1350, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1350, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1351, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1351, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1363, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1363, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1364, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1364, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1397, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1397, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1398, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1398, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1400, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1400, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1401, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1402, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1402, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1404, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1404, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1409, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1409, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1410, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1410, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1412, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1412, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1414, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1414, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1415, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 141 , optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1416, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1416, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria and induces complement activation (e.g. as measured by flow cytometry-based assay), and the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, provided that the antibody has the 6 CDRs of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, provided
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416 provided that the antibody has the 6 CDRs of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, respectively.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1345 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1345, provided that the antibody has the 6 CDRs of antibody 1345.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1347 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1347, provided that the antibody has the 6 CDRs of antibody 1347.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1350 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1350, provided that the antibody has the 6 CDRs of antibody 1350.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1351 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1351, provided that the antibody has the 6 CDRs of antibody 1351.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1363 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1363, provided that the antibody has the 6 CDRs of antibody 1363.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1364 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1364, provided that the antibody has the 6 CDRs of antibody 1364.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1397 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1397, provided that the antibody has the 6 CDRs of antibody 1397.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1398 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1398, provided that the antibody has the 6 CDRs of antibody 1398.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1400 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1400, provided that the antibody has the 6 CDRs of antibody 1400.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1401 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1401, provided that the antibody has the 6 CDRs of antibody 1401.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1402 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1402, provided that the antibody has the 6 CDRs of antibody 1402.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1404 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1404, provided that the antibody has the 6 CDRs of antibody 1404.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1409 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1409, provided that the antibody has the 6 CDRs of antibody 1409.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1410 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1410, provided that the antibody has the 6 CDRs of antibody 1410.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1412 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1412, provided that the antibody has the 6 CDRs of antibody 1412.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1414 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1414, provided that the antibody has the 6 CDRs of antibody 1414.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1415 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1415, provided that the antibody has the 6 CDRs of antibody 1415.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1416 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1416, provided that the antibody has the 6 CDRs of antibody 1416.
  • the present invention provides an antibody that specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • VH variable heavy
  • VL variable light
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1345.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1347.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1350.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1351.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1363.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1364.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1397.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1398.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1400.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1401.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1402.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1404.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1409.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1410.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1412. In one embodiment, the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1414.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1415.
  • the antibody specifically binds KL49 at the surface of Acinetobacter baumannii bacteria, wherein the antibody comprises the VH and VL domain sequences of antibody 1416.
  • the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • the antibody comprises the VH and VL domain sequences of antibody 1345.
  • the antibody comprises the VH and VL domain sequences of antibody 1347.
  • the antibody comprises the VH and VL domain sequences of antibody 1350.
  • the antibody comprises the VH and VL domain sequences of antibody 1351.
  • the antibody comprises the VH and VL domain sequences of antibody 1363.
  • the antibody comprises the VH and VL domain sequences of antibody 1364.
  • the antibody comprises the VH and VL domain sequences of antibody 1397.
  • the antibody comprises the VH and VL domain sequences of antibody 1398.
  • the antibody comprises the VH and VL domain sequences of antibody 1400.
  • the antibody comprises the VH and VL domain sequences of antibody 1401.
  • the antibody comprises the VH and VL domain sequences of antibody 1402.
  • the antibody comprises the VH and VL domain sequences of antibody 1404.
  • the antibody comprises the VH and VL domain sequences of antibody 1409.
  • the antibody comprises the VH and VL domain sequences of antibody 1410.
  • the antibody comprises the VH and VL domain sequences of antibody 1412.
  • the antibody comprises the VH and VL domain sequences of antibody 1414.
  • the antibody comprises the VH and VL domain sequences of antibody 1415.
  • the antibody comprises the VH and VL domain sequences of antibody 1416.
  • the antibody is selected from the group consisting of antibodies 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, and 1416. In one embodiment, the antibody is antibody 1345.
  • the antibody is antibody 1347.
  • the antibody is antibody 1350.
  • the antibody is antibody 1351.
  • the antibody is antibody 1363.
  • the antibody is antibody 1364.
  • the antibody is antibody 1397.
  • the antibody is antibody 1398.
  • the antibody is antibody 1400.
  • the antibody is antibody 1401.
  • the antibody is antibody 1402.
  • the antibody is antibody 1404.
  • the antibody is antibody 1409.
  • the antibody is antibody 1410.
  • the antibody is antibody 1412.
  • the antibody is antibody 1414.
  • the antibody is antibody 1415.
  • the antibody is antibody 1416.
  • Antibodies are provided which bind to the same epitope on KL49 as an antibody described anywhere herein.
  • An antibody which binds to the same epitope as antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1345, e-g- as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1347, e-g- as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1350, e-g- as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1351, e-g- as defined by its VH and VL sequences. In one embodiment, an antibody is provided which binds to the same epitope as antibody 1363, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1364, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1397, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1398, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1400, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1401, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1402, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1404, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1409, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1410, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1412, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1414, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1415, e.g. as defined by its VH and VL sequences.
  • an antibody which binds to the same epitope as antibody 1416, e.g. as defined by its VH and VL sequences.
  • An antibody may contact KL49 with a footprint that fully or partly overlaps with that of an antibody disclosed anywhere herein.
  • competition between antibodies may be determined, for example using SPR, and antibodies are provided which compete for binding to KL49 (compete for binding to their epitope) with an IgG antibody as described anywhere herein.
  • An antibody of the present invention may be one which competes for binding to KL49 with any anti-KL49 antibody described herein, such as antibodies 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, and 1416, e.g. as defined by their respective VH and VL sequences.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1345.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1347.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1350.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1351.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1363.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1364.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1397.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1398.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1400.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1401.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1402.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1404.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1409.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1410.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1412.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1414.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1415.
  • An antibody of the present invention may be one which competes for binding to KL49 with antibody 1416.
  • a nucleic acid sequence provided by the invention may comprise a sequence that encodes a VH domain and/or an VL domain of an anti-KL49 antibody as defined anywhere herein.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1347.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1350.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1351.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1404.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody 1412.
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the nucleic acid may comprise a sequence that encodes a VH domain and/or a VL domain of antibody
  • the antibody as defined anywhere herein shows complement-dependent cytotoxic activity (CDC) activity.
  • An antibody as defined anywhere herein may be a human IgGl or human IgG4.
  • the antibody is a human IgGl .
  • the antibody is a human IgGl comprising a constant region sequence of SEQ ID NO: 418.
  • the antibody is a human IgG4.
  • the antibody is a human IgG4 comprising a constant region sequence of SEQ ID NO: 436.
  • An antibody as defined anywhere herein may be a human IgAl (e.g., comprising a constant region sequence SEQ ID NO: 484) or human IgA2 (e.g., comprising a constant region sequence SEQ ID NO: 485).
  • An antibody as defined anywhere herein may comprise kappa (K) light chain constant regions, preferably constant domain sequence SEQ ID NO: 448.
  • the present invention provides a vector comprising a nucleic acid as defined anywhere herein; optionally wherein the vector is a CHO vector.
  • the present invention provides a host cell comprising a nucleic acid as defined anywhere herein or a vector as defined anywhere herein.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody as defined anywhere herein and a pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an isolated nucleic acid encoding an antibody as defined anywhere herein, or an isolated nucleic acid as defined anywhere herein, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration via injection.
  • the pharmaceutical composition is formulated for intravenous, intramuscular or subcutaneous administration.
  • the pharmaceutical composition further comprises at least one further therapeutic agent.
  • the further therapeutic agent is at least one, preferably one or two, further antibodies.
  • the further therapeutic agent is carbapenem.
  • the further therapeutic agent is colistin.
  • the pharmaceutical composition comprises a first antibody that specifically binds to Oxa-23 and a second antibody that specifically binds to OC1 LOS.
  • the pharmaceutical composition comprises a first antibody that specifically binds Oxa- 23 and a second antibody that specifically binds KL49.
  • the pharmaceutical composition comprises a first antibody that specifically binds OC1 LOS and a second antibody that specifically binds KL49.
  • the pharmaceutical composition comprises a first antibody that specifically binds Oxa- 23, a second antibody that specifically binds OC1 LOS, and a third antibody that specifically binds KL49.
  • the present invention provides a diagnostic kit comprising at least one antibody as defined anywhere herein.
  • the diagnostic kit comprises a first antibody that specifically binds Oxa-23 and a second antibody that specifically binds OC1 LOS.
  • the diagnostic kit comprises a first antibody that specifically binds Oxa-23 and a second antibody that specifically binds KL49.
  • the diagnostic kit comprises a first antibody that specifically binds OC1 LOS and a second antibody that specifically binds KL49.
  • the diagnostic kit comprises a first antibody that specifically binds Oxa-23, a second antibody that specifically binds OC1 LOS, and a third antibody that specifically binds KL49.
  • kits comprising a pharmaceutical composition as defined anywhere herein.
  • the kit further comprises at least one further therapeutic agent.
  • the further therapeutic agent is a further pharmaceutical composition comprising at least one, preferably one or two, further antibodies.
  • the kit further comprises carbapenem.
  • the kit further comprises colistin.
  • the at least one further antibody is selected from: an antibody that specifically binds Oxa-23; an antibody that specifically binds OC1 LOS; and an antibody that specifically binds KL49.
  • the kit comprises a first antibody that specifically binds Oxa-23 and a second antibody that specifically binds OC1 LOS.
  • the kit comprises a first antibody that specifically binds Oxa-23 and a second antibody that specifically binds KL49.
  • the kit comprises a first antibody that specifically binds OC1 LOS and a second antibody that specifically binds KL49.
  • the kit comprises a first antibody that specifically binds Oxa-23, a second antibody that specifically binds OC1 LOS, and a third antibody that specifically binds KL49.
  • the kit further comprises a label or instructions for use to prevent and/or treat a bacterial infection caused by Acinetobacter baumannii in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody.
  • the antibody is contained in a sealed container.
  • the kit contains instructions for simultaneous, separate or sequential administration of the therapeutic agents therein.
  • An antibody as defined anywhere herein or a composition as defined anywhere herein may be provided for use as a medicament.
  • An antibody as defined anywhere herein or a composition as defined anywhere herein may be provided for use in a method of treating a bacterial infection caused by Acinetobacter baumannii, said method comprising administering the antibody or composition to a patient.
  • the antibody as defined anywhere herein, or the composition as defined anywhere herein may be provided for use in a method of preventing a bacterial infection caused by Acinetobacter baumannii, said method comprising administering the antibody or composition to a patient.
  • Oxa-23 is administered to a patient
  • the presence of Oxa-23 may already have been determined in a sample from that patient, although this is not essential.
  • KL49 is administered to a patient
  • the presence of KL49 may already have been determined in a sample from that patient, although this is not essential.
  • the present invention provides a method of treating a bacterial infection caused by Acinetobacter baumannii in a patient comprising administering to said patient a therapeutically effective amount of an antibody as defined anywhere herein, or a composition as defined anywhere herein.
  • the present invention provides a method of preventing a bacterial infection caused by Acinetobacter baumannii in a patient comprising administering to said patient a therapeutically effective amount of an antibody as defined anywhere herein, or a composition as defined anywhere herein.
  • the bacterial infection caused by Acinetobacter baumannii is a nosocomial bacterial infection caused by Acinetobacter baumannii.
  • the patient has a lower respiratory tract infection, for example pneumonia.
  • the patient has sepsis.
  • the patient has bacteremia.
  • the method further comprises administering at least one further therapeutic agent.
  • the administration of the further therapeutic agent is simultaneous, separate or sequential.
  • the further therapeutic agent is at least one, preferably one or two, further antibodies.
  • the method comprises administering a first antibody that specifically binds Oxa-23 and a second antibody that specifically binds OC1 LOS.
  • the method comprises administering a first antibody that specifically binds Oxa-23 and a second antibody that specifically binds KL49.
  • the method comprises administering a first antibody that specifically binds OC1 LOS and a second antibody that specifically binds KL49.
  • the method comprises administering a first antibody that specifically binds Oxa-23, a second antibody that specifically binds OC1 LOS, and a third antibody that specifically binds KL49.
  • the method further comprises administering carbapenem.
  • the method further comprises administering colistin.
  • an antibody as defined anywhere herein, for determining the presence or absence of Acinetobacter baumannii in a sample. Determining the presence of Acinetobacter baumannii in a sample can be used for diagnosis of an infection caused by Acinetobacter baumannii in a patient.
  • a method of determining the presence or absence of Acinetobacter baumannii in a sample may comprise contacting the sample with an antibody as defined anywhere herein; and testing for binding between the antibody and Acinetobacter baumannii in the sample; wherein detection of binding indicates the presence of Acinetobacter baumannii in the sample and wherein absence of binding indicates the absence of Acinetobacter baumannii in the sample.
  • an antibody as defined anywhere herein that specifically binds to Oxa-23 for determining the presence or absence of Oxa-23 in a sample. Determining the presence of Oxa-23 in a sample can be used for determining a treatment protocol in a patient. For example, a patient may be identified for treatment with an antibody that specifically binds to Oxa-23 if the presence of Oxa-23 has been determined in a sample from that patient. The patient may or may not have already been diagnosed as having been infected with Acinetobacter baumannii.
  • an antibody as defined anywhere herein that specifically binds to OC1 LOS for determining the presence or absence of OC1 LOS in a sample. Determining the presence of OC1 LOS in a sample can be used for determining a treatment protocol in a patient. For example, a patient may be identified for treatment with an antibody that specifically binds to OC1 LOS if the presence of OC1 LOS has been determined in a sample from that patient. The patient may or may not have already been diagnosed as having been infected with Acinetobacter baumannii.
  • an antibody as defined anywhere herein that specifically binds to KL49 for determining the presence or absence of KL49 in a sample. Determining the presence of KL49 in a sample can be used for determining a treatment protocol in a patient. For example, a patient may be identified for treatment with an antibody that specifically binds to KL49 if the presence of KL49 has been determined in a sample from that patient. The patient may or may not have already been diagnosed as having been infected with Acinetobacter baumannii.
  • the antibody is conjugated to a detectable label.
  • the sample has been obtained from a human who has been or is suspected of having been infected with Acinetobacter baumannii. In one embodiment, the sample has been obtained from a human who has been or is suspected of having been infected with Acinetobacter baumannii who exhibits one or more symptoms of a bacterial infection. In one embodiment, the sample is a serum, plasma, or whole blood sample, an oral or nasal swab, urine, faeces, or cerebrospinal fluid (CFS), or wherein the sample is from any suspected Acinetobacter baumannii infected organ or tissue.
  • CFS cerebrospinal fluid
  • a diagnostic kit is provided for the use as defined anywhere herein, or the method as defined anywhere herein.
  • the diagnostic kit may comprise an antibody as defined anywhere herein, and optionally one or more buffering solutions.
  • the diagnostic kit comprises a first reagent comprising the antibody as defined anywhere herein, and a second reagent comprising a detector molecule that binds to the first reagent.
  • the detector molecule is an antibody that comprises or is conjugated to a detectable label.
  • Figure la Time resolved core genome phylogeny for GC2 A. baumannii isolates in a Ho Chi Minh ICU. Shading indicates the period during which the carbapenem antibiotic imipenem was used for the empirical treatment of VAP in the ICU. Labelled A-E are the five carbapenem resistant genomic subclades of GC2. The capsule K- locus subtype for the 10 strains tested for OMV production are also listed on the right. Marked with asterisks (*) are 4 strains from which OMVs have been successfully generated and used for immunisation of Kymab Intellisellect Transgenic mice.
