WO2021186398A1 - Anti-klebsiella pneumoniae antibodies and uses thereof - Google Patents

Abstract

The present disclosure is directed to Klebsiella pneumoniae lipopolysaccharide-binding antibodies and antigen-binding fragments thereof. The antibodies and fragments can be used, for example, to detect K. pneumoniae and/or in methods of treating and preventing K. pneumoniae infections.

Description

ANTI -KLIMS I ELLA PNEUMONIAE ANTIBODIES AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 62/991,944, filed on March 19, 2020, which is herein incorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted sequence listing (Name:

2943_129PC01_Seqlisting_ST25.txt; Size: 4,908 Bytes; and Date of Creation: March 11, 2021) is herein incorporated by reference in its entirety.

BACKGROUND

[0003] Klebsiella pneumoniae is a global health concern. K. pneumoniae are normally found in human intestinal microbiota and in the flora of the skin and nasopharynx of healthy individuals. However, among the young and immunocompromised, K. pneumoniae is a leading cause of hospital- and community-acquired infections (including urinary tract infections, pneumonia, bacteremia and soft tissue infections). Antibiotic resistant strains of K. pneumoniae have increased the need for treatment alternatives, but the high diversity of surface antigens has presented a challenge for vaccine design. To address this, the development of pathogen-specific methods of treatment, including monoclonal antibodies (mAbs), to prevent or treat serious bacterial infections, is being explored. Some monoclonal antibodies are currently in development for the prevention or treatment of antibiotic resistant bacterial infections (see, e.g., DiGiandomenico, A., and B.R. Sellman, Curr. Opin. Microbiol ., 27: 78-85 (2015)).

[0004] Serotyping of cell surface antigens in K. pneumoniae is based on the recognition of surface-exposed lipopolysaccharides (“LPS”), such as O-antigens. The number of serotypes for O-antigens is relatively small as compared to serotypes within other bacterial species, and it has been found that only three O-antigen serotypes (01, 02, and 03) account for the majority of K. pneumoniae infections. Moreover, out of these three most prevalent O-antigen subtypes, an estimated 50-68% of clinical isolates, and up to 73 % of multi-drug resistant (“MDR”) isolates, are serotype 01 or 02. Therefore, antibodies that can effectively target multiple O-antigen serotypes are desirable.

[0005] Antibodies that bind to both 01 and 02 serotypes (by biolayer interferometry) have been identified (Pennini et al., Nature Communications , 8:1991, doi: 10.1038/s41467-017-02223-72017). However, in murine models of pneumonia, this antibody was only moderately protective against an 02 strain, no improvement of survival was observed in an 01 pneumonia model, and no OPK activity against an 01 strain was observed (id). Accordingly, there remains a need for antibodies that can not only bind multiple O-antigen serotypes, but are also effective in inhibiting the activity of multiple K. pneumoniae serotypes.

BRIEF SUMMARY

[0006] Provided herein are antibodies and antigen-binding fragments thereof that bind to

Klebsiella pneumoniae (K. pneumoniae) serotype 01 and 02 lipopolysaccharides (LPS).

[0007] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof is capable of inducing opsonophagocytic killing (OPK) in K. pneumoniae 01 and 02 strains.

[0008] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae) 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof has therapeutic activity in both a K. pneumoniae 01 murine pneumonia model and a K. pneumoniae 02 murine pneumonia model.

[0009] In some aspects, the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse about 1 hour after administering K. pneumoniae 01 bacteria to the mouse. In some aspects, the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering K. pneumoniae 1131115 bacteria to the mouse. In some aspects, the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering about 6xl0⁷ cfu of K. pneumoniae 01 bacteria to the mouse. In some aspects, the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after intranasally administering if. pneumoniae 01 bacteria to the mouse. In some aspects, the if. pneumoniae 01 murine pneumonia model comprises intravenously administering the antibody or antigen-binding fragment thereof to a mouse after administering if. pneumoniae 01 bacteria to the mouse. In some aspects, the f. pneumoniae 01 murine pneumonia model comprises administering about 1 mg/kg of the antibody or antigen-binding fragment thereof to a mouse after administering if. pneumoniae 01 bacteria to the mouse.

[0010] In some aspects, the if. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse about 1 hour after administering if. pneumoniae 02 bacteria to the mouse. In some aspects, the if. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering if. pneumoniae 961842 bacteria to the mouse. In some aspects, the if. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering about 2xl0⁸ cfu of if. pneumoniae 02 bacteria to the mouse. In some aspects, the if. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after intranasally administering if. pneumoniae 02 bacteria to the mouse. In some aspects, the if. pneumoniae 01 murine pneumonia model comprises intravenously administering the antibody or antigen-binding fragment thereof to a mouse after administering if. pneumoniae 02 bacteria to the mouse. In some aspects, the if. pneumoniae 02 murine pneumonia model comprises administering about 1 mg/kg of the antibody or antigen-binding fragment thereof to a mouse after administering if. pneumoniae 02 bacteria to the mouse.

[0011] In some aspects, the if. pneumoniae 01 murine pneumonia model and/or the if. pneumoniae 01 murine pneumonia model infects C57BL/6 mice.

[0012] In some aspects, administration of the antibody or antigen-binding fragment thereof results in at least 50% survival 100 hours post-infection in both the if. pneumoniae 01 murine pneumonia model and the if. pneumoniae 02 murine pneumonia model.

[0013] In some aspects, the antibody or antigen-binding fragment comprises a variable heavy chain (VH) complementarity determining region (CDR) 1, a VH CDR2, a VH CDR3, a variable light chain (VL) CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise sequences selected from the group consisting of: SEQ ID NOs:3, 4, 5, 8, 9, and 10, respectively.

[0014] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment comprises a variable heavy chain (VH) complementarity determining region (CDR) 1, a VH CDR2, a VH CDR3, a variable light chain (VL) CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise sequences selected from the group consisting of: SEQ ID NOs:3, 4, 5, 8, 9, and 10, respectively.

[0015] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of B39. In some aspects, the CDRs are the Rabat- defined CDRs, the Chothia-defmed CDRs, the IMGT-defmed CDRs, or the AbM-defmed CDRs.

[0016] In some aspects, the antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO:2. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO:7. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH comprising the sequence of SEQ ID NO:2 and a VL comprising the sequence of SEQ ID NO:7.

[0017] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof binds to the same epitope as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:2 and a VL comprising the amino acid sequence of SEQ ID NO:7.

[0018] In some aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof competitively inhibits binding of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:2 and a VL comprising the amino acid sequence of SEQ ID NO:7 to K. pneumoniae. [0019] In some aspects, the antibody or antigen-binding fragment (a) binds to the K. pneumoniae serotype 01 and/or serotype 02 LPS and/or (b) neutralizes the K. pneumoniae serotype 01 and/or serotype 02 bacteria.

[0020] In some aspects, the antibody or antigen-binding fragment thereof is capable of inducing opsonophagocytic killing (OPK) in K. pneumoniae 01 and 02 strains.

[0021] In some aspects, the antibody or antigen-binding fragment thereof has therapeutic activity in a K. pneumoniae 01 murine pneumonia model.

[0022] In some aspects, the antibody or antigen-binding fragment thereof has therapeutic activity in a K. pneumoniae 02 murine pneumonia model.

[0023] In some aspects, the antibody or antigen-binding fragment further comprises a heavy chain constant region. In some aspects, the heavy chain constant region is selected from the group consisting of human immunoglobulin IgGi, IgG2, IgG3, IgG4, IgAi, and IgA2 heavy chain constant regions. In some aspects, the heavy chain constant region is a human IgGi constant region. In some aspects, the antibody or antigen-binding fragment further comprises a light chain constant region. In some aspects, the light chain constant region is selected from the group consisting of human immunoglobulin IgGK and IgGk light chain constant regions. In some aspects, the light chain constant region is a human IgGK light chain constant region. In some aspects, the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof.

[0024] In some aspects, the antibody or antigen-binding fragment thereof comprises an

Fc region that has been engineered to improve half-life. In some aspects, the antibody or antigen-binding fragment thereof comprises an Fc region with a YTE mutation. In some aspects, the antibody or antigen-binding fragment comprises an Fc region with an N3Y mutation.

[0025] In some aspects, the antibody or antigen-binding fragment is a monoclonal antibody or antigen-binding fragment. In some aspects, the antibody or antigen-binding fragment is a full-length antibody. In some aspects, the antibody or antigen-binding fragment is an antigen-binding fragment. In some aspects, the antigen-binding fragment comprises a Fab, Fab', F(ab')2, single chain Fv (scFv), disulfide linked Fv, intrabody, IgGACH2, minibody, F(ab')3, tetrabody, triabody, diabody, DVD-Ig, Fcab, mAh²,

(SCFV)2, or scFv-Fc. In some aspects, the antigen-binding fragment comprises an scFv. [0026] In some aspects, the antibody or antigen-binding fragment thereof has similar binding affinities for K. pneumoniae serotype 01 LPS and if. pneumoniae serotype 02 LPS, e.g., as shown for B39 in Figure 1.