  • FIG. lb Scanning electron microscope images of un-fixed OMV preparations generated from a A. baumannii clinical isolates used for immunisation.
  • FIG. 2b Polyclonal serum responses of Kymab Intellisellect Transgenic mice immunised with a mixed pool of 4 GC2 A. baumannii OMVs to the immunising OMVs as determined by ELISA, (a) Kinetics of the antigen specific IgGl response to the 4 GC2 A. baumannii OMVs used for immunisation. The total antigen specific IgGl response to the 4 individual GC2 A. baumannii OMVs used for immunisation (BAL 084, BAL 191, BAL 215 and BAL 276 in bold) is comparable to the response to 2 additional GC2 A.
  • FIG. 1 Gating strategy for sorting antigen-specific IgG+ B cells from the spleens of GC2 CRAB OMV- immunised mice.
  • FIG. 4a Sunspot plot of the 951 paired VH and VL chain sequences recovered from the spleens of 4 Kymab Intellisellect Transgenic mice immunised with GC2 CRAB OMVs. Each VH and VL paired sequence is represented by a circle, coloured by the individual mouse from which it was derived. Sequences within a lineage, inferred to have derived from a common B cell progenitor are connected by black lines.
  • Figure 4b Table indicating number of IgH&L paired sequences, proportion mapping to high-quality sequences and apportioned to clusters of related sequences indicative of an actively evolving B cell response to an immunogen.
  • FIG. 5a Comparison of mAb binding to GC2 A. baumannii OMVs and whole, unfixed bacterial cells as determined by ELISA.
  • Figure 5b Selection of mAbs for CHO expression and purification based on binding of both intact bacterial cell wall and ability to trigger deposition of C3b as described above. Examples of selections for subsequent CHO expression are depicted in bold.
  • Figure 7a Table indicating identified targets for each mAb. Methods used include phylogenetic information gleaned from HCI (see above), serological expression cloning using a genomic phage library (SEC) and western blot with specific mAb (WB). The mAbs in bold (*) were tested in an in vivo challenge model of A. baumannii to demonstrate therapeutic efficacy.
  • FIG. 7b Example western blot analysis reveals mAb binding three distinct targets; a high molecular weight target (KL49 capsule-upper panel), lOkD target (OC1 LOS-middle panel), and a 30kD protein (Oxa- 23 -lower panel). 5.
  • the present invention provides monoclonal antibodies for diagnosis and treatment in patients of bacterial infection caused by Acinetobacter baumannii.
  • the term "about” is used to modify, for example, the quantity of an ingredient in a composition, concentration, volume, process temperature, process time, yield, flow rate, pressure, and like values, and ranges thereof, employed in describing the examples of the disclosure.
  • the term “about” refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making compounds, compositions, concentrates or use formulations; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of starting materials or ingredients used to carry out the methods, and like proximate considerations.
  • administer refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., an antibody provided herein, or its encoding nucleic acid e.g. in an expression vector) into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, inhalation e.g. nebulisation and/or any other method of physical delivery described herein or known in the art.
  • a substance as it exists outside the body (e.g., an antibody provided herein, or its encoding nucleic acid e.g. in an expression vector) into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, inhalation e.g. nebulisation and/or any other method of physical delivery described herein or known in the art.
  • administration of the substance typically occurs after the onset of the infection or symptoms thereof.
  • an infection, or symptoms thereof are being prevented, administration of the substance typically occurs before the onset of the infection
  • antibody immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule.
  • a target such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule.
  • the term "antibody” encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies (including dual binding antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity.
  • the term “antibody” can also refer to a Y-shaped glycoprotein with a molecular weight of approximately 150 kDa that is made up of four polypeptide chains: two light (L) chains and two heavy (H) chains.
  • Ig heavy chain isotypes denoted by the Greek letters alpha (a), delta (8), epsilon (e), gamma (y), and mu (p).
  • the type of heavy chain defines the class of antibody, i.e., IgA, IgD, IgE, IgG, and IgM, respectively.
  • the y and a classes are further divided into subclasses on the basis of differences in the constant domain sequence and function, e.g., IgGl, hIgG2, mIgG2A, mIgG2B, IgG3, IgG4, IgAl and IgA2.
  • immunoglobulin light chains X and K.
  • variable region refers to the amino-terminal domains of the heavy or light chain of the antibody.
  • the variable domains of the heavy chain and light chain may be referred to as "VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.
  • An example of antibodies are heavy chain-only (i.e., H2) antibodies that comprise a dimer of a heavy chain (5'- VH-(optional Hinge)-CH2-CH3-3') and are devoid of a light chain.
  • the antibodies described herein may be oligoclonal, polyclonal, monoclonal (including full-length monoclonal antibodies), camelised, chimeric, CDR-grafted, multi-specific, bi-specific (including dualbinding antibodies), catalytic, chimeric, humanized, fully human, anti-idiotypic, including antibodies that can be labelled in soluble or bound form as well as fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences provided by known techniques.
  • An antibody may be from any species.
  • Antibodies described herein can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.
  • antigen binding domain refers to that portion of an antibody which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g. the complementarity determining regions (CDRs)).
  • the antigen binding region can be derived from any animal species, such as rodents (e.g. rabbit, rat or hamster) and humans. Preferably, the antigen binding region will be of human origin.
  • Antigen binding fragments described herein can include single-chain Fvs (scFv), single- chain antibodies, single domain antibodies, domain antibodies, Fv fragments, Fab fragments, F(ab') fragments, F(ab')2 fragments, antibody fragments that exhibit the desired biological activity, disulfide-stabilised variable region (dsFv), dimeric variable region (diabody), anti-idiotypic (anti-Id) antibodies (including, e.g. anti-Id antibodies to antibodies), intrabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments and epitope-binding fragments of any of the above.
  • scFv single-chain Fvs
  • dsFv disulfide-stabilised variable region
  • dimeric variable region dimeric variable region
  • anti-Id anti-idiotypic antibodies
  • antibodies and antibody fragments described herein can include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigenbinding site. Digestion of antibodies with the enzyme, papain, results in two identical antigen-binding fragments, known also as "Fab” fragments, and a "Fc” fragment, having no antigen-binding activity but having the ability to crystallize.
  • Fab when used herein refers to a fragment of an antibody that includes one constant and one variable domain of each of the heavy and light chains.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native- sequence Fc regions and variant Fc regions.
  • the "Fc fragment” refers to the carboxy-terminal portions of both H chains held together by disulfides.
  • the effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells. Digestion of antibodies with the enzyme, pepsin, results in a F(ab')2 fragment in which the two arms of the antibody molecule remain linked and comprise two-antigen binding sites.
  • the F(ab')2 fragment has the ability to crosslink antigen.
  • Fv when used herein refers to the minimum fragment of an antibody that retains both antigen-recognition and antigen-binding sites. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g. isomerizations, amidations) that may be present in minor amounts.
  • Monoclonal antibodies are highly specific and are directed against a single antigenic determinant or epitope.
  • polyclonal antibody preparations typically include different antibodies directed against different antigenic determinants (or epitopes).
  • monoclonal antibody encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site.
  • monoclonal antibody refers to such antibodies made in any number of ways including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals.
  • the monoclonal antibodies herein can include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies that exhibit the desired biological activity.
  • chimeric antibodies immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies that exhibit the desired biological activity.
  • humanized antibody refers to a subset of chimeric antibodies in which a "hypervariable region" from a non-human immunoglobulin (the donor antibody) replaces residues from a hypervariable region in a human immunoglobulin (recipient antibody).
  • a humanized antibody will include substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the framework regions are those of a human immunoglobulin sequence, although the framework regions may include one or more substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc.
  • CDR region refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops.
  • antigen binding sites of an antibody include six hypervariable regions: three in the VH (CDRH1, CDRH2, CDRH3), and three in the VL (CDRL1, CDRL2, CDRL3). These regions of the heavy and light chains of an antibody confer antigen-binding specificity to the antibody.
  • CDRs may be defined according to the Kabat system (see Kabat, E. A.et al., 1991, “Sequences of Proteins of Immunological Interest”, 5th edit., NIH Publication no. 91-3242, U.S. Department of Health and Human Services).
  • CDRs may be used to define CDRs, which as the system devised by Chothia et al (see Chothia, C. & Lesk, A. M., 1987, “Canonical structures for the hypervariable regions of immunoglobulins”, J. Mol. Biol., 196, 901-917) and the IMGT system (see Lefranc, M. P., 1997, “Unique database numbering system for immunogenetic analysis”, Immunol. Today, 18, 50).
  • An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs.
  • the term CDR or CDRs is used here to indicate one or several of these regions. A person skilled in the art is able to readily compare the different systems of nomenclature and determine whether a particular sequence may be defined as a CDR.
  • a "human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies and specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • the term "specifically binds to” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.
  • an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets.
  • the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g. by a radioimmunoassay (RIA).
  • authorization number or “marketing authorization number” refers to a number issued by a regulatory agency upon that agency determining that a particular medical product and/or composition may be marketed and/or offered for sale in the area under the agency’s jurisdiction.
  • regulatory agency refers to one of the agencies responsible for evaluating, e.g. the safety and efficacy of a medical product and/or composition and controlling the sales/marketing of such products and/or compositions in a given area.
  • the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EP A) in Europe are but two examples of such regulatory agencies.
  • Other non-limiting examples can include SDA, MPA, MHPRA, IMA, ANMAT, Hong Kong Department of Health-Drug Office, CDSCO, Medsafe, and KFDA.
  • carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • composition is intended to encompass a product containing the specified ingredients (e.g. an antibody) in, optionally, the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in, optionally, the specified amounts.
  • specified ingredients e.g. an antibody
  • the term "consisting essentially of' refers to those elements required for a given example. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that example.
  • an “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired effect, including a therapeutic or prophylactic result.
  • a “therapeutically effective amount” refers to the minimum concentration required to effect a measurable improvement or prevention of a particular disorder.
  • a therapeutically effective amount herein may vary according to factors such as the infection state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which toxic or detrimental effects of the antibody are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at the dosages and for periods of time necessary, to achieve the desired prophylactic result.
  • the effective amount of an antibody is from about 0.1 mg/kg (mg of antibody per kg weight of the subject) to about 100 mg/kg.
  • an effective amount of an antibody provided therein is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, 3 mg/kg, 5 mg/kg, about 10 mg/kg, about 1 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg about 90 mg/kg or about 100 mg/kg (or a range therein).
  • “effective amount” as used herein also refers to the amount of an antibody to achieve a specified result (e.g. inducing complement activation).
  • epitope refers to a localized region on the surface of an antigen that is capable of being bound to one or more antigen binding regions of an antibody, and that has antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human, that is capable of eliciting an immune response.
  • An epitope having immunogenic activity is a portion of an antigen (e.g., a polypeptide, carbohydrate or lipid molecule) that elicits an antibody response in an animal.
  • An epitope having antigenic activity is a portion of an antigen to which an antibody specifically binds as determined by any method well known in the art, for example, by the immunoassays described herein.
  • Antigenic epitopes need not necessarily be immunogenic. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. A region of a polypeptide contributing to an epitope may be contiguous amino acids of the polypeptide or the epitope may come together from two or more non-contiguous regions of the polypeptide. The epitope may or may not be a three-dimensional surface feature of the antigen. As described elsewhere herein, competition between antibodies may also be determined, for example using SPR.
  • excipients refers to inert substances which are commonly used as a diluent, vehicle, preservatives, binders, or stabilizing agent for drugs and includes, but not limited to, proteins (e.g. serum albumin, etc.), amino acids (e.g. aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g. alkyl sulfonates, caprylate, etc.), surfactants (e.g. SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g.
  • proteins e.g. serum albumin, etc.
  • amino acids e.g. aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.
  • fatty acids and phospholipids e.g. alkyl sulfonates, caprylate, etc.
  • surfactants
  • sucrose, maltose, trehalose, etc. sucrose, maltose, trehalose, etc.
  • polyols e.g. mannitol, sorbitol, etc.
  • heavy chain when used with reference to an antibody refers to five distinct types, called alpha (a), delta (8), epsilon (e), gamma (y) and mu (p), based on the amino acid sequence of the heavy chain constant domain.
  • These distinct types of heavy chains are well known and give rise to five classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including two subclasses of IgA, namely IgAl and IgA2 and four subclasses of IgG, namely IgGl, IgG2, IgG3 and IgG4.
  • the heavy chain is a human heavy chain.
  • the antibodies disclosed herein comprise a heavy chain encoded by a IgGl constant region allele, which includes, but is not limited to, human IGHGl*01, IGHG1*O2, IGHGl*03, IGHG1*O4 and IGHGl*05 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a protein encoded by a IgG4 constant region allele, which includes but is not limited to human IGHG4*01, IGHG4*02, IGHG4*03 and IGHG4*04 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the heavy chain is an IgA isotype, human IgAl or human IgA2, example amino acid sequences for which are shown in Table 2.
  • the heavy chain is a disabled IgG isotype, e.g. a disabled IgG4.
  • the antibodies comprise a human gamma 4 constant region.
  • the heavy chain constant region does not bind Fc-y receptors, and e.g. comprises a Leu235Glu mutation.
  • the heavy chain constant region comprises a Ser228Pro mutation to increase stability.
  • the heavy chain constant region is IgG4-PE.
  • the antibodies disclosed herein comprise a heavy chain constant region encoded by a murine IgGl constant region allele, which includes but is not limited to mouse IGHGl*01 or IGHG1*O2.
  • host refers to an animal, preferably a mammal, and most preferably a human.
  • host cell refers to the particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.
  • a first therapy can be administered before (e.g. 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), concurrently, or after (e.g.
  • any additional therapy can be administered in any order with the other additional therapies.
  • the antibodies can be administered in combination with one or more therapies.
  • injection device refers to a device that is designed for carrying out injections, an injection including the steps of temporarily fluidically coupling the injection device to a person's tissue, typically the subcutaneous tissue. An injection further includes administering an amount of liquid drug into the tissue and decoupling or removing the injection device from the tissue.
  • an injection device can be an intravenous device or IV device, which is a type of injection device used when the target tissue is the blood within the circulatory system, e.g. the blood in a vein.
  • IV device is a needle and syringe.
  • instructions refers to a display of written, printed or graphic matter on the immediate container of an article, for example the written material displayed on a vial containing a pharmaceutically active agent, or details on the composition and use of a product of interest included in a kit containing a composition of interest. Instructions set forth the method of the treatment as contemplated to be administered or performed.
  • an “isolated” or “purified” antibody or protein is one that has been identified, separated and/or recovered from a component of its production environment (e.g. natural or recombinant).
  • the antibody or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the antibody is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized.
  • substantially free of cellular material includes preparations of an antibody in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced.
  • an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”).
  • heterologous protein also referred to herein as a “contaminating protein”.
  • the antibody is recombinantly produced, it is also preferably substantially free of culture medium, i.e. culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the antibody is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest.
  • antibodies are isolated or purified.
  • Kabat numbering and like terms are recognized in the art and refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al., (1971) Ann. NY Acad. Sci., 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • the hypervariable region typically ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3.
  • Label refers to the addition of a detectable moiety to a polypeptide, for example, a radiolabel, fluorescent label, enzymatic label, chemiluminescent label or a biotinyl group or gold.
  • Radioisotopes or radionuclides may include 3H, 14C, 15N, 35S, 90Y, 99Tc, 115In, 1251, 1311, fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, P-galactosidase, luciferase, alkaline phosphatase.
  • Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH”), alpha- D-galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes (e.g. cyanine dyes, e.g. Cy5TM, Cy5.5TM. or Cy7TM); additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein”), other fluorescent proteins (e.g.
  • G6PDH glucose-6-phosphate dehydrogenase
  • alpha- D-galactosidase alpha- D-galactosidase
  • glucose oxydase glucose amylase
  • carbonic anhydrase acetylcholinesterase
  • fluorophores such as lanthanide cryptates and chelates e.g.
  • chemoluminescent labels or chemiluminescers such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or 5 -bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof
  • light chain when used in reference to an antibody refers to the immunoglobulin light chains, of which there are two types in mammals, lambda (X) and kappa (K).
  • the light chain is a human light chain.
  • the light chain constant region is a human constant region. In the human population, multiple light chain constant region alleles exist.
  • the nucleotide and amino acid sequences of these allelic variants are accessible on publicly available databases such as IMGT, ENSEMBL, Swiss-Prot and Uniprot.
  • the antibodies disclosed herein comprise a protein encoded by a human K constant region allele, which includes, but is not limited to, IGKC*01, IGKC*02, IGKC*03, IGKC*04 and IGKC*05 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a protein encoded by a human X constant region allele, which includes but is not limited to IGLCl*01, IGLC1*O2, IGLC2*01, IGLC2*02, IGLC2*03, IGLC3*01, IGLC3*02, IGLC3*03, IGLC3*04, IGLC6*01, IGLC7*01, IGLC7*02, and IGLC7*03 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a light chain constant region encoded by a mouse K constant region allele, which includes, but is not limited to, IGKC*01, IGKC*03 or IGKC*03 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the antibodies disclosed herein comprise a light chain constant region encoded by a mouse X constant region allele, which includes, but is not limited to, IGLCl*01, IGLC2*01 or IGLC3*01 (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Percent (%) amino acid sequence identity with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEG ALIGNTM (DNASTAR) software. In one example, the % identity is about 70%. In one example, the % identity is about 75%.
  • the % identity is about 80%. In one example, the % identity is about 85%. In one example, the % identity is about 90%. In one example, the % identity is about 92%. In one example, the % identity is about 95%. In one example, the % identity is about 97%. In one example, the % identity is about 98%. In one example, the % identity is about 99%. In one example, the % identity is 100%.
  • naturally occurring or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to those which are found in nature and not manipulated by a human being.
  • Packaging refers to how the components are organized and/or restrained into a unit fit for distribution and/or use.
  • Packaging can include, e.g. boxes, bags, syringes, ampoules, vials, tubes, clamshell packaging, barriers and/or containers to maintain sterility, labelling, etc.
  • pharmaceutically acceptable means being approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.
  • nucleic acid molecule As used herein, the term “polynucleotide,” “nucleotide,” nucleic acid” “nucleic acid molecule” and other similar terms are used interchangeable and include DNA, RNA, mRNA and the like.
  • the terms “prevent”, “preventing”, and “prevention” refer to the total or partial inhibition of the development, recurrence, onset or spread of infection, resulting from the administration of a therapy or combination of therapies provided herein (e.g. a combination of prophylactic or therapeutic agents, such as an antibody).
  • soluble refers to a polypeptide that is lacking one or more transmembrane or cytoplasmic domains found in the native or membrane-associated form.
  • the "soluble" form of a polypeptide lacks both the transmembrane domain and the cytoplasmic domain.
  • subject or “patient” refers to any animal, including, but not limited to, mammals.
  • mammal refers to any vertebrate animal that suckle their young and either give birth to living young (eutharian or placental mammals) or are egg-laying (metatharian or nonplacental mammals).
  • mammalian species include, but are not limited to, humans and other primates, including nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats (including cotton rats) and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
  • substantially all refers to refers to at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100%.
  • surfactant refers to organic substances having amphipathic structures; namely, they are composed of groups of opposing solubility tendencies, typically an oil-soluble hydrocarbon chain and a water-soluble ionic group. Surfactants can be classified, depending on the charge of the surface-active moiety, into anionic, cationic, and non- ionic surfactants. Surfactants are often used as wetting, emulsifying, solubilizing, and dispersing agents for various pharmaceutical compositions and preparations of biological materials.
  • the term “tag” refers to any type of moiety that is attached to, e.g. a polypeptide and/or a polynucleotide that encodes an antibody as described herein.
  • a polynucleotide that encodes a an antibody as described herein can contain one or more additional tag-encoding nucleotide sequences that encode e.g. a detectable moiety or a moiety that aids in affinity purification.
  • the tag and the antibody can be in the form of a fusion protein.
  • detectable or “detection” with reference to a tag refers to any tag that is capable of being visualized or wherein the presence of the tag is otherwise able to be determined and/or measured (e.g. by quantitation).
  • a non-limiting example of a detectable tag is a fluorescent tag.
  • the term “therapeutic agent” refers to any agent that can be used in the treatment, management or amelioration of a bacterial infection caused by Acinetobacter baumannii and/or a symptom related thereto.
  • the term “therapeutic agent” refers to an antibody.
  • the term “therapeutic agent” refers to an agent other than an antibody.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment, management or amelioration of a bacterial infection caused by Acinetobacter baumannii and/or one or more symptoms related thereto.
  • the term “therapy” refers to any protocol, method and/or agent that can be used in the prevention, management, treatment and/or amelioration of a bacterial infection caused by Acinetobacter baumannii.
  • the terms “therapies” and “therapy” refer to a biological therapy, supportive therapy, and/or other therapies useful in the prevention, management, treatment and/or amelioration of a bacterial infection caused by Acinetobacter baumannii known to one of skill in the art such as medical personnel.
  • treat refers to the reduction or amelioration of the progression, severity, and/or duration of a bacterial infection caused by Acinetobacter baumannii resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as an antibody).
  • therapies including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as an antibody.
  • such terms refer to the reduction of the bacterial load, and/or the inhibition or reduction of one or more symptoms associated with a bacterial infection caused by Acinetobacter baumannii.
  • Reduction of bacterial load may be measured via enumeration of cultured bacterial colonies on nutrient agar plates after plating of organ homogenates.
  • IL-6 level is measured by ELISA.
  • variable region refers to a portion of the light and heavy chains, typically about the amino-terminal 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen.
  • the variability in sequence is concentrated in those regions called complimentarily determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR).
  • CDRs complimentarily determining regions
  • FR framework regions
  • the CDRs are primarily responsible for the interaction of the antibody with antigen. Numbering of amino acid positions used herein is according to IMGT (Lefranc MP “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains”, Dev. Comp. Immunol. 27(l):55-77 (2003)).
  • the variable region is a human variable region.
  • the antibody sequence may be defined by reference to an antibody internal reference number or a SEQ ID NO. Any disclosure herein reciting an antibody internal reference number should also be taken as disclosure of the same subject- matter where the sequence defined by the antibody internal reference number is replaced by the corresponding SEQ ID NO.
  • the present antibodies bind to Oxa-23 at the surface of intact bacteria (i.e., with non-ruptured membrane/cell wall), such as on, e.g., living bacteria.
  • Oxa-23 carbapenemase enzyme is a 30kD protein expressed by the oxa-23 gene.
  • Oxa-23 is a class D P-lactamase; a major group of enzymes involved in resistance to carbapenem antibiotics (Docquier JD, Mangani S. Structure-Function Relationships of Class D Carbapenemases. Curr Drug Targets. 2016;17(9): 1061-71. doi: 10.2174/1389450116666150825115824. PMID: 26302798., the contents of which are incorporated herein by reference).
  • Oxa-23 gene encoding the Oxa-23 carbapenemase enzyme is widespread in Acinetobacter baumannii clinical isolates and compromises treatment with carbapenem antibiotics.
  • the identification of mAbs binding to Oxa-23 is highly significant.
  • the present inventors have unexpectedly found Oxa-23 is targetable by antibody in or closely associated with the Acinetobacter baumannii cell membrane which was previously unknown.
  • the present inventors have unexpectedly found that the Oxa-23 enzyme is a membrane protein, present at the surface of live bacteria.
  • the present inventors have unexpectedly found that it is possible to use antibodies to block enzymatic function of Oxa-23, to render Acinetobacter baumannii susceptible to carbapenems.
  • the present inventors have unexpectedly found that Oxa-23 binding epitopes are highly conserved across strains of the G2 clone of Acinetobacter baumannii.
  • the present invention has demonstrated that targeting the Oxa-23 enzyme is highly attractive as a target for antibodybased diagnosis and treatment of Acinetobacter baumannii.
  • an antibody targeting Oxa-23 at the surface of live bacteria can be considered as a pan- Acinetobacter baumannii antibody.
  • the antibodies of the invention that specifically bind to Oxa-23 are of great importance for diagnosis of an infection caused by Acinetobacter baumannii and for treatment of an infection caused by Acinetobacter baumannii in patients, particularly where Oxa-23 has been determined to be present in the patient.
  • Oxa-23 had not been considered as a potential antibody target at the surface of bacteria since it was widely considered to be associated with the periplasm of the bacteria (Chiu CH, Liu YH, Wang YC, Lee YT, Kuo SC, Chen TL, Lin JC, Wang FD.
  • SecA inhibitors in combination with carbapenems against carbapenem-hydrolysing class D P-lactamase-producing Acinetobacter baumannii. J Antimicrob Chemother. 2016 Dec;71(12):3441-3448. doi:
  • the antibody is a fully human antibody, such as a fully human monoclonal antibody.
  • Antibody 1348 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 21, comprising the CDRH1 amino acid sequence of SEQ ID No: 22 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 23 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 24 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 20.
  • Antibody 1348 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 26, comprising the CDRL1 amino acid sequence of SEQ ID No: 27 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 29 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 25.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1349 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 31, comprising the CDRH1 amino acid sequence of SEQ ID No: 32 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 34 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 30.
  • Antibody 1349 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 36, comprising the CDRL1 amino acid sequence of SEQ ID No: 37 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 38 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 35.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the heavy chain constant region sequence is SEQ ID NO: 418.
  • the light chain constant region sequence is SEQ ID NO: 448.
  • the antibody comprises a heavy chain comprising heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 31 and heavy chain constant region amino acid sequence of SEQ ID NO: 418. In one embodiment, the antibody comprises a light chain comprising light chain variable region (VL) amino acid sequence of SEQ ID NO: 36 and light chain constant region amino acid sequence of SEQ ID NO: 448. In one embodiment, the antibody is antibody 1349.
  • Antibody 1349 has heavy chain variable region (VH) amino acid sequence SEQ ID NO: 31 , heavy chain constant region amino acid sequence SEQ ID NO: 418, light chain variable region (VL) amino acid sequence SEQ ID NO: 36, and light chain constant region amino acid sequence SEQ ID NO: 448).
  • Antibody 1540 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 21, comprising the CDRH1 amino acid sequence of SEQ ID No: 22 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 23 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 24 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 20.
  • Antibody 1 40 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 26, comprising the CDRL1 amino acid sequence of SEQ ID No: 27 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 29 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 25.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1548 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 172, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 173 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 174 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 171.
  • Antibody 1548 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 176, comprising the CDRL1 amino acid sequence of SEQ ID No: 149 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 177 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 178 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 175.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1550 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 180, comprising the CDRH1 amino acid sequence of SEQ ID No: 181 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 173 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 182 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 179.
  • Antibody 1550 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 184, comprising the CDRL1 amino acid sequence of SEQ ID No: 185 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 186 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 183.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the present antibodies bind to OC1 LOS at the surface of intact bacteria (i.e., with non-ruptured membrane/cell wall), such as on, e.g., living bacteria.
  • LPS and LOS Bacterial lipopolysaccharides
  • LPS and LOS include a core oligosaccharide combined with repeated saccharide units that extend out from the cell surface.
  • LPS and LOS constitute a protective barrier known to cover the wall of bacteria.
  • OC1 LOS is a lOkD lipooligosaccharide expressed by the OC1 gene. Detail of its structure can be found in Kenyon JJ, Nigro SJ, Hall RM. Variation in the OC locus of Acinetobacter baumannii genomes predicts extensive structural diversity in the lipooligosaccharide. PLoS One. 2014 Sep 23;9(9):el07833. doi: 10.1371/joumal.pone.0107833. PMID: 25247305; PMCID: PMC4172580, the contents of which are incorporated herein by reference.
  • the present inventors have unexpectedly found not only that OC1 LOS can be targeted by diagnostic and therapeutic antibodies but also that its binding epitopes are highly conserved across strains of the G2 clone of Acinetobacter baumannii. In particular, it is thought that its binding epitopes are conserved across at least 70% of strains of the G2 clone of Acinetobacter baumannii. As such, targeting the OC 1 LOS is highly attractive as a target for antibody-based diagnosis and treatment of Acinetobacter baumannii. In other words, an antibody targeting OC1 LOS at the surface of live bacteria can be considered as a pan- Acinetobacter baumannii antibody.
  • the antibodies of the invention bind to the core oligosaccharide of OC1 LOS.
  • the antibodies of the invention that specifically bind to OC1 LOS are of great importance for diagnosis of an infection caused by Acinetobacter baumannii and for treatment of an infection caused by Acinetobacter baumannii in patients, particularly where OC1 LOS has been determined to be present in the patient.
  • the antibody is a fully human antibody, such as a fully human monoclonal antibody.
  • Antibody 1042 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 188, comprising the CDRH1 amino acid sequence of SEQ ID No: 32 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 189 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 187.
  • Antibody 1042 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 191, comprising the CDRL1 amino acid sequence of SEQ ID No: 37 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 192 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 190.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1043 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 194, comprising the CDRH1 amino acid sequence of SEQ ID No: 195 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 196 (IMGT).
  • VH heavy chain variable region
  • IMGT CDRH1 amino acid sequence of SEQ ID No: 195
  • IMGT CDRH2 amino acid sequence of SEQ ID No: 33
  • IMGT CDRH3 amino acid sequence of SEQ ID No: 196
  • Antibody 1043 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 198, comprising the CDRL1 amino acid sequence of SEQ ID No: 37 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 9 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 199 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 197.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1403 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 88, comprising the CDRH1 amino acid sequence of SEQ ID No: 22 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 89 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 90 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 87.
  • Antibody 1403 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 92, comprising the CDRL1 amino acid sequence of SEQ ID No: 93 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 94 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 91.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1405 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 103, comprising the CDRH1 amino acid sequence of SEQ ID No: 104 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 105 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 102.
  • Antibody 1405 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 107, comprising the CDRL1 amino acid sequence of SEQ ID No: 27 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 108 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 106.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1407 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 110, comprising the CDRH1 amino acid sequence of SEQ ID No: 111 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 112 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 109.
  • Antibody 1407 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 114, comprising the CDRL1 amino acid sequence of SEQ ID No: 115 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 116 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 113.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1408 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 118, comprising the CDRH1 amino acid sequence of SEQ ID No: 104 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 119 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 117.
  • Antibody 1408 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 121, comprising the CDRL1 amino acid sequence of SEQ ID No: 122 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 28 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 123 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 120.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1413 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 144, comprising the CDRH1 amino acid sequence of SEQ ID No: 145 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 33 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 146 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 143.