[0027] In some aspects, the antibody or antigen-binding fragment thereof further comprises a detectable label.

[0028] In some aspects, provided herein is a composition comprising an antibody or antigen-binding fragment provided herein and optionally, a pharmaceutically-acceptable carrier.

[0029] In some aspects, provided herein is a method of treating or preventing a if. pneumoniae infection in a subject comprising administering to the subject an antibody or antigen-binding fragment thereof provided herein ns. In some aspects, the if. pneumoniae infection is meningitis. In some aspects, the if. pneumoniae infection is a urinary tract infection (UTI). In some aspects, the if. pneumoniae infection is a bloodstream infection. In some aspects, the if. pneumoniae infection is septicemia. In some aspects, the if. pneumoniae infection is pneumonia. In some aspects, the if. pneumoniae infection is bronchopneumonia or bronchitis. In some aspects, the if. pneumoniae infection is ICU pneumonia. In some aspects, the if. pneumoniae infection is a skin or soft tissue infection (SSTI). In some aspects, the if. pneumoniae infection is diarrhea. In some aspects, the if. pneumoniae infection is an infection following an organ transplant. In some aspects, the if. pneumoniae infection is a surgery infection. In some aspects, the if. pneumoniae infection is a wound infection. In some aspects, the if. pneumoniae infection is a lung infection. In some aspects, the if. pneumoniae infection is a pyogenic liver abscess. In some aspects, the if. pneumoniae infection is endophthalmitis. In some aspects, the if. pneumoniae infection is ankylosing spondylitis. In some aspects, the f. pneumoniae infection is a spondyloarthropathy. In some aspects, the if. pneumoniae infection is a nosocomial infection. In some aspects, the if. pneumoniae infection is an opportunistic infection. In some aspects, the if. pneumoniae infection is an infection caused by exposure to a if/efc/e//a-contaminated medical device. In some aspects, the if. pneumoniae infection comprises antibiotic-resistant if. pneumoniae. In some aspects, the if. pneumoniae infection comprises multi-drug resistant if. pneumoniae. In some aspects, the subject is a surgical subject. In some aspects, the subject is human. In some aspects, the treating or preventing a K pneumoniae infection comprises inhibiting the growth of Klebsiella or reducing the number of Klebsiella in an infected subject.

[0030] In some aspects, provided herein is an isolated polynucleotide comprising a nucleic acid molecule encoding the VH or heavy chain of an antibody or antigen-binding fragment that specifically binds to K pneumoniae 01 and 02 antigens. In some aspects, the isolated polynucleotide comprises a nucleic acid molecule encoding the VL or light chain of such an antibody or antigen-binding fragment thereof. In some aspects, provided herein is an isolated vector comprising a polynucleotide provided herein. In some aspects, provided herein is a host cell comprising a polynucleotide provided herein, a vector provided herein, or a first vector comprising a first polynucleotide and a second vector comprising a second polynucleotide provided herein. In some aspects, the host cell is a prokaryotic or eukaryotic cell. In some aspects, the host cell is isolated. In some aspects, provided herein is a method of producing an antibody or antigen-binding fragment thereof comprising culturing the host cell so that the antibody or antigen-binding fragment thereof is produced.

[0031] In some aspects, provided herein is a method for detecting K pneumoniae or K pneumoniae LPS in a sample comprising contacting said sample with an antibody or antigen-binding fragment thereof that specifically binds to K pneumoniae 01 and 02 antigens.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0032] Figure 1 A provides a graph showing the binding of B39 to purified LPS from 01 and 02 strains of K pneumoniae using biolayer interferometry. Line “A” shows binding to the 01 strain. Line “B” shows binding to the 02 strain.

[0033] Figure IB provides an image (63 x magnification) showing the binding of B39 to encapsulated f. pneumoniae 43816 WT by confocal microscopy. The stained areas show bacteria that were fixed and treated with B39 (1 pg/ml), then stained with nuclear stain DAPI and anti -human antibody AF647. The scalebar represents 10 pm.

[0034] Figure 1C provides a graph showing the performance of B39 in an OPK assay, as compared to Nip228, measured by the percentage of K pneumoniae killing (Y-axis).

[0035] Figure ID provides an enlarged micrograph showing the clearance of K pneumoniae in the presence of B39 (top) and Nip228 (bottom) by high-content imaging. [0036] Figure 2 shows the experimental design for testing the therapeutic efficacy of B39 in murine models of pneumonia.

[0037] Figure 3 A provides a graph showing the therapeutic activity of B39 in a K. pneumoniae serotype 01 in vivo pneumonia model. The data is representative of three independent experiments. R347 = isotype control; KPE33 = 01 IgG. A Mantel-Cox test was performed to compare each IgG with RS347. P-values: ** = P < 0.01; *** = P < 0.001. N = 8.

[0038] Figure 3B provides a graph showing the therapeutic activity of B39 in a K. pneumoniae serotype 02 in vivo pneumonia model. The data is representative of three independent experiments. R347 = isotype control; 02 IgG = an 02 IgG control. A Mantel-Cox test was performed to compare each IgG with RS347. P-values: * = P < 0.1; ** = P < 0_.01; *** = p < 0_.001_. N = 8_.

DETAILED DESCRIPTION

[0039] The present disclosure provides antibodies and antigen-binding fragments thereof

(e.g., monoclonal antibodies and antigen-binding fragments thereof) that bind to LPS from K. pneumoniae 01 and 02 serotypes. The present disclosure also provides methods of using such antibodies and antigen-binding fragments, for example, in detecting K. pneumoniae and in the treatment or prevention of K. pneumoniae infections.

I. Definitions

[0040] The term “ Klebsiella " refers to a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria in the Enterobacteriaceae family. Klebsiella include, for example, K. pneumoniae, K. oxytoca, K. planticola K. granulomatis, K. ozaenae , and K. rhinosclermoatis .

[0041] The term “lipopolysaccharide” or “LPS” refers to a molecule containing lipids and polysaccharides. An “O-antigen” is a repetitive glycan polymer contained within an LPS.

[0042] The term “strain” refers to isolates from distinct bacterial cultures. Strains of the same bacterial species can differ in the antigenic determinants expressed on the cell surface.

[0043] The term “serotype” refers to a group of organisms (e.g., bacteria) within a species that share the same cell-surface antigens. [0044] The term “anti-01 and 02” K. pneumoniae antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens.

[0045] The term “antibody” means an 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. As used herein, the term “antibody” encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antibody, and any other modified immunoglobulin molecule so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc.

[0046] The term “monoclonal antibodies,” as used herein, refers to antibodies that are produced by a single clone of B-cells and bind to the same epitope. In contrast, the term “polyclonal antibodies” refers to a population of antibodies that are produced by different B-cells and bind to different epitopes of the same antigen.

[0047] The term “antibody fragment” refers to a portion of an intact antibody. An

“antigen-binding fragment,” “antigen-binding domain,” or “antigen-binding region,” refers to a portion of an intact antibody that binds to an antigen. An antigen-binding fragment can contain the antigenic determining regions of an intact antibody (e.g., the complementarity determining regions (CDR)). Examples of antigen-binding fragments of antibodies include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single chain antibodies. An antigen-binding fragment of an antibody can be derived from any animal species, such as rodents (e.g., mouse, rat, or hamster) and humans or can be artificially produced.

[0048] A whole antibody typically consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three C- terminal constant (CHI, CH2, and CH3) regions, and each light chain contains one N- terminal variable (VL) region and one C-terminal constant (CL) region. The variable regions of each pair of light and heavy chains form the antigen binding site of an antibody. The VH and VL regions have the same general structure, with each region comprising four framework regions, whose sequences are relatively conserved. The term “framework region,” as used herein, refers to the relatively conserved amino acid sequences within the variable region which are located between the hypervariable or complementary determining regions (CDRs). There are four framework regions in each variable domain, which are designated FR1, FR2, FR3, and FR4. The framework regions form the b sheets that provide the structural framework of the variable region (see, e.g., C.A. Janeway et al. (eds.), Immunobiology , 5th Ed., Garland Publishing, New York, NY (2001)). The three CDRs, known as CDR1, CDR2, and CDR3, form the “hypervariable region” of an antibody, which is responsible for antigen binding.

[0049] The term “neutralizing,” or “neutralizes,” in the context of a neutralizing antibody, as used herein, means an antibody that reduces or destroys infectivity of an infectious agent. Thus, an antibody that is capable of neutralizing a K. pneumoniae , is capable of reducing or destroying the infectivity of that f. pneumoniae.

[0050] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody or antigen-binding fragment thereof.

[0051] The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody or antigen-binding fragment thereof.

[0052] The term “Rabat numbering” and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody or an antigen-binding fragment thereof. In certain aspects, CDRs can be determined according to the Rabat numbering system (see, e.g. , Rabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Rabat EA etal, (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Using the Rabat numbering system, CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Rabat numbering scheme as 35 A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3). In some aspects, the CDRs of the antibodies described herein have been determined according to the Kabat numbering scheme.

[0053] Chothia refers instead to the location of the structural loops (Chothia and Lesk, J.

Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.

Loop Kabat AbM Chothia

LI L24-L34 L24-L34 L24-L34

L2 L50-L56 L50-L56 L50-L56

L3 L89-L97 L89-L97 L89-L97

HI H31-H35B H26-H35B H26-H32..34

(Kabat Numbering)

HI H31-H35 H26-H35 H26-H32

(Chothia Numbering)

H2 H50-H65 H50-H58 H52-H56

H3 H95-H102 H95-H102 H95-H102

[0054] As used herein, the term “constant region” or “constant domain” are interchangeable and have its meaning common in the art. The constant region is an antibody portion, e.g ., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0055] As used herein, the term “heavy chain” when used in reference to an antibody can refer to any distinct type, e.g ., alpha (a), delta (d), epsilon (e), gamma (g), and mu (m), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g. , IgGi, IgG2, IgG3, and IgG4. Heavy chain amino acid sequences are well known in the art. In some aspects, the heavy chain is a human heavy chain.

[0056] As used herein, the term “light chain” when used in reference to an antibody can refer to any distinct type, e.g. , kappa (K) or lambda (l) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In some aspects, the light chain is a human light chain.

[0057] A “chimeric” antibody refers to an antibody or fragment thereof comprising both human and non-human regions. A “humanized” antibody is an antibody comprising a human antibody scaffold and at least one CDR obtained or derived from a non-human antibody. Non-human antibodies include antibodies isolated from any non-human animal, such as, for example, a rodent (e.g., a mouse or rat). A humanized antibody can comprise, one, two, or three CDRs obtained or derived from a non-human antibody. A fully human antibody does not contain any amino acid residues obtained or derived from a non-human animal. It will be appreciated that fully human and humanized antibodies carry a lower risk for inducing immune responses in humans than mouse or chimeric antibodies (see, e.g., Harding et ah, mAbs , 2(3): 256-26 (2010)).

[0058] As used herein, an “epitope” is a term in the art and refers to a localized region of an antigen to which an antibody or antigen-binding fragment thereof can specifically bind. An epitope can be, for example, contiguous amino acids of a polypeptide (linear or contiguous epitope) or an epitope can, for example, come together from two or more non contiguous regions of a polypeptide or polypeptides (conformational, non-linear, discontinuous, or non-contiguous epitope). In some aspects, the epitope to which an antibody or antigen-binding fragment thereof binds can be determined by, e.g. , NMR spectroscopy, X-ray diffraction crystallography studies, ELISA assays, hydrogen/deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligo-peptide scanning assays, and/or mutagenesis mapping ( e.g ., site-directed mutagenesis mapping). For X-ray crystallography, crystallization can be accomplished using any of the known methods in the art (e.g., Giege R et al, (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4): 339-350; McPherson A (1990) Eur J Biochem 189: 1-23; Chayen NE (1997) Structure 5: 1269- 1274; McPherson A (1976) J Biol Chem 251: 6300-6303). Antibody/antigen-binding fragment thereof: antigen crystals can be studied using well known X-ray diffraction techniques and can be refined using computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see, e.g., Meth Enzymol (1985) volumes 114 & 115, eds Wyckoff HW et al.,; U.S. 2004/0014194), and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1): 37-60; Bricogne G (1997) Meth Enzymol 276A: 361-423, ed Carter CW; Roversi P et al, (2000) Acta Crystallogr D Biol Crystallogr 56(Pt 10): 1316-1323). Mutagenesis mapping studies can be accomplished using any method known to one of skill in the art. See, e.g, Champe M etal, (1995) J Biol Chem 270: 1388-1394 and Cunningham BC & Wells JA (1989) Science 244: 1081-1085 for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques.

[0059] An antibody that “binds to the same epitope” as a reference antibody refers to an antibody that binds to the same amino acid residues as the reference antibody. The ability of an antibody to bind to the same epitope as a reference antibody can determined by a hydrogen/deuterium exchange assay (see Coales et al. Rapid Commun. Mass Spectrom. 2009; 23: 639-647) or x-ray crystallography.

[0060] As used herein, the terms “immunospecifically binds,” “immunospecifically recognizes,” “specifically binds,” and “specifically recognizes” are analogous terms in the context of antibodies or antigen-binding fragments thereof. These terms indicate that the antibody or antigen-binding fragment thereof binds to an epitope via its antigen-binding domain and that the binding entails some complementarity between the antigen binding domain and the epitope. Accordingly, for example, if an antibody “specifically binds” to K. pneumoniae LPS, the extent of binding to an un-related, non-LPS protein is less than about 10% of the binding of the antibody to the K. pneumoniae LPS.

[0061] An antibody is said to "competitively inhibit" binding of a reference antibody to a given epitope if it preferentially binds to that epitope or an overlapping epitope to the extent that it blocks, to some degree, binding of the reference antibody to the epitope. Competitive inhibition can be determined by any method known in the art, for example, competition ELISA assays. An antibody can be said to competitively inhibit binding of the reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0062] The term “nucleic acid sequence” is intended to encompass a polymer of DNA or

RNA, i.e., a polynucleotide, which can be single-stranded or double-stranded and which can contain non-natural or altered nucleotides. The terms “nucleic acid” and “polynucleotide” as used herein refer to a polymeric form of nucleotides of any length, either ribonucleotides (RNA) or deoxyribonucleotides (DNA). These terms refer to the primary structure of the molecule, and thus include double- and single-stranded DNA, and double- and single-stranded RNA. The terms include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs and modified polynucleotides such as, though not limited to, methylated and/or capped polynucleotides. Nucleic acids are typically linked via phosphate bonds to form nucleic acid sequences or polynucleotides, though many other linkages are known in the art (e.g., phosphorothioates, boranophosphates, and the like).

[0063] “Transfection,” “transformation,” or “transduction,” as used herein, refer to the introduction of one or more exogenous polynucleotides into a host cell by using physical or chemical methods. Many transfection techniques are known in the art and include, for example, calcium phosphate DNA co-precipitation (see, e.g., Murray E.J. (ed.), Methods in Molecular Biology, Vol. 7, Gene Transfer and /_’Expression Protocols, Humana Press (1991)); DEAE-dextran; electroporation; cationic liposome-mediated transfection; tungsten particle-facilitated microparticle bombardment (Johnston, Nature , 346 776-777 (1990)); and strontium phosphate DNA co-precipitation (Brash et al, Mol Cell Biol., 7: 2031-2034 (1987)). Phage or viral vectors can be introduced into host cells, after growth of infectious particles in suitable packaging cells, many of which are commercially available.

[0064] As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. In some aspects, the effect is therapeutic, i.e., the effect partially or completely cures a disease and/or adverse symptom attributable to the disease. [0065] As used herein, the term "a condition associated with a Klebsiella infection" refers to any pathology caused by (alone or in association with other mediators), exacerbated by, associated with, or prolonged by Klebsiella infection (e.g. infection with K pneumoniae , K oxytoca, K planticola, K ozaenae, K rhinosclermoatis and/or K granulomatis) in the subject having the condition.

[0066] A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., treatment of K pneumoniae infection). The therapeutically effective amount can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antigen-binding fragment to elicit a desired response in the individual.

[0067] A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result (e.g., prevention of K pneumoniae infection or disease onset).

[0068] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that can be used to enable delivery of a drug, e.g., an LPS- binding antibody or antigen-binding fragment thereof to the desired site of biological action (e.g., intravenous administration). Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman,

The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington’s, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa.

[0069] As used in the present disclosure and claims, the singular forms "a," "an," and

"the" include plural forms unless the context clearly dictates otherwise.

[0070] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. The term "and/or" as used in a phrase such as "A and/or B" herein is intended to include both "A and B," "A or B," "A," and "B." Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0071] It is understood that wherever aspects are described herein with the language

“comprising,” otherwise analogous aspects described in terms of “consisting of’ and/or “consisting essentially of’ are also provided. [0072] The term “about,” as used herein, includes the recited number ± 10%. Thus,

“about 10” means 9 to 11. As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) instances that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

II. Anti-Ol and 02 K. pneumoniae antibodies

[0073] Provided herein are antibodies and antigen-binding fragments thereof that bind to two different K. pneumoniae serotypes

[0074] The K. pneumoniae antibodies and antigen-binding fragments provided herein bind to the cell-surface LPS on both 01 and 02 serotypes of K. pneumoniae.