  • Antibody 1413 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 148, comprising the CDRL1 amino acid sequence of SEQ ID No: 149 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 150 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 151 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 147.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the present antibodies bind to KL49 at the surface of intact bacteria (i.e., with non-ruptured membrane/cell wall), such as on, e.g., living bacteria.
  • KL49 is a form of capsular polysaccharide (CPS) produced by strains of A. baumannii and surrounding the outer cell membrane.
  • CPS capsular polysaccharide
  • CPS is a densely packed high-molecular weight carbohydrate composed of repeating oligosaccharide units, providing a barrier against environmental stressors and confers resistance against antimicrobial compounds and immunological protective mechanisms.
  • KL49 capsule The presence of the KL49 capsule is associated with hyper virulence and increased mortality, and Acinetobacter baumannii KL49 is currently emerging as the major clone in South East Asia (Zhou K, Tang X, Wang L, Guo Z, Xiao S, Wang Q, Zhuo C. An Emerging Clone (ST457) of Acinetobacter baumannii Clonal Complex 92 With Enhanced Virulence and Increasing Endemicity in South China. Clin Infect Dis. 2018 Nov 13;67(suppl_2):S179-S188. doi: 10. 1093/cid/ciy691. PMID: 30423046, the contents of which are incorporated herein by reference).
  • the KL49 protein is present at the surface of live bacteria and can be targeted by diagnostic and therapeutic antibodies is of significant value for enabling early diagnosis and treatment of these patients.
  • the antibodies of the invention that specifically bind to KL49 are of great importance for diagnosis of an infection caused by Acinetobacter baumannii and for treatment of an infection caused by Acinetobacter baumannii in patients, particularly where KL49 has been determined to be present in the patient.
  • the antibody is a fully human antibody, such as a fully human monoclonal antibody.
  • Antibody 1345 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 2, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 4 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 5 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 1.
  • Antibody 1345 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 7, comprising the CDRL1 amino acid sequence of SEQ ID No: 8 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 9 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 10 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 6.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1347 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 12, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 14 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 11.
  • Antibody 1347 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 16, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 19 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 15.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1350 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 40, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 41 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 39.
  • Antibody 1350 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 16, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 19 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 42.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1351 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 44, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 45 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 43.
  • Antibody 1351 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 47, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 10 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 46.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1363 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 49, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 50 (IMGT).
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 48.
  • Antibody 1363 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 52, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 19 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 1.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1364 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 54, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 55 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 53.
  • Antibody 1364 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 57, comprising the CDRL1 amino acid sequence of SEQ ID No: 58 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 59 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 56.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1397 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 61, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 62 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 60.
  • Antibody 1397 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 64, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 59 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 63.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1398 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 66, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 67 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 65.
  • Antibody 1398 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 69, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 59 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 68.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1400 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 71, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 72 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 70.
  • Antibody 1400 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 74, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 59 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 73.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1401 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 76, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 77 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 75.
  • Antibody 1401 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 79, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 80 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 78.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1402 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 82, comprising the CDRH1 amino acid sequence of SEQ ID No: 3(IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 83 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 81.
  • Antibody 1402 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 85, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 86 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 84.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1404 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 96, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 97 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 98 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 95.
  • Antibody 1404 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 100, comprising the CDRL1 amino acid sequence of SEQ ID No: 101 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 59 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 99.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1409 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 125, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 126 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 124.
  • Antibody 1409 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 128, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 129 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 127.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1410 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 131, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 132 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 130.
  • Antibody 1410 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 134, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 135 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 133.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1412 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 137, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 138 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 139 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 136.
  • Antibody 1412 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 141, comprising the CDRL1 amino acid sequence of SEQ ID No: 142 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 86 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 140.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1414 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 153, comprising the CDRH1 amino acid sequence of SEQ ID No: 154 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 155 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 156 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 152.
  • Antibody 1414 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 158, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 159 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 157.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1415 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 161, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 162(IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 163 (IMGT).
  • VH heavy chain variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 160.
  • Antibody 1415 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 165, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 135 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 164.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • Antibody 1416 has a heavy chain variable region (VH) amino acid sequence of SEQ ID No: 167, comprising the CDRH1 amino acid sequence of SEQ ID No: 3 (IMGT), the CDRH2 amino acid sequence of SEQ ID No: 13 (IMGT), and the CDRH3 amino acid sequence of SEQ ID No: 168 (IMGT).
  • VH variable region
  • the heavy chain nucleic acid sequence of the VH domain is SEQ ID No: 166.
  • Antibody 1416 has a light chain variable region (VL) amino acid sequence of SEQ ID No: 170, comprising the CDRL1 amino acid sequence of SEQ ID No: 17 (IMGT), the CDRL2 amino acid sequence of SEQ ID No: 18 (IMGT), and the CDRL3 amino acid sequence of SEQ ID No: 10 (IMGT).
  • the light chain nucleic acid sequence of the VL domain is SEQ ID No: 169.
  • the VH domain may be combined with any of the heavy chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the VL domain may be combined with any of the light chain constant region sequences described herein (the nucleotide and corresponding amino acid sequences of which are set out in Table 2).
  • the heavy chain constant region sequence is SEQ ID NO: 418. In one embodiment, the light chain constant region sequence is SEQ ID NO: 448. In one embodiment, the antibody comprises a heavy chain comprising heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 167 and heavy chain constant region amino acid sequence of SEQ ID NO: 418. In one embodiment, the antibody comprises a light chain comprising light chain variable region (VL) amino acid sequence of SEQ ID NO: 170 and light chain constant region amino acid sequence of SEQ ID NO: 448. In one embodiment, the antibody is antibody 1416.
  • Antibody 1416 has heavy chain variable region (VH) amino acid sequence SEQ ID NO: 167, heavy chain constant region amino acid sequence SEQ ID NO: 418, light chain variable region (VL) amino acid sequence SEQ ID NO: 170, and light chain constant region amino acid sequence SEQ ID NO: 448).
  • VH heavy chain variable region
  • VL light chain variable region amino acid sequence
  • SEQ ID NO: 448 light chain constant region amino acid sequence
  • An antibody that specifically binds at the surface of Acinetobacter baumannii bacteria can be identified, for example, by immunoassays (e.g. ELISA), BIAcoreTM, or other techniques known to those of skill in the art.
  • immunoassays e.g. ELISA
  • BIAcoreTM e.g. BIAcoreTM
  • an antibody binds specifically to a target when it binds with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme- linked immunosorbent assays (ELISAs).
  • RIA radioimmunoassays
  • ELISAs enzyme- linked immunosorbent assays
  • a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times (such as more than 15 times, more than 20 times, more than 50 times or more than 100 times) background. See, e.g. Paul, ed., 1989, Fundamental Immunology Second Edition, Raven Press, New Y ork at pages 332-336 for a discussion regarding antibody specificity.
  • Any suitable method may be used to determine whether an antibody binds at the surface of Acinetobacter baumannii bacteria.
  • Such a method may comprise an ELISA to determine specificity of antibodies.
  • An antibody may be said to bind its antigen if the level of binding to antigen is at least 2.5-fold greater, e.g., at least 10 fold greater, than binding to a control antigen. Binding between an antibody and its cognate antigen is often referred to as specific binding. Precise identification of the residues bound by an antibody can usually be obtained using x-ray crystallography. This technique may be used to determine that an antibody described herein binds one or more residues of Oxa-23 enzyme, OC1 LOS, or KL49 at the surface of Acinetobacter baumannii bacteria.
  • Measurements for binding assays can conveniently use an indirect whole bacterial cell ELISA.
  • measurements for binding assays can conveniently use OMVs rather than bacterial cells.
  • binding to OMVs suitably may be used as the plate-coating antigen. If the antibody epitope is a linear continuous epitope, then binding and binding affinity can be determined using synthetic purified peptide sequences.
  • the particular binding antigen (e.g. Oxa-23, OC1 LOS, or KL49) of an antibody may be determined using a phage expression library e.g. as described in Example 5.
  • a phage expression library e.g. as described in Example 5.
  • shotgun A. Baumannii genomic DNA is incorporated into a phage expression library.
  • the antibody is then screened for reactivity with phage plaques from the expression library and the individual phage binding to the antibody is identified.
  • the identified phage is sequenced, and the sequencing information used to elucidate the binding antigen of the antibody.
  • a suitable phage method for antigen identification will be known to a person skilled in the art.
  • a suitable phage method is described in Lodes MJ, Dillon DC, Houghton RL, Skeiky YA. Expression cloning. Methods Mol Med. 2004;94:91-106. doi: 10.1385/1-59259-679-7:91. PMID: 1495
  • Identification of Oxa-23, OC1 LOS, or KL49 as the binding antigen may also be carried out using western blotting on specific GC2 strains genetically identified as producing the respective molecule.
  • a high-content imaging (HCI) assay and a system for image-based morphological profiling can be used to screen binding of mAbs to panels of clinically relevant CRAB isolates to assess binding affinity and crossreactivity.
  • HCI high-content imaging
  • CRAB isolates to assess binding affinity and crossreactivity.
  • a novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131. Sci Rep. 2020 Jul 24; 10( 1 ): 12414. doi: 10.1038/s41598-020-69300-8, the contents of which are incorporated herein by reference).
  • SPR might be used to determine binding of an antibody to Oxa-23, OC1 LOS, or KL49 out of the cell wall context.
  • a suitable SPR protocol is set out below:
  • mouse anti-human or other relevant human, rat or non-human vertebrate antibody constant region species-matched
  • IgG to a biosensor chip (e.g. dextran-coated gold chip) such as by primary amine coupling.
  • a biosensor chip e.g. dextran-coated gold chip
  • an anti-Fc antibody may be covalently immobilised on the chip surface using amine coupling.
  • the buffer may optionally be 0.01 M HEPES (4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid), 0.15 M NaCl and 0.05% v/v surfactant P20 in aqueous solution, buffered to pH 7.4; and
  • KD, Ka and Kd may then be calculated.
  • SPR can be carried out using any standard SPR apparatus, such as by BiacoreTM or using the ProteOn XPR36TM (Bio-Rad®).
  • Regeneration of the capture surface can be carried out with 3 M magnesium chloride solution. This removes the captured test antibody and allows the surface to be used for another interaction.
  • the binding data can be fitted to 1 : 1 model inherent using standard techniques, e.g. using analysis software such as Biacore Insight Evaluation Software.
  • Methods of determining binding can also be used to determine competition between molecules such as between a test antibody and a known antibody and may be performed with the test antibody and known antibody in IgG format, or optionally in scFv format.
  • Methods of determining binding can also be used to determine cross-reactivity of an antibody with different clones or strains of Acinetobacter baumannii.
  • the complement cascade is a powerful serum-based mechanism leading to insertion of protein pores into the membrane of gram-negative bacteria resulting in bacterial killing. This protein pathway is triggered by antibody and as such, the ability for an antibody to trigger the complement cascade is a key functional outcome for certain antibodies of the invention.
  • C3b is cleaved from the serum C3 protein to drive the complement cascade and mAb binding to the bacterial cell membrane initiates formation of an enzymatic complex involving the complement proteins Clq, C2 and C4 that cleave C3. Therefore, detection of C3b on the bacterial membrane is a correlate for successful initiation of the complement cascade.
  • the ability of an antibody to induce complement activation may be determined by in vitro assays, such as by flow cytometry-based assay to detect mAb-induced deposition of the complement component C3b on the surface of OMVs.
  • in vitro assays such as by flow cytometry-based assay to detect mAb-induced deposition of the complement component C3b on the surface of OMVs.
  • flow cytometry-based assay to detect mAb-induced deposition of the complement component C3b on the surface of OMVs.
  • Such an assay is described in Fishinger et al., Journal of Immunological Methods, https://doi.org/10.1016Zi.iim.2019.07.002, the contents of which are incorporated by reference.
  • Such an assay is used herein in the Examples herein and involves 5 major steps:
  • the bead-OMV complexes are added to the small-scale expressed mAbs in HEK 293 supernatant, normalised to 100 pg/ml and incubated together for 3 hr at 37°C.
  • Complement proteins are prepared by reconstituting lyophilised guinea pig complement in gelatin veronal buffer and added to the bead-OMV-antibody complexes before incubation at 37°C for 15 mins. 4. A FITC-conjugated anti-C3 detection antibody is added to the bead-based complexes after washing and incubated for a further 15 mins.
  • C3b complement deposition is reported as a fold change/HuIgGl isotype control of the geomean fluorescence intensity on the FITC channel.
  • the antibody comprises VH and/or VL domain and framework regions of human germline gene segment sequences.
  • Gene segment sequences from which the exemplary antibodies described herein are derived are set out in Table 3.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV3-23*04, IGHV3-9*01, IGHV2-5*10, IGHV3-9*01, or IGHV3-30*18; and/or the J gene segment is IGHJ2*01, IGHJ3*02, IGHJ4*02, IGHJ6*02, or IGHJ5*02.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV3-23*04.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV3-9*01.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV2-5*10.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV3-9*01.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment is IGHV3-30*18.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the J gene segment is IGHJ2*01.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the J gene segment is IGHJ3*02.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the J gene segment is IGHJ4*02.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the J gene segment is IGHJ6*02.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the J gene segment is IGHJ5*02.
  • the antibody comprises an antibody VH domain which is derived from recombination of a human heavy chain V gene segment, a human heavy chain D gene segment and a human heavy chain J gene segment, wherein the V gene segment and the J gene segment for the heavy chain is the combination shown in Table 3 for any one of the antibodies.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV3-15*01, IGKV3D-15*d01, IGKV1-17*O1, IGKVl-9*d01, IGKV1D-39*O1, IGKV1-16*O2, IGKV1-6*O1, IGKV3D-15*d01, IGKV1-12*O1, or IGKV1D-16*O1; and/or the J gene segment is IGKJ4*01, IGKJ3*01, IGKJl*01, or IGKJ2*04.
  • the V gene segment is IGKV3-15*01, IGKV3D-15*d01, IGKV1-17*O1, IGKVl-9*d01, IGKV1D-39*O1, IGKV1-16*O2, IGKV1-6
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV3-15*01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment isIGKV3D-15*d01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-17*O1.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKVl-9*d01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1D-39*O1.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1- 16*02.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV 1-6*01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV3D-15*d01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment is IGKV1-12*O1.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the J gene segment is IGKJ4*01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the J gene segment is IGKJ3*01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the J gene segment is IGKJl*01.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the J gene segment is IGKJ2*04.
  • the antibody comprises an antibody VL domain which is derived from recombination of a human light chain V gene segment and a human light chain J gene segment, wherein the V gene segment and the J gene segment for the light chain is the combination shown in Table 3 for any one of the antibodies.
  • the antibody comprises an amino acid sequence which has a high level of sequence identity to the amino acid sequence of one of the exemplary antibodies described herein and set out in Table 1.
  • the amino acid sequence is at least 70% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 75% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 95% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 96% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 97% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 98% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 99% identical to the specified SEQ ID No.
  • the amino acid sequence is at least 99.5% identical to the specified SEQ ID No.
  • an antibody having a full heavy chain sequence that is at least 70% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full heavy chain sequence that is at least 75% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein.
  • an antibody having a full heavy chain sequence that is at least 80% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full heavy chain sequence that is at least 85% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein.
  • an antibody having a full heavy chain sequence that is at least 90% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full heavy chain sequence that is at least 95% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein.
  • an antibody having a full heavy chain sequence that is at least 96% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full heavy chain sequence that is at least 97% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein.
  • an antibody having a full heavy chain sequence that is at least 98% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full heavy chain sequence that is at least 99% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein.