[0075] In some aspects, the K. pneumoniae antibodies and antigen-binding fragments provided herein have therapeutic activity in both a K. pneumoniae 01 murine pneumonia model and a K. pneumoniae 02 murine pneumonia model. As used herein a K. pneumoniae 01 murine pneumonia model refers to a murine model that is infected with 01 bacteria and then treated with a potential therapeutic, e.g., an antibody or antigen binding fragment thereof that binds to 01 and 02 K. pneumoniae. As used herein a K. pneumoniae 02 murine pneumonia model refers to a murine model that is infected with 02 bacteria and then treated with a potential therapeutic, e.g., an antibody or antigen binding fragment thereof that binds to 01 and 02 K. pneumoniae.

[0076] In some aspects, the antibodies or antigen-binding fragments thereof are capable of inducing OPK killing in K. pneumoniae 01 and 02 strains.

[0077] In some aspects, an antibody or antigen-binding fragment (e.g., monoclonal antibody or fragment) that specifically binds to K. pneumoniae 01 and 02 antigens comprises, consists essentially of, or consists of (i) a heavy chain polypeptide comprising a CDR1 amino acid sequence of SEQ ID NO:3, a CDR2 amino acid sequence of SEQ ID NO:4, and a CDR3 amino acid sequence of SEQ ID NO:5, and (ii) a light chain polypeptide comprising a CDR1 amino acid sequence of SEQ ID NO:8, a CDR2 amino acid sequence of SEQ ID NO:9, and a CDR3 amino acid sequence of SEQ ID NO: 10.

[0078] In some aspects, an antibody or antigen-binding fragment (e.g., monoclonal antibody or fragment) that specifically binds to K. pneumoniae 01 and 02 antigens comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2. In some aspects, an antibody or antigen-binding fragment (e.g., monoclonal antibody or fragment) that specifically binds to at least f. pneumoniae 01 and 02 antigens comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:7. In some aspects, an antibody or antigen-binding fragment (e.g., monoclonal antibody or fragment) that specifically binds to K. pneumoniae 01 and 02 antigens comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:7.

[0079] Sequences of exemplary K. pneumoniae antibodies are provided below. In certain instances, an antibody or antigen-binding fragment thereof described herein binds to K. pneumoniae 01 and 02 antigens and comprises six CDRs (i.e., a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and VL CDR3) from Tables 1 and 2 below.

[0080] B39 comprises the VH CDRs of SEQ ID NOs:3-5 and the VL CDRs of SEQ ID

NOs:8-10.

Table 1. VH CDR Amino Acid Sequences

Table 2. VL CDR Amino Acid Sequences

[0081] In certain instances, an antibody or antigen-binding fragment thereof described herein binds to K. pneumoniae 01 and 02 antigens and comprises the VH of an antibody listed in the following table, e.g., in combination with a VL. Table 3. Variable Heavy Chain (VH) Sequences

[0082] In certain instances, an antibody or antigen-binding fragment thereof described herein binds to K. pneumoniae 01 and 02 antigens and comprises the VL of an antibody listed in the following table, e.g., in combination with a VH, optionally a VH listed in the preceding table.

Table 4. Variable Light Chain (VL) Sequences

[0083] In some aspects, the CDRs of an antibody or antigen-binding fragment thereof can be determined according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g ., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al. , (1997) J Mol Biol 273: 927-948; Chothia C et al. , (1992) J Mol Biol 227: 799-817; Tramontano A et al. , (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). Typically, when using the Kabat numbering convention, the Chothia CDR-H1 loop is present at heavy chain amino acids 26 to 32, 33, or 34, the Chothia CDR-H2 loop is present at heavy chain amino acids 52 to 56, and the Chothia CDR-H3 loop is present at heavy chain amino acids 95 to 102, while the Chothia CDR- LI loop is present at light chain amino acids 24 to 34, the Chothia CDR-L2 loop is present at light chain amino acids 50 to 56, and the Chothia CDR-L3 loop is present at light chain amino acids 89 to 97. The end of the Chothia CDR-H1 loop when numbered using the Rabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Rabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34).

[0084] In some aspects, provided herein are antibodies and antigen-binding fragments thereof that comprise the Chothia VH and VL CDRs of B39. In some aspects, antibodies or antigen-binding fragments thereof comprise one or more CDRs, in which the Chothia and Rabat CDRs have the same amino acid sequence. In some aspects, provided herein are antibodies and antigen-binding fragments thereof that comprise combinations of Rabat CDRs and Chothia CDRs.

[0085] In some aspects, the CDRs of an antibody or antigen-binding fragment thereof can be determined according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132-136 and Lefranc M-P et al, (1999) Nucleic Acids Res 27: 209-212. According to the IMGT numbering scheme, VH-CDR1 is at positions 26 to 35, VH-CDR2 is at positions 51 to 57, VH-CDR3 is at positions 93 to 102, VL-CDR1 is at positions 27 to 32, VL-CDR2 is at positions 50 to 52, and VL-CDR3 is at positions 89 to 97. In some aspects, provided herein are antibodies and antigen-binding fragments thereof that comprise the IMGT VH and VL CDRs of B39, for example, as described in Lefranc M-P (1999) supra and Lefranc M-P et al. , (1999) supra).

[0086] In some aspects, the CDRs of an antibody or antigen-binding fragment thereof can be determined according to MacCallum RM et al ., (1996) J Mol Biol 262: 732-745. See also , e.g, Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Rontermann and Diibel, eds., Chapter 31, pp. 422- 439, Springer- Verlag, Berlin (2001). In some aspects provided herein are antibodies or antigen-binding fragments thereof that comprise the VH and VL CDRs of B39 determined by the method in MacCallum RM et al.

[0087] In some aspects, the CDRs of an antibody or antigen-binding fragment thereof can be determined according to the AbM numbering scheme, which refers AbM hypervariable regions which represent a compromise between the Rabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.). In some aspects, provided herein are antibodies or antigen-binding fragments that comprise the VH and VL CDRs of B39 as determined by the AbM numbering scheme.

[0088] In some aspects, the antibody or antigen-binding fragment thereof (e.g., monoclonal antibody or fragment) described herein can comprise a constant region (Fc) of any suitable class (e.g., IgG, IgA, IgD, IgM, and IgE).

[0089] In some aspects, the antibody or antigen-binding fragment thereof (e.g., monoclonal antibody or fragment) described herein can comprise a constant region (Fc) of any suitable class (e.g., IgG, IgA, IgD, IgM, and IgE) that has been modified in order to improve the half-life of the antibody or antigen-binding fragment (e.g., monoclonal antibody or fragment). For example, the antibody or antigen-binding fragment thereof (e.g., monoclonal antibody or fragment) described herein can comprise an Fc that comprises a mutation that extends half-life relative to the same antibody without the mutation.

[0090] Fc region engineering is widely used in the art to extend the half-life of therapeutic antibodies and protect from degradation in vivo. In some aspects, the Fc region of an IgG antibody or antigen-binding fragment can be modified in order to increase the affinity of the IgG molecule for the Fc Receptor-neonate (FcRn), which mediates IgG catabolism and protects IgG molecules from degradation. Suitable Fc region amino acid substitutions or modifications are known in the art and include, for example, the triple substitution M252Y/S254T/T256E (referred to as “YTE”) (see, e.g., U.S. Patent 7,658,921; U.S. Patent Application Publication 2014/0302058; and Yu et al., Antimicrob. Agents Chemother., 67(1): e01020-16 (2017)). In certain aspects, an antibody or antigen-binding binding fragment (e.g., monoclonal antibody or fragment) that binds to at least one K. pneumoniae serotype 01 and serotype 02 epitope comprises an Fc region comprising the YTE mutation. In certain aspects, an antibody or antigen-binding binding fragment (e.g., monoclonal antibody or fragment) that binds to at least one K. pneumoniae serotype 01 and serotype 02 epitope comprises an Fc region comprising the N3Y mutation. The sequence of an Fc region (starting from the hinge) comprising the N3Y mutation CSYHLC (SEQ ID NO: 11) is CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNST YRVV S VLTVLHQDWLNGKEYKCKV SNKALP APIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFL Y SKLT VDKSRWQQGNVF SC S VMHEAC S YHLCQKSL SL SPGK (SEQ ID NO: 12). [0091] An antibody or antigen-binding fragment (e.g. monoclonal antibody or fragment) described herein can be, or can be obtained from, a human antibody, a humanized antibody, a non-human antibody, or a chimeric antibody. In one aspect, an antibody described herein, or antigen-binding fragment thereof, is a fully human antibody.

[0092] A human antibody, a non-human antibody, a chimeric antibody, or a humanized antibody can be obtained by any means, including via in vitro sources (e.g., a hybridoma or a cell line producing an antibody recombinantly) and in vivo sources (e.g., rodents, human tonsils). Methods for generating antibodies are known in the art and are described in, for example, Kohler and Milstein, Eur. J. Immunol ., 5: 511-519 (1976); Harlow and Lane (eds.), Antibodies: A Laboratory Manual, CSH Press (1988); and Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, N.Y. (2001)). In some aspects, a human antibody or a chimeric antibody can be generated using a transgenic animal (e.g., a mouse) wherein one or more endogenous immunoglobulin genes are replaced with one or more human immunoglobulin genes. Examples of transgenic mice wherein endogenous antibody genes are effectively replaced with human antibody genes include, but are not limited to, the Medarex HUMAB-MOUSE™, the Kirin TC MOUSE™, and the Kyowa Kirin KM-MOUSE™ (see, e.g., Lonberg, Nat. Biotechnol., 23(9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)). A humanized antibody can be generated using any suitable method known in the art (see, e.g., An, Z. (ed.), Therapeutic Monoclonal Antibodies: From Bench to Clinic, John Wiley & Sons, Inc., Hoboken, N.J. (2009)), including, e.g., grafting of non-human CDRs onto a human antibody scaffold (see, e.g., Kashmiri et al., Methods, 36(1): 25-34 (2005); and Hou et al., J. Biochem., 144(1): 115-120 (2008)). In some aspects, a humanized antibody can be produced using the methods described in, e.g., U.S. Patent Application Publication 2011/0287485 Al.

[0093] In some aspects, an antibody or antigen-binding fragment provided herein specifically binds to K. pneumoniae 01 and 02 antigens as measured by biolayer interferometry. In some aspects, an antibody or antigen-binding fragment provided herein specifically binds to K. pneumoniae 01 antigens as measured by confocal microscopy. In some aspects, an antibody or antigen-binding fragment provided herein specifically binds to K. pneumoniae 02 antigens as measured by confocal microscopy. In some aspects, an antibody or antigen-binding fragment provided herein specifically binds to K. pneumoniae 01 and 02 antigens as measured by biolayer interferometry and by confocal microscopy.

[0094] In some aspects, the antibody or antigen-binding fragment thereof has similar binding affinities for K. pneumoniae serotype 01 LPS and K. pneumoniae serotype 02 LPS, e.g., as shown for B39 in Figure 1.

[0095] In some aspects, the antibodies or antigen-binding fragments provided herein have therapeutic activity in a K. pneumoniae murine pneumonia model. Exemplary K. pneumoniae murine pneumonia models are provided herein in Example 2. Therapeutic activity in K. pneumoniae murine pneumonia models can be demonstrated, e.g., by increased survival in mice receiving the antibody or antigen-binding fragment thereof as compared to mice that do not receive a treatment or mice that are treated with a control antibody.

[0096] In the K. pneumoniae murine pneumonia, an antibody or antigen-binding fragment can be administered to a mouse about 30 minutes to about 2 hours (e.g., about 1 hour) after administering K. pneumoniae bacteria to the mouse. The antibody or antigen binding fragment can be administered, e.g., intravenously. The antibody or antigen binding fragment can be administered, e.g., in an amount from about 1 to about 30 mg/kg.

[0097] In the K. pneumoniae murine pneumonia, the bacteria can be administered to the mice intranasally. In a K. pneumoniae 01 murine pneumonia model, the 01 bacteria can be, for example, K. pneumoniae 1131115, which can be administered, e.g., at about 6xl0⁷ CFU. In a K. pneumoniae 02 murine pneumonia model, the 02 bacteria can be, for example, K. pneumoniae 961842, which can be administered, e.g., at about 2xl0⁸ CFU.

[0098] The mice used a K. pneumoniae murine pneumonia model (e.g., K. pneumoniae

01 murine pneumonia model and/or a K. pneumoniae 02 murine pneumonia model) can be C57BL/6 mice.

[0099] In some aspects, the K. pneumoniae antibodies and antigen-binding fragments provided herein have therapeutic activity in a K. pneumoniae 01 murine pneumonia model. [0100] In some aspects, the K. pneumoniae antibodies and antigen-binding fragments provided herein have therapeutic activity in a K. pneumoniae 02 murine pneumonia model.

[0101] In some aspects, when treated with an antibody or antigen-binding fragment provided herein, at least 50% of mice in a K. pneumoniae 01 murine pneumonia model and at least 50% of the mice in a K. pneumoniae 02 murine pneumonia model survive at least 100 hours post-infection.

[0102] In some aspects, an antibody or antigen-binding fragment provided herein induces opsonophagocytic killing (OPK) oiK. pneumoniae serotypes 01 and 02, e.g., in an OPK assay as provided herein in Example 1.

[0103] In some aspects, an antibody or antigen-binding fragment provided herein (e.g., at a dose of 1 mg/kg) increases survival (e.g., as compared to untreated mice or mice treated with a control antibody) in mice exposed to an 01 K. pneumoniae , e.g., 1131115. In some aspects, an antibody or antigen-binding fragment provided herein (e.g., at a dose of 15 mg/kg) increases survival in mice (e.g., as compared to untreated mice or mice treated with a control antibody) exposed to an 02 K. pneumoniae , e.g., 961842. In some aspects, an antibody or antigen-binding fragment provided herein increases survival (e.g., as compared to untreated mice or mice treated with a control antibody) in mice exposed to an 01 f. pneumoniae e.g., 1131115 (optionally when administered at a dose of 1 mg/kg) and increases survival (e.g., as compared to untreated mice or mice treated with a control antibody) in mice exposed to an 02 K. pneumoniae , e.g., 961842 (optionally when administered at a dose of 15 mg/kg).

III. Nucleic acids, vectors, and host cells

[0104] Also provided herein are one or more isolated nucleic acid sequences that encode an antibody or antigen-binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens (optionally wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or fragment).

[0105] The disclosure further provides one or more vectors comprising one or more nucleic acid sequences encoding an antibody or antigen-binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens (optionally wherein the antibody or antigen binding fragment thereof is a monoclonal antibody or fragment). The vector can be, for example, a plasmid, episome, cosmid, viral vector (e.g., retroviral or adenoviral), or phage. Suitable vectors and methods of vector preparation are well known in the art (see, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 3rd edition , Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2001), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994)).

[0106] In addition to the nucleic acid sequence encoding the antibody or antigen-binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens (optionally wherein the antibody or antigen-binding fragments thereof is a monoclonal antibody or fragment), the vector can comprise expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, that provide for the expression of the coding sequence in a host cell. Exemplary expression control sequences are known in the art and described in, for example, Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0107] The vector(s) comprising the nucleic acid(s) encoding the antibody or antigen binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens (optionally wherein one or more of the antibodies or antigen-binding fragments thereof is a monoclonal antibody or fragment) can be introduced into a host cell that is capable of expressing the polypeptides encoded thereby, including any suitable prokaryotic or eukaryotic cell. As such, the present disclosure provides an isolated cell comprising the vector. Host cells that can be used include those that can be easily and reliably grown, have reasonably fast growth rates, have well characterized expression systems, and can be transformed or transfected easily and efficiently. Examples of suitable prokaryotic cells include, but are not limited to, cells from the genera Bacillus (such as Bacillus subtilis and Bacillus brevis), Escherichia (such as E. coli), Pseudomonas, Streptomyces, Salmonella , and Erwinia. Particularly useful prokaryotic cells include the various strains of Escherichia coli (e.g., K12, HB101 (ATCC No. 33694), DH5a, DH10, MC1061 (ATCC No. 53338), and CC102). Suitable eukaryotic cells are known in the art and include, for example, yeast cells, insect cells, and mammalian cells. In some aspects, the vector is expressed in mammalian cells. A number of suitable mammalian host cells are known in the art, and many are available from the American Type Culture Collection (ATCC, Manassas, VA). Examples of suitable mammalian cells include, but are not limited to, Chinese hamster ovary cells (CHO) (ATCC No. CCL61), CHO DHFR- cells (Urlaub et al, Proc. Natl. Acad. Sci. USA, 97: 4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (ATCC No. CRL1573), and 3T3 cells (ATCC No. CCL92). Other suitable mammalian cell lines are the monkey COS-1 (ATCC No. CRL1650) and COS-7 cell lines (ATCC No. CRL1651), as well as the CV-1 cell line (ATCC No. CCL70).