  • an antibody having a full heavy chain sequence that is at least 99.5% identical to the amino acid sequence of the full heavy chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the heavy chain variable domain and heavy chain constant domain sequences disclosed herein.
  • an antibody having a full light chain sequence that is at least 70% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full light chain sequence that is at least 75% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein.
  • an antibody having a full light chain sequence that is at least 80% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full light chain sequence that is at least 85% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein.
  • an antibody having a full light chain sequence that is at least 90% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full light chain sequence that is at least 95% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein.
  • an antibody having a full light chain sequence that is at least 96% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full light chain sequence that is at least 97% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein.
  • an antibody having a full light chain sequence that is at least 98% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein. In one example, an antibody is provided having a full light chain sequence that is at least 99% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein.
  • an antibody having a full light chain sequence that is at least 99.5% identical to the amino acid sequence of the full light chain sequence of any antibody disclosed herein e.g., the combination of the SEQ ID Nos for the light chain variable domain and light chain constant domain sequences disclosed herein.
  • an antibody having at least 70% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 75% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 80% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 85% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 90% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences.
  • an antibody having at least 95% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 96% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 97% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 98% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 99% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences. In one example, an antibody is provided having at least 99.5% sequence identity to the sequence of any antibody disclosed herein across both the full heavy and light chain sequences.
  • the antibody comprises amino acid substitutions as compared to the sequences defined herein.
  • an antibody is provided that is defined by the same sequence(s) as one of the exemplary antibodies described herein and set out in Table 1, but where the sequence(s) comprises amino acid substitutions.
  • Amino acid substitutions include alterations in which an amino acid is replaced with a different naturally- occurring amino acid residue. Such substitutions may be classified as “conservative", in which case an amino acid residue contained in a polypeptide is replaced with another naturally occurring amino acid of similar character either in relation to polarity, side chain functionality or size. Such conservative substitutions are well known in the art. Substitutions encompassed by the present invention may also be “non-conservative", in which an amino acid residue which is present in a peptide is substituted with an amino acid having different properties, such as naturally-occurring amino acid from a different group (e.g.
  • the conservative amino acid substitutions are as described herein.
  • the substitution may be of Y with F, T with S or K, P with A, E with D or Q, N with D or G, R with K, G with N or A, T with S or K, D with N or E, I with L or V, F with Y, S with T or A, R with K, G with N or A, K with R, A with S, K or P.
  • the conservative amino acid substitutions may be wherein Y is substituted with F, T with A or S, I with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, I with L or V, F with Y or L, S with A or T and A with S, G, T or V.
  • amino acid substitutions are located outside the CDR sequences.
  • the antibody comprises a kappa light chain.
  • Kappa light chain constant region amino acid and nucleotide sequences are set out in SEQ ID Nos: 447-456.
  • the light chain may be a lambda light chain.
  • Lambda light chain constant region amino acid and nucleotide sequences can be found in SEQ ID Nos: 457-481.
  • Selection of an appropriate format for the antibody e.g., IgG4 or IgGl, can be used to achieve desirable outcomes.
  • the format for that antibody could be an antibody with limited Fc effector functions, e.g., an IgG4, e.g., a stabilised IgG4 isotype.
  • the antibodies described herein may comprise a constant region, such as a human constant region, for example an effector-null human constant region, e.g. an IgG4 constant region or an IgGl constant region, optionally wherein the constant region is IgG4-PE (SEQ ID Nos: 441-446 and 482-483), or a disabled IgGl as defined in SEQ ID Nos: 425-426.
  • a human constant region for example an effector-null human constant region, e.g. an IgG4 constant region or an IgGl constant region, optionally wherein the constant region is IgG4-PE (SEQ ID Nos: 441-446 and 482-483), or a disabled IgGl as defined in SEQ ID Nos: 425-426.
  • the antibody’s constant region is SEQ ID NO: 418.
  • the antibody is any of the isotypes or constant regions as defined hereinabove.
  • the constant region is wild-type human IgGl (SEQ ID Nos: 417-424).
  • the constant region is an effector-enabled IgGl constant region, optionally having ADCC and/or CDC activity.
  • the constant region is engineered for enhanced ADCC and/or CDC and/or ADCP.
  • the constant region is engineered for enhanced effector function.
  • the antibody may comprise modifications that enhance the ability of the antibody to cluster and therefore be a better substrate for complement fixation.
  • the Fc domain of IgGl may be mutated for example at E345 or E430 to reinforce inter-antibody Fc:Fc interactions, stimulating formation of hexamers, which enhances the induction of CDC and ADCC of target cells (de Jong et al., PloS Biol 14(1) el002344 2016). Hexamer formation is optionally combined with a bispecific antibody format.
  • the IgG4 constant region may be any of the IgG4 constant region amino acid sequences, or encoded by any of the nucleic acid sequences (SEQ ID Nos: 435-440).
  • a heavy chain constant region may be an IgG4 comprising both the Leu235Glu mutation and the Ser228Pro mutation. This “IgG4-PE” heavy chain constant region (SEQ ID Nos: 441-446 and 482-483) is effector null.
  • an alternative effector null human constant region is a disabled IgGl being an IgG 1*01 allele comprising the L235A and/or G237A mutations (e.g. LAGA, SEQ ID Nos: 425-426).
  • the antibodies or antibody fragments disclosed herein comprise an IgGl heavy chain constant region, wherein the sequence contains alanine at position 235 and/or 237 (EU index numbering).
  • the antibody-dependent cell phagocytosis (ADCP) mechanism is discussed in Gill et al., “Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer”, Cancer Res., 75(23), December 1, 2015.
  • the potency of Fc-mediated effects may be enhanced by engineering the Fc domain by various established techniques. Such methods increase the affinity for certain Fc-receptors or decrease the affinity for inhibitory Fc-receptors, thus creating potential diverse profiles of activation enhancement. This can be achieved by modification of one or several amino acid residues (e.g. as described in Lazar et al., 2006, Proc. Natl. Acad. Sci. U.S.A., Mar 14; 103(11):4005-10; the modifications disclosed therein are incorporated herein by reference). Human IgGl constant regions containing specific mutations or altered glycosylation on residue Asn297 (e.g. N297Q, EU index numbering) have been shown to enhance binding to certain Fc receptors.
  • such mutations are one or more of the residues selected from 239, 332 and 330 for human IgGl constant regions (or the equivalent positions in other IgG isotypes).
  • the antibody or fragment comprises a human IgGl constant region having one or more mutations independently selected from N297Q, S239D, I332E and A330L (EU index numbering).
  • the increase in affinity for Fc-receptors is achieved by altering the natural glycosylation profile of the Fc domain by, for example, generating under fucosylated or de-fucosylated variants (as described in Natsume et al., 2009, Drug Des. Devel. Then, 3:7-16 or by Zhou Q., Biotechnol. Bioeng., 2008, Feb 15, 99(3):652-65, the modifications described therein are incorporated herein by reference).
  • Non- fucosylated antibodies harbour a tri-mannosyl core structure of complex-type N-glycans of Fc without fucose residue.
  • glycoengineered antibodies that lack core fucose residue from the Fc N-glycans may exhibit stronger ADCC than fucosylated equivalents due to enhancement of FcyRIIIa binding capacity.
  • residues in the hinge region can be altered to increase binding to Fc-yRIII (see, for example, Shields et al., 2001, J. Biol. Chem., Mar 2; 276(9):6591-604; the modifications described therein are incorporated herein by reference).
  • the antibody or fragment comprises a human IgG heavy chain constant region that is a variant of a wild-type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human Fey receptors selected from the group consisting of FcyRIIB and FcyRIIA with higher affinity than the wild type human IgG heavy chain constant region binds to the human Fey receptors.
  • the antibody or fragment comprises a human IgG heavy chain constant region that is a variant of a wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to human FcyRIIB with higher affinity than the wild type human IgG heavy chain constant region binds to human FcyRIIB.
  • the variant human IgG heavy chain constant region is a variant human IgGl, a variant human IgG2, or a variant human IgG4 heavy chain constant region.
  • the variant human IgG heavy chain constant region comprises one or more amino acid mutations selected from G236D, P238D, S239D, S267E, L328F, and L328E (EU index numbering system).
  • the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S267E and L328F; P238D and L328E; P238D and one or more substitutions selected from the group consisting of E233D, G237D, H268D, P271G, and A330R; P238D, E233D, G237D, H268D, P271G, and A330R; G236D and S267E; S239D and S267E; V262E, S267E, and L328F; and V264E, S267E, and L328F (EU index numbering system).
  • the variant human IgG heavy chain constant region further comprises one or more amino acid mutations that reduce the affinity of the IgG for human FcyRIIIA, human FcyRIIA, or human FcyRI.
  • the FcyRIIB is expressed on a cell selected from the group consisting of macrophages, monocytes, B-cells, dendritic cells, endothelial cells, and activated T-cells.
  • the variant human IgG heavy chain constant region comprises one or more of the following amino acid mutations G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305I, A330L, I332E, E333A, K334A, A339T, and P396L (EU index numbering system).
  • the variant human IgG heavy chain constant region comprises a set of amino acid mutations selected from the group consisting of: S239D; T256A; K290A; S298A; I332E; E333A; K334A; A339T; S239D and I332E; S239D, A330L, and I332E; S298A, E333A, and K334A; G236A, S239D, and I332E; and F243L, R292P, Y300L, V305I, and P396L (EU index numbering system).
  • the variant human IgG heavy chain constant region comprises a S239D, A330L, or I332E amino acid mutations (EU index numbering system). In one example, the variant human IgG heavy chain constant region comprises an S239D and I332E amino acid mutations (EU index numbering system). In one example, the variant human IgG heavy chain constant region is a variant human IgGl heavy chain constant region comprising the S239D and I332E amino acid mutations (EU index numbering system). In one example, the antibody or fragment comprises an afucosylated Fc region. In another example, the antibody or fragment thereof is defucosylated. In another example, the antibody or fragment is under fucosylated.
  • the antibodies and fragments disclosed herein may comprise a triple mutation (M252Y/S254T/T256E) which enhances binding to FcRn. See Dall’ Aqua et al., Immunol 2002; 169:5171- 180 for a discussion of mutations affection FcRn binding in table 2, the mutations described therein are incorporated herein by reference.
  • the enhancement of CDC may be achieved by amino acid changes that increase affinity for C 1 q, the first component of the classic complement activation cascade (see Idusogie et al., J. Immunol., 2001, 166:2571-2575; the modifications described are incorporated herein by reference).
  • Another approach is to create a chimeric Fc domain created from human IgGl and human IgG3 segments that exploit the higher affinity if IgG3 for Clq (Natsume et al., 2008, Cancer Res., 68: 3863-3872; the modifications are incorporated herein by reference).
  • the antibody or antibody fragments disclosed herein may comprise mutated amino acids at residues 329, 331 and/or 322 to alter the Clq binding and/or reduced or abolished CDC activity.
  • the antibodies or antibody fragments disclosed herein may contain Fc regions with modifications at residues 231 and 239, whereby the amino acids are replaced to alter the ability of the antibody to fix complement.
  • the antibody or fragment has a constant region comprising one or more mutations selected from E345K, E430G, R344D and D356R, in particular a double mutation comprising R344D and D356R (EU index numbering system).
  • An antibody may have a heavy chain constant region that binds one or more types of Fc receptor but does not induce cellular effector functions, i.e. which does not mediate ADCC, CDC or ADCP activity. Such a constant region may be unable to bind the particular Fc receptor(s) responsible for triggering ADCC, CDC or ADCP activity.
  • An antibody may have a heavy chain constant region that does not bind Fey receptors.
  • the constant region may comprise a Leu235Glu mutation (EU index numbering system).
  • the antibodies disclosed herein are modified to increase or decrease serum half-life.
  • one or more of the following mutations: T252L, T254S or T256F are introduced to increase biological half-life of the antibody.
  • Biological half-life can also be increased by altering the heavy chain constant region CHI domain or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Patent Numbers. 5,869,046 and 6,121,022, the modifications described therein are incorporated herein by reference.
  • the Fc hinge region of an antibody or antigen-binding fragment of the invention is mutated to decrease the biological half-life of the antibody or fragment.
  • One or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody or fragment has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • Other methods of increasing serum half-life are known to those skilled in the art.
  • the antibody or fragment is PEGylated.
  • the antibody or fragment is fused to an albuminbinding domain, e.g. an albumin binding single domain antibody (dAb).
  • the antibody or fragment is PASylated (i.e. genetic fusion of polypeptide sequences composed of PAS (XL-Protein GmbH) which forms uncharged random coil structures with large hydrodynamic volume).
  • the antibody or fragment is XTENylated®/rPEGylated (i.e. genetic fusion of non-exact repeat peptide sequence (Amunix, Versartis) to the therapeutic peptide).
  • the antibody or fragment is ELPylated (i.e. genetic fusion to ELP repeat sequence (PhaseBio)).
  • the antibody may have a modified constant region which increases stability.
  • the heavy chain constant region comprises a Ser228Pro mutation.
  • the antibodies and fragments disclosed herein comprise a heavy chain hinge region that has been modified to alter the number of cysteine residues. This modification can be used to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody. 5.12 Acinetobacter baumannii classification clone G2 and G2 strains
  • GC2 strains are defined based on whole genome sequencing data and phylogenetic analysis. GC2 representative strains are available from ATCC and NCTC.
  • NCTC 13424 may be used to reproduce all assays for OC1 LOS and Oxa-23 described herein.
  • Prototype strain LAC-4 (GenBank reference: GCA 000786735.1) also is highly cited in the literature and may be used to reproduce all assays for KL49 described herein (https://www.genome.jp/kegg- bin/show organ ism?org ⁇ abal. PMID: 25728466. Sci Rep 5:8643 (2015) DOI: 10.1038/srep08643, the contents of which are incorporated herein by reference).
  • An antibody that specifically binds to the G2 clone of Acinetobacter baumannii may be cross-reactive with related antigens such as those of other clones of Acinetobacter baumannii.
  • Methods of determining binding as described herein can also be used to determine cross-reactivity of an antibody with different clones or strains of Acinetobacter baumannii.
  • the antibody is a monoclonal antibody.
  • Methods of making monoclonal antibodies include, for example, fusing myeloma cells with the cells from an animal that was immunized with the desired antigen.
  • the monoclonal antibodies may be generated using recombinant DNA technology.
  • the antibody is a human antibody. In one example, the antibody is a fully human antibody. In one example, the antibody is a fully human monoclonal antibody.
  • Nucleic acids that encode a VH domain and/or a VL domain of any one of the antibodies described herein are also provided.
  • a nucleic acid that encodes the VH domain of any one of the antibodies described herein is provided.
  • a nucleic acid that encodes the VL domain of any one of the antibodies described herein is provided.
  • SEQ ID Nos and the nucleic acid sequences encoding the VH and VL domains of each the exemplary antibodies described herein are set out in Table 1.
  • the nucleic acid sequence is at least 70% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 80% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 90% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 95% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 96% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 97% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 98% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 99% identical to the specified SEQ ID No. In one example, the nucleic acid sequence is at least 99.5% identical to the specified SEQ ID No.
  • the nucleic acid encodes a heavy chain of any one of the antibodies described herein. In another example, the nucleic acid encodes a light chain of any one of the antibodies described herein.
  • the nucleic acid is an isolated and purified nucleic acid.
  • Vectors comprising the nucleic acids described above are also provided.