[0108] The mammalian cell can be a human cell. For example, the mammalian cell can be a human lymphoid or lymphoid derived cell line, such as a cell line of pre-B lymphocyte origin, a PER.C6® cell line (Crucell Holland B.V., The Netherlands), HeLa cells, or human embryonic kidney (HEK) 293 or 293T cells (ATCC No. CRL1573).

[0109] A nucleic acid sequence encoding amino acids of any of the antibodies or antigen binding fragments (optionally monoclonal antibodies or fragments) described herein can be introduced into a cell by transfection, transformation, or transduction.

IV. Pharmaceutical compositions and methods of using anti-Ol and 02 K. pneumoniae antibodies

[0110] The present disclosure provides compositions comprising an antibody or antigen binding fragment thereof described herein and a pharmaceutically acceptable carrier.

[0111] The present disclosure also provides compositions comprising one or more nucleic acid sequences encoding an antibody or antigen-binding fragment thereof provided herein, or one or more vectors comprising such nucleic acid sequences.

[0112] A composition provided herein (e.g., comprising an antibody or antigen-binding fragment thereof, one or more nucleic acid sequences, or one or more vectors) can be a pharmaceutically acceptable (e.g., physiologically acceptable) composition, which comprises a carrier, such as a pharmaceutically acceptable (e.g., physiologically acceptable) carrier and the antibody or antigen-binding fragment, nucleic acid sequence(s), or vector(s).

[0113] Any suitable carrier can be used within the context of the disclosure, and such carriers are well known in the art. The choice of carrier will be determined, in part, by the particular site to which the composition can be administered and the particular method used to administer the composition. The composition optionally can be sterile. The composition can be frozen or lyophilized for storage and reconstituted in a suitable sterile carrier prior to use. The compositions can be generated in accordance with conventional techniques described in, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA (2001).

[0114] The composition desirably comprises the antibody or antigen-binding fragment in an amount that is effective to treat and/or prevent a K. pneumoniae infection. To this end, the disclosed method comprises administering a therapeutically effective amount or prophylactically effective amount of an antibody or antigen-binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens or a composition comprising the aforementioned antibody or antigen-binding fragment thereof (including monoclonal antibodies or fragments).

[0115] The disclosure provides a method of treating or preventing a Klebsiella pneumonia (K. pneumoniae ) infection in a subject (e.g., a human), which comprises administering the antibody or antigen-binding fragment described herein to a subject in need thereof, whereupon the K. pneumoniae infection is treated or prevented in the subject. In some aspects, treating or preventing a K. pneumoniae infection includes inhibiting the growth of Klebsiella or reducing the number of Klebsiella in a subject infected with Klebsiella (including e.g., antibiotic-resistant Klebsiella ) The disclosure also provides use of antibody or antigen-binding fragment, described herein, or the composition comprising the antibodies or fragments thereof described herein, in the manufacture of a medicament for treating or preventing a K pneumoniae infection. Non limiting examples of conditions associated with a Klebsiella infection include pneumonia, urinary tract infection, septicemia / sepsis, neonatal septicemia, diarrhea, soft tissue infections, infections following an organ transplant, surgery infection, wound infection, lung infection, pyogenic liver abscesses, endophthalmitis, meningitis, necrotizing meningitis, ankylosing spondylitis and spondyloarthropathies. In some aspects, the Klebsiella infection is a nosocomial infection. In some aspects, the Klebsiella infection is an opportunistic infection. In some aspects, the Klebsiella infection follows an organ transplant. In some aspects, the subject is exposed to & Klebsiella contaminated medical device, including, e.g., a ventilator, a catheter, or an intravenous catheter.

[0116] In certain instances, a therapeutically effective amount of the K pneumoniae LPS- binding antibody or antigen-binding fragment, is an amount which inhibits K pneumoniae infections and related symptoms, e.g., sepsis, in a human. [0117] Alternatively, the pharmacologic and/or physiologic effect can be prophylactic, i.e., the effect completely or partially prevents a disease or symptom thereof. In this respect, the disclosed method comprises administering a “prophylactically effective amount” of the anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment, (including monoclonal antibodies or fragments).

[0118] Therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment can be repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens can be useful and are within the scope of the present disclosure. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.

[0119] The composition(s) comprising an effective amount of an antibody or antigen binding fragment thereof described herein, nucleic acid sequence(s) encoding any of the foregoing, or vector(s) comprising the nucleic acid sequence can be administered to a subject, such as a human, using standard administration techniques, including intravenous, intraperitoneal, subcutaneous, and intramuscular administration routes. The composition can be suitable for parenteral administration. The term “parenteral,” as used herein, includes intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In some aspects, the composition is administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0120] The anti-Ol and 02 K. pneumoniae antibody or antigen-binding fragment or composition comprising the same, can be administered alone or in combination with other drugs (e.g., as an adjuvant) conventionally used for treating f. pneumoniae infections.

The composition comprising the anti-01 and 02 K. pneumoniae antibody or antigen binding fragment can be used in combination with, for example, one or more antibiotics, including cephalosporins, aminoglycosides, quinolones, fluoroquinolones, tetracyclines, chloramphenicols, trimethoprims, sulfonamides, carbapenems, penicilins, b-lactamase inhibitors, rifamycins, macrolides, and/or colistins.

[0121] The anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment or composition comprising the same and the antibiotic can be administered simultaneously or sequentially. The anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment or composition comprising the same can be administered in the same pharmaceutical composition. The anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment or composition comprising the same can be administered in separate pharmaceutical compositions simultaneously or sequentially.

[0122] In addition to therapeutic and prophylactic uses, any antibody or antigen-binding fragment thereof described herein can be used in diagnostic or research applications. In this respect, the anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment can be used in an assay to monitor f. pneumoniae infection in a subject. Research applications include, for example, methods that utilize the anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment and a label to detect K. pneumoniae in a sample, e.g., in a human body fluid or in a cell or tissue extract. The anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment can be used with or without modification, such as covalent or non-covalent labeling with a detectable moiety. For example, the detectable moiety can be a radioisotope (e.g., ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵I), a fluorescent or chemiluminescent compound (e.g., fluorescein isothiocyanate, rhodamine, or luciferin), an enzyme (e.g., alkaline phosphatase, beta-galactosidase, or horseradish peroxidase), or prosthetic groups. Any method known in the art for separately conjugating an antibody or antigen-binding fragment thereof to a detectable moiety can be employed in the context of the present disclosure (see, e.g., Hunter et ah, Nature , 194: 495-496 (1962); David et ah, Biochemistry, 13: 1014-1021 (1974); Pain et ah, J. Immunol. Meth., 40: 219-230 (1981); and Nygren, J., Histochem. And Cytochem., 30: 407-412 (1982)).

[0123] Any antibody or antigen-binding fragment thereof described herein (e.g., monoclonal antibodies or fragments), the nucleic acid sequence(s) encoding any of the foregoing, the vector(s) comprising the nucleic acid sequence(s), or the composition(s) comprising any of the foregoing, can be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a diagnostic assay. If the anti-01 and 02 K. pneumoniae antibody or antigen-binding fragment is labeled with an enzyme, the kit desirably includes substrates and cofactors required by the enzyme (e.g., a substrate precursor which provides a detectable chromophore or fluorophore). In addition, other additives can be included in the kit, such as stabilizers, buffers (e.g., a blocking buffer or lysis buffer), and the like. The relative amounts of the various reagents can be varied to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay. The reagentscan be provided as dry powders (typically lyophilized), including excipients which on dissolution will provide a reagent solution having the appropriate concentration.

[0124] The following examples further illustrate the present disclosure but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1

[0125] This example describes the production and in vitro characterization of the anti K. pneumoniae B39.

[0126] B39 was isolated in a phage display campaign against K. pneumoniae. It originated from a three-round output, in which two rounds were performed on K. pneumoniae 43816 M, and a third round was performed on K. pneumoniae 43816 WT. K. pneumoniae 43816 (Kp 43816) is an American Type Culture Collection (ATCC) strain (ATCC 43816). The 43816 M strain was generated by deleting a gene within cpsB of Kp 43816. The 43816 M strain lacks capsular polysaccharide and has an exposed O-antigen. Both of these strains are 01 serotype.

[0127] B39 was shown to bind to LPS purified from both 01 and 02 strains using biolayer interferometry (Figure 1 A). Binding of B39 to K. pneumoniae was also assed using confocal microscopy. In these experiments, K. pneumoniae 43816 M and K. pneumoniae 43816 WT were fixed and treated with B39 (1 pg/ml), and then stained with nuclear stain DAPI and the anti-human antibody AF647. Images were acquired using an Octet system with 63 x magnification (ForteBio, San Jose, CA), and visualized by Columbus image-analysis software (PerkinElmer, Waltham, MA). The images demonstrated that the epitope of B39 is accessible on encapsulated K. pneumoniae 43816 (Figure IB).

Opsonophagocytic Killing (OPK) Assay

[0128] B39 was also tested in an in vitro opsonophagocytic killing (OPK) assay, in which it was found to be a highly potent promoter of killing by primary human macrophages (Figure 1C).

[0129] OPK assays were performed as described by (Wang et ak, J Infect Dis 273: 1800-8

(2016)) with some modifications. Briefly, overnight K. pneumoniae 43816 M harboring the plasmid pLux containing the luxABCDE operon were collected and resuspended at approximately 3.0^c10⁵ cells/ml in OPK buffer (RPMI 1640 medium without phenol red (Gibco, Thermo Fisher Scientific, Waltham, MA) + 1% BSA (Sigma-Aldrich, St. Louis, MO)). Baby rabbit serum (Cedarlane Labs, Burlington, NC) providing complement was diluted 1 in 10 in OPK buffer and incubated with K. pneumoniae for 1 hour to clear the complement of existing antibodies. Test antibodies were serially diluted in OPK buffer at 4 times the test concentration. Monocyte-derived macrophages (MDMs) at 3.0^c10⁴ cells/well in 96-well white, clear bottom microplates (Corning, Tewksbury, MA) were suspended in 25 pi OPK buffer. Antibodies, bacteria, and complement (25 mΐ of each) were added to the 96-well plate containing macrophages. The plates were sealed with Breathe-Easy sealing membranes (Merck, Kenilworth, NJ) and incubated at 37 °C for 5 hours with 5% C02. Total luminescence units were read using an Envision multilabel plate reader (PerkinElmer, Waltham, MA). Killing (%) was calculated by comparing signal of test IgG wells to signal of wells without antibody.

[0130] B39 was also found to promote enhanced clearance of K. pneumoniae in an high- content imaging OPK assay, as compared to clearance of K. pneumoniae by Nip228, the negative isotype control (Figure ID). Briefly, Kp 43816 M bacteria were added to plates containing primary human macrophages and incubated for 7 hours. At 7 hours, plates were fixed and treated with rabbit polyclonal anti-43816, then stained with nuclear stain Hoechst (blue), AF488 anti-rabbit (green) and cell mask orange. Images were acquired using an Octet system with 20 x magnification (ForteBio, San Jose, CA), and visualized by Columbus image-analysis software (PerkinElmer, Waltham, MA).

[0131] Taken together, these data demonstrate that B39 is a promising therapeutic construct.

EXAMPLE 2

[0132] The therapeutic activity of B39, which specifically binds K. pneumoniae , was assessed using murine models of pneumonia.

[0133] Because B39 was able to bind to both 01 and 02 LPS by biolayer interferometry

(Figure 1A), both K. pneumoniae serotype 01 and serotype 02 bacterial challenge models were performed. The in vivo experiments were performed using methods described previously (Pennini et ak, Nature Communications , 8:1991, doi: 10.1038/s41467-017-02223-72017). Both strains utilized in these experiments (i.e., Kp 1131115 (01) and Kp 961842 (02)), are multi-drug resistant. IgG constructs were expressed and purified, and tested to confirm the absence of endotoxin. C57BL/6 mice were infected intranasally with 6.0 x 10⁷ cfu K. pneumoniae 1131115 (01 pneumonia model) or 2.0><10⁸ cfu f pneumoniae 961842 (02 pneumonia model). In the 01 pneumonia model, 15 mg/kg, 1 mg/kg, and 0.2 mg/kg (mpk) dosages of B39 were tested. In the 02 pneumoniae model, 30 mg/kg, 15 mg/kg, and 1 mg/kg (mpk) dosages of B39 were tested. The IgG constructs were administered intravascularly one hour post infection at various doses as indicated. For each model, other antibodies to the 01 and 02 serotypes were provided to one animal in each group as a benchmark. The benchmark antibody against 01 is KPE33 (see WO 2018/075375, which is herein incorporated by reference in its entirety). The benchmark antibody against 02 is referred to as “02 IgG”. Isotype control antibody RS347 was included in all experiments. Three independent experiments were performed, each with 8 mice per group. The experimental design is shown Figure 2. B39 was protective in both 01 and 02 models. The results from one representative experiment of each model is shown in Figures 3 A and 3B and discussed further below.

[0134] In the 01 pneumonia model, B39 at 1 mpk was as protective as the benchmark

IgG, KPE33, at the same dose. Treatments with both B39 and KPE33 led to an 87.5 % survival rate at day 7, compared to a 12.5 % survival rate at day 7 when treated with isotype control RS347 (P < 0.01). At 0.2 mpk, B39 was less protective than KPE33, with 7 day survival rates of 62.5 % and 75 % respectively. At the highest concentration of 15 mpk, B39 elicited a 100 % survival rate at day 7. KPE33 was not tested at this concentration. This data suggests that B39 is as effective as the benchmark IgG (KPE33) at promoting in vivo survival against 01 pneumoniae.

[0135] In the 02 pneumonia model, B39 elicited a 87.5 % survival rate at day 7 at both

30 and 15 mpk, similar to the benchmark 02 IgG at a dose of 0.4 mpk (P < 0.01). At 1 mpk, B39 performed similarly to 02 IgG at 0.2 mpk, with a 62.5 % survival rate at day 7 (P< 0.1). This result indicates that B39 is protective in an in vivo model of 02 pneumonia. However, a higher dose than the 02 IgG control is required to elicit the same level of protection. [0136] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Claims

WHAT IS CLAIMED IS:

1. An antibody or antigen-binding fragment thereof that specifically binds to Klebsiella pneumoniae (K. pneumoniae) 01 and 02 antigens, wherein the antibody or antigen binding fragment thereof is capable of inducing opsonophagocytic killing (OPK) in K. pneumoniae 01 and 02 strains.

2. An antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof is has therapeutic activity in both a K. pneumoniae 01 murine pneumonia model and a K. pneumoniae 02 murine pneumonia model.

3. The antibody or antigen-binding fragment thereof of claim 2, wherein the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse about 1 hour after administering K. pneumoniae 01 bacteria to the mouse.

4. The antibody or antigen-binding fragment thereof of claim 2 or 3, wherein the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering K. pneumoniae 1131115 bacteria to the mouse.

5. The antibody or antigen-binding fragment thereof of any one of claims 2-4, wherein the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering about 6xl0⁷ cfu of K. pneumoniae 01 bacteria to the mouse.

6. The antibody or antigen-binding fragment thereof of any one of claims 2-5, wherein the K. pneumoniae 01 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after intranasally administering K. pneumoniae 01 bacteria to the mouse.

7. The antibody or antigen-binding fragment thereof of any one of claims 2-6, wherein the K. pneumoniae 01 murine pneumonia model comprises intravenously administering the antibody or antigen-binding fragment thereof to a mouse after administering K. pneumoniae 01 bacteria to the mouse.

8. The antibody or antigen-binding fragment thereof of any one of claims 2-7, wherein the K. pneumoniae 01 murine pneumonia model comprises administering about 1 mg/kg of the antibody or antigen-binding fragment thereof to a mouse after administering K. pneumoniae 01 bacteria to the mouse.

9. The antibody or antigen-binding fragment thereof of any one of claims 2-8, wherein the K. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse about 1 hour after administering K. pneumoniae 02 bacteria to the mouse.

10. The antibody or antigen-binding fragment thereof of any one of claims 2-9, wherein the K. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering f. pneumoniae 961842 bacteria to the mouse.

11. The antibody or antigen-binding fragment thereof of any one of claims 2-10, wherein the K. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after administering about 2xl0⁸ cfu of K. pneumoniae 02 bacteria to the mouse.

12. The antibody or antigen-binding fragment thereof of any one of claims 2-11, wherein the K. pneumoniae 02 murine pneumonia model comprises administering the antibody or antigen-binding fragment thereof to a mouse after intranasally administering K. pneumoniae 02 bacteria to the mouse.

13. The antibody or antigen-binding fragment thereof of any one of claims 2-12, wherein the K. pneumoniae 01 murine pneumonia model comprises intravenously administering the antibody or antigen-binding fragment thereof to a mouse after administering K. pneumoniae 02 bacteria to the mouse.

14. The antibody or antigen-binding fragment thereof of any one of claims 2-13, wherein the K. pneumoniae 02 murine pneumonia model comprises administering about 1 mg/kg of the antibody or antigen-binding fragment thereof to a mouse after administering K. pneumoniae 02 bacteria to the mouse.

15. The antibody or antigen-binding fragment thereof of any one of claims 2-14, wherein the K. pneumoniae 01 murine pneumonia model and/or the K. pneumoniae 01 murine pneumonia model infects C57BL/6 mice.