  • the vector may be a CHO cell expression vector.
  • the vector may be a HEK293 cell expression vector.
  • Host cells comprising the nucleic acids described above are also provided.
  • the host cells are eukaryotic cells, e.g., mammalian cells, preferably CHO cells (e.g., CHO cells grown in suspension culture).
  • HEK293 cells are an alternative cell line for manufacture.
  • a pharmaceutical composition comprising an effective amount of an antibody as described herein and a pharmaceutically acceptable excipient.
  • An effective amount of antibody to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the patient.
  • the composition includes other excipients or stabilizers.
  • compositions are known and include carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable excipient is an aqueous pH buffered solution.
  • physiologically acceptable excipient examples include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as Ethylenediaminetetraacetic acid (EDTA); sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • the antibodies can be administered intravenously or through the nose, lung, for example, as a liquid or powder aerosol (lyophilized) or by nebulisation of a liquid.
  • the composition can also be administered parenterally or subcutaneously.
  • the composition should be sterile, pyrogen-free and in a physiologically acceptable solution having due regard for pH, isotonicity and stability. These conditions are known to those skilled in the art.
  • Methods of administering a prophylactic or therapeutic agent include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g., intranasal and oral routes).
  • parenteral administration e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous
  • epidural e.g., intranasal and oral routes
  • mucosal e.g., intranasal and oral routes.
  • a prophylactic or therapeutic agent e.g., an antibody as disclosed herein
  • a pharmaceutical composition is administered intranasally, intramuscularly, intravenously, or subcutaneously.
  • the prophylactic or therapeutic agents, or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, intranasal mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. Each dose may or may not be administered by an identical route of administration.
  • a prophylactic or therapeutic agent e.g., an antibody as disclosed herein
  • a prophylactic or therapeutic agent e.g., an antibody as disclosed herein
  • encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibody, receptor-mediated endocytosis see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)
  • construction of a nucleic acid as part of a retroviral or other vector etc.
  • pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. See, e.g., U.S. Pat.
  • a prophylactic or therapeutic agent or a pharmaceutical composition as described herein locally to the area in need of treatment.
  • This may be achieved by, for example, local infusion, by topical administration (e.g., by intranasal spray), by injection, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibres.
  • care must be taken to use materials to which the antibody does not absorb.
  • an antibody may be provided as an IgA isotype antibody.
  • human IgAl or human IgA2 antibodies are preferred.
  • Medicaments formulated for inhalation and/or for delivery of antibody (or its encoding nucleic acid, e.g., in a DNA vector) to the upper and/or lower respiratory tract, including formulations for delivery of a nebulised medicament may comprise an IgA (e.g., human IgAl or human IgA2) antibody.
  • Inhalers, nebulisers and similar devices may thus be provided containing a medicament comprising an IgA antibody or its encoding nucleic acid, together with any buffers or other excipients suitable for stabilisation of the medicament and/or for promoting its delivery to the target tissue. 5.16 Therapeutic use
  • Antibodies described herein may be used to treat or prevent a bacterial infection caused by Acinetobacter baumannii.
  • One aspect includes use of an antibody or composition described herein as a medicament.
  • antibodies described herein or compositions described herein for use in a method of treating a bacterial infection caused by Acinetobacter baumannii are provided, said method comprising administering the antibody or composition to a patient.
  • antibodies described herein or compositions described herein for use in a method of preventing a bacterial infection caused by Acinetobacter baumannii are provided, said method comprising administering the antibody or composition to a patient.
  • the patient may be any animal, including, but not limited to, mammals.
  • the patient is a human.
  • the patient is an adult human.
  • the patient is a human over 12 years old.
  • the bacterial infection caused by Acinetobacter baumannii is a nosocomial bacterial infection caused by Acinetobacter baumannii.
  • the patient has a lower respiratory tract infection, for example pneumonia, e.g. ventilator associated pneumonia.
  • a lower respiratory tract infection for example pneumonia, e.g. ventilator associated pneumonia.
  • the patient has sepsis.
  • the patient has bacteremia.
  • the antibody for use or the composition for use described above one or more symptoms of a bacterial infection caused by Acinetobacter baumannii are reduced.
  • the progression of a bacterial infection caused by Acinetobacter baumannii is reduced.
  • the risk of developing a bacterial infection caused by Acinetobacter baumannii is reduced.
  • the risk of transmission of a bacterial infection caused by Acinetobacter baumannii to and/or from a patient is reduced.
  • an antibody described herein or a composition described herein in the manufacture of a medicament for treating a bacterial infection caused by Acinetobacter baumannii.
  • Use of an antibody described herein or a composition described herein in the manufacture of a medicament for preventing a bacterial infection caused by Acinetobacter baumanniiis also provided.
  • one or more symptoms of bacterial infection caused by Acinetobacter baumannii are reduced.
  • the progression of bacterial infection caused by Acinetobacter baumannii is reduced.
  • the risk of developing a bacterial infection caused by Acinetobacter baumannii is reduced.
  • the risk of transmission of a bacterial infection caused by Acinetobacter baumannii to and/or from a human is reduced.
  • a method of treating a bacterial infection caused by Acinetobacter baumannii in a human, comprising administering to said human a therapeutically effective amount of an antibody described herein or a composition described herein is provided.
  • a method of preventing a bacterial infection caused by Acinetobacter baumannii in a human, comprising administering to said human a therapeutically effective amount of an antibody described herein or a composition described herein is also provided.
  • one or more symptoms of bacterial infection caused by Acinetobacter baumannii are reduced.
  • the progression of bacterial infection caused by Acinetobacter baumannii is reduced.
  • the risk of developing a bacterial infection caused by Acinetobacter baumannii is reduced.
  • the risk of transmission of a bacterial infection caused by Acinetobacter baumannii to and/or from a human is reduced.
  • the use of an antibody or composition described herein or the method further comprises administering at least one further therapeutic agent.
  • the first antibody and further therapeutic agent are administered simultaneously, separately or sequentially.
  • the further therapeutic agent is a further antibody.
  • the further therapeutic agent is carbapenem.
  • the present inventors have identified a synergy between administering carbapenem and administering an anti-Oxa-23 mAb as described herein due to the mode of action of the anti-Oxa-23 antibody, namely the antibody inhibiting the activity of the Oxa-23 carbapenemase enzyme, thereby inhibiting the associated resistance to carbapenem.
  • the further therapeutic agent is colistin.
  • the antibody is administered as an antibody-drug conjugate in which the antibody is linked to a drug moiety.
  • the antibody may be linked to a drug moiety which may be a cytokine, chemokine, or small molecule antiviral.
  • Antibodies described herein may be used to prevent death and shorten the time to recovery and discharge for patients having a bacterial infection caused by Acinetobacter baumannii. Patients will generally be human patients and may be patients diagnosed as having a bacterial infection caused by Acinetobacter baumannii. Further, patients may be patients that have already been admitted to hospital for another reason.
  • kits for treating a bacterial infection caused by Acinetobacter baumannii wherein the kit includes an antibody as described herein and instructions to administer the antibody to a subject in need of treatment.
  • a pharmaceutical or diagnostic pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions as disclosed herein, such as one or more anti-Oxa-23 antibodies provided herein.
  • a pharmaceutical or diagnostic pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions as disclosed herein, such as one or more anti-OCl LOS antibodies provided herein.
  • a pharmaceutical or diagnostic pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions as disclosed herein, such as one or more anti-KL49 antibodies provided herein.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration, e.g., an authorisation number.
  • an article of manufacture that includes a container in which a composition containing an antibody as described herein and a packaging insert or label indicating that the composition can be used to treat a bacterial infection caused by Acinetobacter baumannii.
  • a kit for treating and/or preventing a bacterial infection caused by Acinetobacter baumannii comprising an antibody as disclosed herein in any example or combination of examples (and optionally a further therapeutic agent as described elsewhere herein) optionally in combination with a label or instructions for use to treat and/or prevent said infection in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody.
  • a marketing authorisation number e.g., an FDA or EMA authorisation number
  • the kit comprises an antibody contained within a container or an IV bag.
  • the container or IV bag is a sterile container or a sterile IV bag.
  • the antibody is formulated into a pharmaceutical composition contained within a (sterile) container or contained within a (sterile) IV bag.
  • the kit further comprises instructions for use.
  • kits for treating bacterial infection caused by Acinetobacter baumannii includes an antibody as described herein and instructions to administer the antibody to a subject in need of treatment.
  • the subject in need may be specifically defined in the kit as someone of a specific higher risk group defined by epidemiological data, risk stratification data from the person’s health records, risk stratification by the genotype of certain genes of the individual or the presence of certain biomarkers in the person's blood or other tissue sample.
  • the combined product will act as a linked diagnostic/prognostic and treatment kit.
  • Antibodies as described herein may be used prophylactically. Administration of antibodies may prevent infection or reduce the risk of infection by Acinetobacter baumannii. Antibodies may for example be used to prevent infection in those at risk in high transmission environments, such as for example in hospitals. Antibodies may be administered to a patient connected to a ventilator, to reduce the patient's risk of contracting ventilator associated pneumonia.
  • Antibodies as described herein can be used to detect the presence, absence and/or level of Acinetobacter baumannii in a biological sample from a patient.
  • the biological sample is a tissue sample (e.g., in pathology studies or biopsy samples of tissue used for diagnostics and prognostics).
  • the biological sample is blood, plasma, serum, urine, faeces, cerebrospinal fluid (CFS).
  • the biological sample is from a nasal or throat swab. Liquid samples are convenient for use in many types of diagnostic assays.
  • the antibodies described herein can be used to identify the presence, absence and/or level of Acinetobacter baumannii at baseline, i.e., before treatment.
  • the antibodies described herein can be used to guide therapy, particularly to identify the presence, absence and/or level of Acinetobacter baumannii during or after treatment.
  • the antibodies described herein can be used for patient monitoring, to help evaluate whether a course of treatment is effective and whether or not treatment should be continued.
  • the antibody described herein is labelled with a detectable moiety, for example, a radiolabel, fluorescent label, enzymatic label, chemiluminescent labelled or a biotinyl group.
  • Radioisotopes or radionuclides may include 3H, 14C, 15N, 35S, 90Y, 99Tc, 115In, 1251, 1311
  • fluorescent labels may include rhodamine, lanthanide phosphors or FITC and enzymatic labels may include horseradish peroxidase, P-galactosidase, luciferase, alkaline phosphatase.
  • Additional labels include, by way of illustration and not limitation: enzymes, such as glucose-6-phosphate dehydrogenase ("G6PDH”), alpha- D- galactosidase, glucose oxydase, glucose amylase, carbonic anhydrase, acetylcholinesterase, lysozyme, malate dehydrogenase and peroxidase; dyes; additional fluorescent labels or fluorescers include, such as fluorescein and its derivatives, fluorochrome, GFP (GFP for "Green Fluorescent Protein”), dansyl, umbelliferone, phycoerythrin, phycocyanin, allophycocyanin, o- phthaldehyde, and fiuorescamine; fluorophores such as lanthanide cryptates and chelates e.g.
  • enzymes such as glucose-6-phosphate dehydrogenase (“G6PDH”), alpha- D- galactosidase, glucose oxydase
  • chemoluminescent labels or chemiluminescers such as isoluminol, luminol and the dioxetanes; sensitisers; coenzymes; enzyme substrates; particles, such as latex or carbon particles; metal sol; crystallite; liposomes; cells, etc., which may be further labelled with a dye, catalyst or other detectable group; molecules such as biotin, digoxygenin or -bromodeoxyuridine; toxin moieties, such as for example a toxin moiety selected from a group of Pseudomonas exotoxin (PE or a cytotoxic fragment or mutant thereof), Diptheria toxin or a cytotoxic fragment or mutant thereof, a botulinum toxin A, B, C, D, E or F, ricin or a cytotoxic fragment thereof e.g. ricin A, abrin or a cytotoxic fragment thereof,
  • PE Pseudomonas exotoxin
  • the antibody can be administered to a patient, wherein the antibody is conjugated to a label.
  • the presence of the label in the patient can be measured or observed, wherein a relatively high amount of the label may indicate a high risk of infection and a relatively low amount of the label may indicate a relatively low risk of the infection.
  • the label is a contrast agent, isotopic tag, or fluorescent marker, such as green fluorescent protein.
  • antibodies with high affinity are particularly valuable.
  • the diagnostic assay could be a double antigen binding assay (DABA).
  • DABA double antigen binding assay
  • a first antibody is used as a capture antibody to bind the Acinetobacter baumannii in a sample (for this purpose, a high affinity antibody with fast on-rate and slow off-rate is desirable, as noted above), and a second antibody, specific for an epitope that is different from the capture antibody's epitope, is used for detection.
  • the second antibody may thus be detectably labelled, by direct or indirect labelling.
  • a DABA may comprise providing the first antibody (optionally immobilised on a surface), contacting the surface with a sample to allow capture of antigen, if present, followed by washing to remove unbound antigen and sample, and then exposing the surface to the detection antibody to allow binding to the antigen, if present, washing to remove unbound detection antibody, and detecting the presence of the detection antibody.
  • the presence of the detection antibody indicates that the sample is positive for Acinetobacter baumannii. This type of assay may be used to determine whether a patient is infected with Acinetobacter baumannii.
  • kits for detecting Acinetobacter baumannii in a biological sample can be used to screen for Acinetobacter baumannii infection.
  • the kit includes an antibody according to the invention as described anywhere herein and a means for determining whether the antibody is bound to Acinetobacter baumannii in a sample.
  • the antibody is specific for Acinetobacter baumannii.
  • the antibody is labelled.
  • the antibody is an unlabelled primary antibody and the kit includes means for detecting the primary antibody.
  • the means for detecting includes a labelled secondary antibody that is an anti-immunoglobulin antibody.
  • the antibody may be labelled with any suitable marker, including, for example, a fluorochrome, an enzyme, a radionuclide and a radiopaque material.
  • kits for detecting Acinetobacter baumannii wherein the kit includes an antibody as described herein. In one example, the kit may also include instructions and one or more reagents for detecting Acinetobacter baumannii.
  • the present invention represents a completely new approach to antibody generation and discovery for antibodies to be used in the diagnosis and treatment of pathogen, particularly bacterial, infections.
  • the new approach involves immunising a transgenic mouse, such as a humanised mouse, with a bacteria or other pathogen to generate antibodies in a manner that is antigen agnostic in that it has no inherent bias towards any potential target antigen on the pathogen.
  • the new approach provides the opportunity to combine multiple strains of a pathogen in the immunisation step, whereby the present inventors have discovered that it is possible to discover monoclonal antibodies with cross-reactivity across multiple strains of the pathogen.
  • the present inventors have further discovered that the approach is particularly suitable for bacteria producing outer-membrane vesicles (OMVs), where pooled, purified vesicles from multiple bacterial strains can be used to immunise humanised mice.
  • OMVs outer-membrane vesicles
  • the present inventors have discovered excellent correlation between antibodies capable of binding to purified vesicles produced by bacteria and antibodies capable of binding to live bacteria.
  • pooled OMVs have the potential to induce cross-reactive serum responses to additional bacterial strains, thereby producing cross reactive mAbs within the mouse polyclonal response.
  • the present invention provides a sample comprising a number of different strains of a pathogen, e.g., a bacteria, where the sample is suitable for use in immunising a transgenic mouse, such as a humanised mouse.
  • the sample comprises pooled membrane vesicles isolated from a number of strains of the same bacteria.
  • the present invention provides a method of making a polyclonal human antibodies comprising: a) exposing a transgenic mouse, such as a humanised mouse, to antigenic stimulation, such that the mouse produces polyclonal antibodies against the antigen; b) isolating the polyclonal antibodies from the mouse; wherein the antigen comprises a number of different strains of a pathogen, e.g., a bacteria.
  • the present invention provides a method comprising a step of preparing a sample comprising a number of different strains of a pathogen, e.g., a bacteria, suitable for use in immunising a transgenic mouse, such as a humanised mouse.
  • the method further comprises immunising the mouse with the prepared sample and collecting the polyclonal antibodies generated by the mouse.
  • the method further comprises characterising the binding of the antibodies generated by the mouse.
  • the method further comprises isolating a monoclonal antibody, such as a fully human monoclonal antibody, from the polyclonal antibodies generated by the mouse.
  • a monoclonal antibody such as a fully human monoclonal antibody
  • the present invention further provides a transgenic mouse, such as a humanised mouse, that produces antibodies, wherein said mouse has been immunised with a sample comprising a number of different strains of a pathogen, e.g., a bacteria.
  • a transgenic mouse such as a humanised mouse
  • a pathogen e.g., a bacteria
  • the transgenic mouse is a transgenic mouse that produces hybrid antibodies containing human variable regions and mouse constant regions.
  • the transgenic mouse is a humanised mouse that produces antibodies with human variable regions e.g., fully human antibodies, such as the Kymab proprietary IntelliSelect Transgenic mouse platform (e.g., "Darwin").
  • mice rats or other non-human animals such as chickens or llamas may be used for antibody discovery by immunisation, as is well known in the art.
  • Figure la Time resolved core genome phylogeny for GC2 A. baumannii isolates in a Ho Chi Minh ICU. Shading indicates the period during which the carbapenem antibiotic imipenem was used for the empirical treatment of VAP in the ICU. Labelled A-E are the five carbapenem resistant genomic subclades of GC2. The capsule K- locus subtype for the 10 strains tested for OMV production are also listed on the right. Marked with asterisks (*) are 4 strains from which OMVs have been successfully generated and used for immunisation of Kymab Intellisellect Transgenic mice.
  • FIG. lb Scanning electron microscope images of un-fixed OMV preparations generated from a A. baumannii clinical isolates used for immunisation.
  • FIG. 2b Polyclonal serum responses of Kymab Intellisellect Transgenic mice immunised with a mixed pool of 4 GC2 A. baumannii OMVs to the immunising OMVs as determined by ELISA, (a) Kinetics of the antigen specific IgGl response to the 4 GC2 A. baumannii OMVs used for immunisation. The total antigen specific IgGl response to the 4 individual GC2 A. baumannii OMVs used for immunisation (BAL 084, BAL 191, BAL 215 and BAL 276 in bold) is comparable to the response to 2 additional GC2 A.
  • baumannii OMV mean fluorescence intensity > 7.2 after arcsinh (inverse of hyperbolic sine function) transformation and no duplication at the amino acid level.
  • the 4 most highly mutated sequences were selected from within clusters containing large numbers of related sequences, while the more highly mutated sequence from doublets (containing 2 related sequences) were selected.
  • Antigen-binding, IgG+ B cells were sorted from the spleens of GC2 CRAB OMV-immunised mice. Figure 4. Selection to include only those Antigen binding-enriched B cells that bound to the FM4-64 fluorescently labelled GC2 CRAB OMVs was performed.
  • FIG. 4a Sunspot plot of the 951 paired VH and VL chain sequences recovered from the spleens of 4 Kymab Intellisellect Transgenic mice immunised with GC2 CRAB OMVs. Each VH and VL paired sequence is represented by a circle, coloured by the individual mouse from which it was derived. Sequences within a lineage, inferred to have derived from a common B cell progenitor are connected by black lines.
  • Figure 4b Table indicating number of IgH&L paired sequences, proportion mapping to high-quality sequences and apportioned to clusters of related sequences indicative of an actively evolving B cell response to an immunogen.
  • baumannii OMVs only represents a correlate for binding to the intact bacterial cell wall and that target proteins may be more abundant in OMVs than in the context of the native bacterial membrane.
  • the ELISA protocol was adapted to utilise whole, unfixed bacterial cells as the plate coating antigen.
  • the number of mAbs that bound to the bacterial cells at a level above that of the threshold, determined by the isotype control: human IgG 1 + 3 standard deviations was 136, compared to 179 identified as binding to OMVs.
  • OMVs as a sorting reagent for B cell plasma blasts is highly effective in identifying IgH/L pairs that can also bind the intact, unfixed bacterial cell wall of the clinical strains used to generate the OMVs. Further, these data validate consistency of bacterial target configuration between OMV and native cell wall contexts. Although we are confident that this should also apply to other gram-negative pathogens as well as Acinetobacter spp., the level of this consistency should be determined for each bacterial species used in our process.
  • the complement cascade is a powerful serum-based mechanism leading to insertion of protein pores into the membrane of gram-negative bacteria resulting in bacterial killing.
  • This protein pathway is triggered by antibody and as such, the ability for an antibody to trigger the complement cascade is a key functional outcome of target engagement in our mAb discovery approach.
  • C3b is cleaved from the serum C3 protein to drive the complement cascade and mAb binding to the bacterial cell membrane initiates formation of an enzymatic complex involving the complement proteins C 1 q, C2 and C4 that cleave C3. Therefore, detection of C3b on the bacterial membrane is a correlate for successful initiation of the complement cascade.
  • This triage has generated a total of 136 mAbs able to bind to the native bacterial surface of at least one of the four clinical strains used to generate OMVs that were combined in the immunising panel.
  • the next level of analysis involves expression in Chinese Hamster Ovary (CHO) cells and purification of selected mAbs enabling enough pure material to carry out multiple in vitro and in vivo assays.
  • CHO Chinese Hamster Ovary
  • FIG. 5a Comparison of mAb binding to GC2 A. baumannii OMVs and whole, unfixed bacterial cells as determined by ELISA.
  • Figure 5b Selection of mAbs for CHO expression and purification based on binding of both intact bacterial cell wall and ability to trigger deposition of C3b as described above. Examples of selections for subsequent CHO expression are depicted in bold.
  • phage expression library incorporating shotgun A. baumannii genomic DNA from strains BAL 084 and BAL 276. Because the mAbs could potentially bind a polypeptide epitope, we screened mAbs for reactivity with phage plaques from the phage expression library. Using this screening mechanism, we were able to identify individual phage binding to Abs 1348, 1349. By sequencing the phage, we were able to elucidate 1348 and 1349 bound Oxa-23, a class D - lactamase that is a major group of enzymes involved in resistance to carbapenem antibiotics.
  • Oxa-23 is targetable by antibody in or closely associated with the A. baumannii cell membrane which was previously unknown.
  • Oxa-23 is a functional enzyme that inactivates carbapenem and carbapenem resistance is a major clinical issue for the treatment of nosocomial A. baumannii infection, it may be possible to block enzymatic function of Oxa-23 by mAbs and render A. baumannii susceptible to carbapenems.
  • coli NCTC 13441 LPS was extracted using the same method as a control and probed with a mAb specific for 025b O-antigen (ASN-4). Specific binding was observed with 1-42 to a lOkD target for OC1 isolates A. baumannii BAL 191, BAL 339, BAL 372 and no binding was observed to ATCC 17978 (OCL2) or E. coli NCTC 13441 (025b) as expected. This data indicates that the lOkD target is OC1 LOS. We hypothesised that mAbs exclusively binding strains bearing the K49 capsule subtype were likely to be binding directly to capsule antigen.
  • Capsule antigens were extracted from selected strains bearing KL49 and analyzed by subsequent SDS- PAGE and Western blot analysis using the mAb 1416. These results show that mAb 1416 was able to bind KL49 extracted from strains BAL 186 (KL49), BAL 242 (KL49), BAL 191 (KL49), BAL 316 (KL49), CM5132 (KL49), CM4980 (KL49), CM15768 (KL49) but not capsule antigen extracted from 9 lan (KL2) or BAL 339 (KL58). The presence of the KL49 capsule is associated with hyper virulence and increased mortality, and A.
  • baumannii KL49 is currently emerging as the major clone in South East Asia.We were able to confirm that all mAbs binding to A. baumannii bearing the KL49 capsule subtype 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415 and 1416 bound to KL49 by western blot and correlated with the intense binding pattern to KL49 isolates observed in the HCI screen.
  • Figure 7a Table indicating identified targets for each mAb. Methods used include phylogenetic information gleaned from HCI (see above), serological expression cloning using a genomic phage library (SEC) and western blot with specific mAb (WB). The mAbs in bold (*) were tested in an in vivo challenge model of A. baumannii to demonstrate therapeutic efficacy.
  • FIG. 7b Example western blot analysis reveals mAb binding three distinct targets; a high molecular weight target (KL49 capsule-upper panel), lOkD target (OC1 LOS-middle panel), and a 30kD protein (Oxa- 23 -lower panel).
  • KL49 capsule-upper panel high molecular weight target
  • lOkD target OC1 LOS-middle panel
  • 30kD protein Oxa- 23 -lower panel
  • the antibody sequence may be defined by reference to an antibody internal reference number or a SEQ ID NO. Any clauses herein reciting an antibody internal reference number should also be taken as disclosure of the same subject-matter where the sequence defined by the antibody internal reference number is replaced by the corresponding SEQ ID NO.
  • variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, and wherein the HCDR3 is the HCDR3 of antibody 1348, 1349, 1540, 1548, or 1550.
  • VH variable heavy
  • VL variable light
  • VH variable heavy
  • VL variable light domain sequence comprising complementarity determining regions LCDR1 , LCDR2 and LCDR3, and wherein the 6 CDRs are those of antibody 1348, 1349, 1540, 1548, or 1550.
  • variable heavy (VH) domain sequence and a variable light (VL) domain sequence respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550 , optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • variable heavy (VH) domain sequence of antibody 1348 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1348, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1540 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VH variable heavy
  • VL variable light
  • variable heavy (VH) domain sequence and variable light (VL) domain sequence respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550, provided that the antibody has the CDRs of antibody 1348, 1349, 1540, 1548, or 1550, respectively.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1348 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1349 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1349 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1540, provided that the antibody has the CDRs of antibody 1540.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1349 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1548, provided that the antibody has the CDRs of antibody 1548.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1349 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1550, provided that the antibody has the CDRs of antibody 1550.
  • variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1348, 1349, 1540, 1548, or 1550.
  • VH variable heavy
  • VL variable light
  • the antibody comprises the VH and VL domain sequences of antibody 1349.
  • An antibody according to clause 1 or clause 2 that specifically binds OCL1 lipooligosaccharide (LOS) at the surface of Acinetobacter baumannii bacteria.
  • OCL1 lipooligosaccharide LOS
  • OCL1 LOS outer membrane vesicles
  • an antibody according to clause 37 or clause 38 wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, and wherein the HCDR3 is the HCDR3 of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • VH complementarity determining regions
  • VL variable light domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, and wherein the 6 CDRs are those of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • An antibody according to clause 47, wherein the antibody has the 6 CDRs of antibody 1042.
  • An antibody according to clause 47, wherein the e antibody has the 6 CDRs of antibody 1043.
  • the antibody has the 6 CDRs of antibody 1403.
  • variable heavy (VH) domain sequence and variable light (VL) domain sequence respectively comprise the variable heavy (VH) domain and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • variable heavy domain sequence of antibody 1042 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody
  • variable heavy (VH) domain sequence of antibody 1043 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • an antibody according to clause 55 wherein the antibody comprises a variable heavy (VH) domain sequence of antibody 1403, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1403, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • VH variable heavy
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 14008 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1413 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • variable heavy (VH) domain sequence and variable light (VL) domain sequence respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, provided that the antibody has the 6 CDRs of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413, respectively.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1042 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1043 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1403
  • variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1403, provided that the antibody has the 6 CDRs of antibody 1403.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1405 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1405, provided that the antibody has the 6 CDRs of antibody 1405.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1407 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1408 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1413
  • variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1413, provided that the antibody has the 6 CDRs of antibody 1413.
  • variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences of antibody 1042, 1043, 1403, 1405, 1407, 1408, or 1413.
  • An antibody according to clause 71 wherein the antibody comprises the VH and VL domain sequences of antibody 1042.
  • the antibody comprises the VH and VL domain sequences of antibody 1043.
  • the antibody comprises the VH and VL domain sequences of antibody 1403.
  • an antibody according to clause 71 wherein the antibody comprises the VH and VL domain sequences of antibody 1405.
  • An antibody according to clause 1 or clause 2 that specifically binds KL49 at the surface of Acinetobacter baumannii bacteria.
  • An antibody according to clause 1 or clause 2 that specifically binds KL49 on outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria.
  • OMVs outer membrane vesicles
  • an antibody according to clause 81 or clause 82 wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, and wherein the HCDR3 is the HCDR3 of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • An antibody according to clause 83 wherein the HCDR3 is the HCDR3 of antibodyl345.
  • an antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl347.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibody 1350.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibody 1351.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl363.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibody 1364.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibody 1397.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibody 1398.
  • an antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl400.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl401.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl404.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl409.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl410.
  • An antibody according to clause 83, wherein the HCDR3 is the HCDR3 of antibodyl412.
  • VH complementarity determining regions
  • VL variable light domain sequence comprising complementarity determining regions LCDR1 , LCDR2 and LCDR3, and wherein the 6 CDRs are those of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1345..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1347..
  • an antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl350..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl351.
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl363.
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl364.
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl397..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl398..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1400. .
  • an antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1401..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1402..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1404..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1409..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1410..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1412..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibodyl414..
  • An antibody according to clause 102, wherein the antibody has the 6 CDRs of antibody 1415..
  • an antibody according to clause 102 wherein the antibody has the 6 CDRs of antibody 1416.
  • CDRs complementarity determining regions
  • An antibody according to clause 121 wherein the antibody comprises a variable heavy (VH) domain sequence of antibody 1345, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1345, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1347 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1347, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1350, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody
  • variable heavy (VH) domain sequence of antibody 1351 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1363 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light domain sequence of antibody 1363, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • variable heavy (VH) domain sequence of antibody 1364 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody 1364, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • the antibody comprises a variable heavy (VH) domain sequence of antibody 1397, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody
  • variable heavy (VH) domain sequence of antibody 1398 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1400 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1401 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1402 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody
  • variable heavy (VH) domain sequence of antibody 1404 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • variable heavy (VH) domain sequence of antibody 1409 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody
  • variable heavy (VH) domain sequence of antibody 1410 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1412 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • variable heavy (VH) domain sequence of antibody 1414 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain sequence of antibody
  • variable heavy (VH) domain sequence of antibody 1415 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence of antibody 1416 optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL variable light
  • variable heavy (VH) domain sequence and variable light (VL) domain sequence respectively comprise a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the variable heavy (VH) and variable light (VL) domain sequences of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, provided that the antibody has the 6 CDRs of antibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416, respectively.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1345 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1345, provided that the antibody has the 6 CDRs of antibody 1345.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1347 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1347, provided that the antibody has the 6 CDRs of antibody 1347.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1350 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1350, provided that the antibody has the 6 CDRs of antibody 1350.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1351 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1351, provided that the antibody has the 6 CDRs of antibody 1351.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1363 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1364 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1397 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1398 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1400 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1401 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1402 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1404 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1404, provided that the antibody has the 6 CDRs of antibody 1404.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1409 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1410 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1412
  • variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody 1412, provided that the antibody has the 6 CDRs of antibody 1412.
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1414 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1415 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • variable heavy (VH) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain sequence of antibody 1416 and the variable light (VL) domain sequence comprises a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain sequence of antibody
  • an antibody according to clause 81 or clause 82 wherein the antibody comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence and wherein the variable heavy (VH) domain and variable light (VL) domain sequences respectively comprise the variable heavy (VH) and variable light (VL) domain sequences ofantibody 1345, 1347, 1350, 1351, 1363, 1364, 1397, 1398, 1400, 1401, 1402, 1404, 1409, 1410, 1412, 1414, 1415, or 1416.
  • An antibody according to clause 159 wherein the antibody comprises the VH and VL domain sequences of antibody 1345.
  • an antibody according to clause 159 wherein the antibody comprises the VH and VL domain sequences of antibody 1347.
  • the antibody comprises the VH and VL domain sequences of antibody 1397. .
  • an antibody according to clause 159 wherein the antibody comprises the VH and VL domain sequences of antibody 1398. .
  • An antibody according to clause 159, wherein the antibody comprises the VH and VL domain sequences of antibody 1404. .
  • an antibody according to clause 159 wherein the antibody comprises the VH and VL domain sequences of antibody 1410. .
  • the antibody comprises the VH and VL domain sequences of antibody 1416. .
  • an antibody according to any one of clauses 1 to 180 wherein the antibody is a human IgAl (e.g., comprising a constant region sequence SEQ ID NO: 484) or human IgA2 (e.g., comprising a constant region sequence SEQ ID NO: 485).
  • K constant domain sequence
  • a nucleic acid sequence comprising a sequence that encodes a VH domain and/or an VL domain of an antibody according to any preceding clause.
  • a vector comprising a nucleic acid according to clause 186 or clause 187, optionally wherein the vector is a CHO vector.
  • a host cell comprising a nucleic acid according to clause 186 or clause 187, or a vector according to clause 188.
  • a pharmaceutical composition comprising (i) an isolated nucleic acid encoding an antibody according to any one of clauses 1 to 185, or (ii) a nucleic acid according clause 186 or clause 187, and a pharmaceutically acceptable excipient. .
  • a pharmaceutical composition comprising an antibody according to any one of clauses 1 to 185, and a pharmaceutically acceptable excipient. .
  • the further therapeutic agent is at least one, preferably one or two, further antibodies. .
  • the further therapeutic agent is carbapenem. .
  • a pharmaceutical composition according to clause 193, wherein the further therapeutic agent is colistin.
  • kits according to clause 198 wherein the kit further comprises a label or instructions for use to prevent and/or treat a bacterial infection caused by Acinetobacter baumannii in a human; optionally wherein the label or instructions comprise a marketing authorisation number (e.g., an FDA or EMA authorisation number); optionally wherein the kit comprises an IV or injection device that comprises the antibody. .
  • a kit according to clause 198 or clause 199 wherein the antibody is contained in a sealed container..
  • an antibody according to any one of clauses 1 to 185, or a composition according to any one of clauses 190 to 196, or a nucleic acid according to clause 186 or clause 187 in the manufacture of a medicament for use in a method of preventing a bacterial infection caused by Acinetobacter baumannii in a patient.
  • a method of treating a bacterial infection caused by Acinetobacter baumannii in a patient comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses 1 to 185, or a composition according to any one of clauses 190 to 196, or a nucleic acid according clause 186 or clause 187.
  • a method of preventing a bacterial infection caused by Acinetobacter baumannii in a patient comprising administering to said patient a therapeutically effective amount of an antibody according to any one of clauses 1 to 185, or a composition according to any one of clauses 190 to 196, or a nucleic acid according to clause 186 or clause 187.
  • a method of determining the presence or absence of Acinetobacter baumannii in a sample comprising contacting the sample with an antibody according to any one of 1 to 185; and testing for binding between the antibody and Acinetobacter baumannii in the sample; wherein detection of binding indicates the presence of Acinetobacter baumannii in the sample and wherein absence of binding indicates the absence of Acinetobacter baumannii in the sample. .
  • any one of clauses 222 to 225 wherein the sample has been obtained from a human who has been or is suspected of having been infected with Acinetobacter baumannii.
  • CFS cerebrospinal fluid
  • a diagnostic kit comprising an antibody according to any one of clauses 1 to 185, and optionally one or more buffering solutions.
  • a diagnostic kit according to clause 229 wherein the kit comprises a first reagent comprising the antibody according to any one of clauses 1 to 185, and a second reagent comprising a detector molecule that binds to the first reagent.
  • the detector molecule is an antibody that comprises or is conjugated to a detectable label.
  • CLAUSES WITH SEQ ID NOS An antibody that specifically binds at the surface of Acinetobacter baumannii bacteria. An antibody according to clause 1, wherein the antibody induces complement activation (e.g. as measured by flow cytometry-based assay).
  • An antibody according to clause 1 or clause 2 that specifically binds to Oxa-23 at the surface of Acinetobacter baumannii bacteria.
  • An antibody according to clause 1 or clause 2 that specifically binds Oxa-23 on outer membrane vesicles (OMVs) of Acinetobacter baumannii bacteria.
  • An antibody according to clause 5, wherein the HCDR3 is SEQ ID NO: 24.
  • An antibody according to clause 5, wherein the HCDR3 is SEQ ID NO: 34.
  • an antibody according to clause 5, wherein the HCDR3 is SEQ ID NO: 174.
  • An antibody according to clause 5, wherein the HCDR3 is SEQ ID NO: 182.
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • HCDR1 consists of SEQ ID NO: 22
  • HCDR2 consists of SEQ ID NO: 23
  • HCDR3 consists of SEQ ID NO: 24
  • LCDR1 consists of SEQ ID NO: 27
  • HCDR1 consists of SEQ ID NO: 32
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 34
  • LCDR1 consists of SEQ ID NO: 37
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 38
  • HCDRl consists of SEQ ID NO: 3
  • HCDR2 consists of SEQ ID NO: 173
  • HCDR3 consists of SEQ ID NO: 174
  • LCDR1 consists of SEQ ID NO: 149
  • LCDR2 consists of SEQ ID NO: 177
  • LCDR3 consists of SEQ ID NO: 178, or
  • HCDR1 consists of SEQ ID NO: 181
  • HCDR2 consists of SEQ ID NO: 173
  • HCDR3 consists of SEQ ID NO: 182
  • LCDR1 consists of SEQ ID NO: 185
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 186.
  • HCDR1 consists of SEQ ID NO: 22
  • HCDR2 consists of SEQ ID NO: 23
  • HCDR3 consists of SEQ ID NO: 24
  • LCDR1 consists of SEQ ID NO: 27
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 29.
  • HCDR1 consists of SEQ ID NO: 32
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 34
  • LCDR1 consists of SEQ ID NO: 37
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 38.
  • HCDR1 consists of SEQ ID NO: 22
  • HCDR2 consists of SEQ ID NO: 23
  • HCDR3 consists of SEQ ID NO: 24
  • LCDR1 consists of SEQ ID NO: 27
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 29.
  • HCDR1 consists of SEQ ID NO: 3
  • HCDR2 consists of SEQ ID NO: 173
  • HCDR3 consists of SEQ ID NO: 174
  • LCDR1 consists of SEQ ID NO: 149
  • LCDR2 consists of SEQ ID NO: 177
  • LCDR3 consists of SEQ ID NO: 178.
  • HCDR1 consists of SEQ ID NO: 181
  • HCDR2 consists of SEQ ID NO: 173
  • HCDR3 consists of SEQ ID NO: 182
  • LCDR1 consists of SEQ ID NO: 185
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 186.
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 21 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO: 26,
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 31 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO:36,
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 172 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO: 176, or
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 180 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO: 184, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable heavy (VH) domain sequence and optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs) in the variable light (VL) domain sequence.
  • CDRs complementarity determining regions
  • variable heavy (VH) domain comprising, preferably consisting of SEQ ID NO: 21, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL domain comprising, preferably consisting of SEQ ID NO: 26, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • variable heavy (VH) domain comprising, preferably consisting of SEQ ID NO: 31, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL domain comprising, preferably consisting of SEQ ID NO: 36, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • variable heavy (VH) domain comprising, preferably consisting of SEQ ID NO: 21, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL domain comprising, preferably consisting of SEQ ID NO: 26, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • variable heavy (VH) domain comprising, preferably consisting of SEQ ID NO: 172, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs)
  • VL domain comprising, preferably consisting of SEQ ID NO: 176, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • variable heavy (VH) domain comprising, preferably consisting of SEQ ID NO: 180, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs), and a variable light (VL) domain comprising, preferably consisting of SEQ ID NO: 184, optionally with 1, 2, 3, 4 or 5 amino acid alterations outside the complementarity determining regions (CDRs).
  • VH variable heavy
  • VL variable light
  • variable heavy (VH) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 21 and the variable light (VL) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 26, provided that HCDR1 consists of SEQ ID NO: 22, HCDR2 consists of SEQ ID NO: 23, HCDR3 consists of SEQ ID NO: 24, LCDR1 consists of SEQ ID NO: 27, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 29,
  • variable heavy (VH) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 31 and the variable light (VL) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 36, provided that HCDR1 consists of SEQ ID NO: 32, HCDR2 consists of SEQ ID NO: 33, HCDR3 consists of SEQ ID NO: 34, LCDR1 consists of SEQ ID NO: 37, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 38,
  • variable heavy (VH) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 172 and the variable light (VL) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 176, provided that HCDR1 consists of SEQ ID NO: 3, HCDR2 consists of SEQ ID NO: 173, HCDR3 consists of SEQ ID NO: 174, LCDR1 consists of SEQ ID NO: 149, LCDR2 consists of SEQ ID NO: 177, and LCDR3 consists of SEQ ID NO: 178, or
  • variable heavy (VH) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 180 and the variable light (VL) domain comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 184, provided that HCDR1 consists of SEQ ID NO: 181, HCDR2 consists of SEQ ID NO: 173, HCDR3 consists of SEQ ID NO: 182, LCDR1 consists of SEQ ID NO: 185, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 186.
  • variable heavy (VH) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain having SEQ ID NO: 2
  • variable light (VL) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain having SEQ ID NO: 26, provided that HCDR1 consists of SEQ ID NO: 22, HCDR2 consists of SEQ ID NO: 23, HCDR3 consists of SEQ ID NO: 24, LCDR1 consists of SEQ ID NO: 27, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 29.
  • variable heavy (VH) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain having SEQ ID NO: 31 and the variable light (VL) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain having SEQ ID NO: 36, provided that HCDR1 consists of SEQ ID NO: 32, HCDR2 consists of SEQ ID NO: 33, HCDR3 consists of SEQ ID NO: 34, LCDR1 consists of SEQ ID NO: 37, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 38.
  • variable heavy (VH) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain having SEQ ID NO: 21 and the variable light (VL) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain having SEQ ID NO: 26, provided that HCDR1 consists of SEQ ID NO: 22, HCDR2 consists of SEQ ID NO: 23, HCDR3 consists of SEQ ID NO: 24, LCDR1 consists of SEQ ID NO: 27, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 29.
  • variable heavy (VH) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain having SEQ ID NO: 172 and the variable light (VL) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain having SEQ ID NO: 176, provided that HCDR1 consists of SEQ ID NO: 3, HCDR2 consists of SEQ ID NO: 173, HCDR3 consists of SEQ ID NO: 174, LCDR1 consists of SEQ ID NO: 149, LCDR2 consists of SEQ ID NO: 177, and LCDR3 consists of SEQ ID NO: 178.
  • variable heavy (VH) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VH domain having SEQ ID NO: 180 and the variable light (VL) domain sequence comprises, preferably consists of a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to the VL domain having SEQ ID NO: 184, provided that HCDR1 consists of SEQ ID NO: 181, HCDR2 consists of SEQ ID NO: 173, HCDR3 consists of SEQ ID NO: 182, LCDR1 consists of SEQ ID NO: 185, LCDR2 consists of SEQ ID NO: 28, and LCDR3 consists of SEQ ID NO: 186.
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 21 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO: 26,
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 31 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO:36,
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 172 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO: 176, or
  • variable heavy (VH) domain comprises, preferably consists of SEQ ID NO: 180 and the variable light (VL) domain comprises, preferably consists of SEQ ID NO: 184.
  • VH domain comprising, preferably consisting of SEQ ID NO: 21 and the VL domain comprising, preferably consisting of SEQ ID NO: 26.
  • the antibody comprises the VH domain comprising, preferably consisting of SEQ ID NO: 3 land the VL domain comprising, preferably consisting of SEQ ID NO: 36.
  • OCL1 lipooligosaccharide LOS
  • OCL1 LOS outer membrane vesicles
  • an antibody according to clause 37 or clause 38 wherein the antibody comprises a variable heavy (VH) domain sequence comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and a variable light (VL) domain sequence comprising complementarity determining regions LCDR1, LCDR2 and LCDR3, and wherein the HCDR3 is selected from the group consisting of SEQ ID NO: 189, SEQ ID NO: 196, SEQ ID NO: 90, SEQ ID NO: 105, SEQ ID NO: 112, SEQ ID NO: 119, and SEQ ID NO: 146.
  • an antibody according to clause 39, wherein the HCDR3 is SEQ ID NO: 196.
  • An antibody according to clause 39, wherein the HCDR3 is SEQ ID NO: 90.
  • An antibody according to clause 39, wherein the HCDR3 is SEQ ID NO: 105.
  • An antibody according to clause 39, wherein the HCDR3 is SEQ ID NO: 112.
  • An antibody according to clause 39, wherein the HCDR3 is SEQ ID NO: 119.
  • An antibody according to clause 39, wherein the HCDR3 is SEQ ID NO: 146.
  • VH variable heavy
  • CDRs complementarity determining regions
  • VL variable light
  • HCDR1 consists of SEQ ID NO: 32
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 189
  • LCDR1 consists of SEQ ID NO: 37
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 192
  • HCDR1 consists of SEQ ID NO: 195
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 196
  • LCDR1 consists of SEQ ID NO: 37
  • LCDR2 consists of SEQ ID NO: 9
  • LCDR3 consists of SEQ ID NO: 199
  • HCDRl consists of SEQ ID NO: 22
  • HCDR2 consists of SEQ ID NO: 89
  • HCDR3 consists of SEQ ID NO: 90
  • LCDR1 consists of SEQ ID NO: 93
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 94
  • HCDRl consists of SEQ ID NO: 104
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 105
  • LCDR1 consists of SEQ ID NO: 27
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 108
  • HCDR1 consists of SEQ ID NO: 111
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 112
  • LCDR1 consists of SEQ ID NO: 115
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 116
  • HCDRl consists of SEQ ID NO: 104
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 119
  • LCDR1 consists of SEQ ID NO: 122
  • LCDR2 consists of SEQ ID NO: 28
  • LCDR3 consists of SEQ ID NO: 123, or
  • HCDR1 consists of SEQ ID NO: 145
  • HCDR2 consists of SEQ ID NO: 33
  • HCDR3 consists of SEQ ID NO: 146
  • LCDR1 consists of SEQ ID NO: 149
  • LCDR2 consists of SEQ ID NO: 150
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