16. The antibody or antigen-binding fragment thereof of any one of claims 2-15, wherein administration of the antibody or antigen-binding fragment thereof results in at least 50% survival 100 hours post-infection in both the K. pneumoniae 01 murine pneumonia model and the K. pneumoniae 02 murine pneumonia model.

17. The antibody or antigen-binding fragment of any one of claims 1-16, wherein the antibody or antigen-binding fragment comprises a variable heavy chain (VH) complementarity determining region (CDR) 1, a VH CDR2, a VH CDR3, a variable light chain (VL) CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise sequences selected from the group consisting of: SEQ ID NOs:3, 4, 5, 8, 9, and 10, respectively.

18. An antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment comprises a variable heavy chain (VH) complementarity determining region (CDR) 1, a VH CDR2, a VH CDR3, a variable light chain (VL) CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise sequences selected from the group consisting of: SEQ ID NOs:3, 4, 5, 8, 9, and 10, respectively.

19. An antibody or antigen-binding fragment thereof that specifically binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of B39.

20. The antibody or antigen-binding fragment thereof of claim 19, wherein the CDRs are the Kabat-defmed CDRs, the Chothia-defmed CDRs, the IMGT-defmed CDRs, or the AbM- defined CDRs.

21. The antibody or antigen-binding fragment thereof of any one of claims 1-20, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO:2.

22. The antibody or antigen-binding fragment thereof of any one of claims 1-20, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO:7.

23. The antibody or antigen-binding fragment thereof of any one of claims 1-20, wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the sequence of SEQ ID NO:2 and a VL comprising the sequence of SEQ ID NO:7.

24. An antibody or antigen-binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof binds to the same epitope as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:2 and a VL comprising the amino acid sequence of SEQ ID NO:7.

25. An antibody or antigen-binding fragment thereof that binds to K. pneumoniae 01 and 02 antigens, wherein the antibody or antigen-binding fragment thereof competitively inhibits binding of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:2 and a VL comprising the amino acid sequence of SEQ ID NO:7 to K. pneumoniae.

26. The antibody or antigen-binding fragment thereof of any one of claims 1-25, wherein the antibody or antigen-binding fragment neutralizes the K. pneumoniae serotype 01 and/or serotype 02 bacteria.

27. The antibody or antigen-binding fragment thereof of any one of claims 1-26, wherein the antibody or antigen-binding fragment thereof is capable of inducing opsonophagocytic killing (OPK) in K. pneumoniae 01 and 02 strains.

28. The antibody or antigen-binding fragment thereof of any one of claims 1 and 17-27, wherein the antibody or antigen-binding fragment thereof has therapeutic activity in a K. pneumoniae 01 murine pneumonia model.

29. The antibody or antigen-binding fragment thereof of any one of claims 1 and 17-28, wherein the antibody or antigen-binding fragment thereof has therapeutic activity in a K. pneumoniae 02 murine pneumonia model.

30. The antibody or antigen-binding fragment thereof of any one of claims 1-29, wherein the antibody or antigen-binding fragment further comprises a heavy chain constant region.

31. The antibody or antigen-binding fragment thereof of claim 30, wherein the heavy chain constant region is selected from the group consisting of human immunoglobulin IgGi, IgG2, IgG3, IgG4, IgAi, and IgA2 heavy chain constant regions.

32. The antibody or antigen-binding fragment thereof of claim 31, wherein the heavy chain constant region is a human IgGi constant region.

33. The antibody or antigen-binding fragment thereof of any one of claims 1-32, wherein the antibody or antigen-binding fragment further comprises a light chain constant region.

34. The antibody or antigen-binding fragment thereof of claim 33, wherein the light chain constant region is selected from the group consisting of human immunoglobulin IgGK and IgG light chain constant regions.

35. The antibody or antigen-binding fragment thereof of claim 34, wherein the light chain constant region is a human IgGK light chain constant region.

36. The antibody or antigen-binding fragment thereof of any one of claims 1-35, wherein the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof.

37. The antibody or antigen-binding fragment thereof of any one of claims 1-36, wherein the antibody or antigen-binding fragment thereof comprises an Fc region that has been engineered to improve half-life.

38. The antibody or antigen-binding fragment thereof of any one of claims 1-37, wherein the antibody or antigen-binding fragment thereof comprises an Fc region with a YTE mutation and/or an N3 Y mutation.

39. The antibody or antigen-binding fragment thereof of any one of claims 1-38, wherein the antibody or antigen-binding fragment is a monoclonal antibody or antigen-binding fragment.

40. The antibody or antigen-binding fragment thereof of any one of claims 1-39, wherein the antibody or antigen-binding fragment is a full-length antibody.

41. The antibody or antigen-binding fragment thereof of any one of claims 1-39, wherein the antibody or antigen-binding fragment is an antigen-binding fragment.

42. The antigen-binding fragment of claim 41, wherein the antigen-binding fragment comprises a Fab, Fab', F(ab')2, single chain Fv (scFv), disulfide linked Fv, intrabody, IgGACFLZ, minibody, F(ab')3, tetrabody, triabody, diabody, DVD-Ig, Fcab, mAb²,

(SCFV)2, or scFv-Fc.

43. The antigen-binding fragment of claim 52, wherein the antigen-binding fragment comprises an scFv.

44. The antibody or antigen-binding fragment thereof of any one of claims 1-43, wherein the antibody or antigen-binding fragment thereof has similar binding affinities for K. pneumoniae serotype 01 LPS and K. pneumoniae serotype 02 LPS.

45. The antibody or antigen-binding fragment thereof of any one of claims 1-44, further comprising a detectable label.

46. An isolated polynucleotide comprising a nucleic acid molecule encoding the VH or heavy chain of the antibody or antigen-binding fragment thereof of any one of claims 1-45, optionally wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO:l.

47. An isolated polynucleotide comprising a nucleic acid molecule encoding the VL or light chain of the antibody or antigen-binding fragment thereof of any one of claims 1-45, optionally wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO:6.

48. An isolated vector comprising the polynucleotide of claim 46 and/or claim 47.

49. A host cell comprising the polynucleotide of claim 46 and/or 47, the vector of claim 48, or a first vector comprising the polynucleotide of claim 46 and a second vector comprising the polynucleotide of claim 47.

50. The host cell of claim 49, wherein the host cell is selected is a prokaryotic or eukaryotic cell.

51. The host cell of claim 49 or 50, wherein the host cell is isolated.

52. A method of producing an antibody or antigen-binding fragment thereof comprising culturing the host cell of any one of claims 49-51 so that the antibody or antigen-binding fragment thereof is produced.

53. An isolated antibody or antigen-binding fragment thereof that is encoded by the polynucleotide of any one of claims 46-47 or produced by the method of claim 52.

54. A composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1-45 or 53 and, optionally, a pharmaceutically-acceptable carrier.

55. A method of treating or preventing a K. pneumoniae infection in a subject comprising administering to the subject the antibody or antigen-binding fragment of any one of claims 1-45 or 53 or the composition of claim 54.

56. The method of claim 55, wherein the K. pneumoniae infection is meningitis.

57. The method of claim 55, wherein the K. pneumoniae infection is a urinary tract infection (UTI).

58. The method of claim 55, wherein the K. pneumoniae infection is a bloodstream infection.

59. The method of claim 55, wherein the K. pneumoniae infection is septicemia.

60. The method of claim 55, wherein the K. pneumoniae infection is pneumonia.

61. The method of claim 55, wherein the K. pneumoniae infection is bronchopneumonia or bronchitis.

62. The method of claim 54, wherein the K. pneumoniae infection is ICU pneumonia.

63. The method of claim 55, wherein the K. pneumoniae infection is a skin or soft tissue infection (SSTI).

64. The method of claim 55, wherein the K. pneumoniae is an infection associated withdiarrhea.

65. The method of claim 55, wherein the K pneumoniae infection is an infection following an organ transplant.

66. The method of claim 55, wherein the K pneumoniae infection is a surgery infection.

67. The method of claim 55, wherein the K pneumoniae infection is a wound infection.

68. The method of claim 55, wherein the K pneumoniae infection is a lung infection.

69. The method of claim 55, wherein the K pneumoniae infection is a pyogenic liver abscess.

70. The method of claim 55, wherein the K pneumoniae infection is endophthalmitis.

71. The method of claim 55, wherein the f. pneumoniae infection is ankylosing spondylitis.

72. The method of claim 55, wherein the K pneumoniae infection is a spondyloarthropathy.

73. The method of any one of claims 55-72, wherein the K pneumoniae infection is a nosocomial infection.

74. The method of any one of claims 55-73, wherein the K pneumoniae infection is an opportunistic infection.

75. The method of any one of claims 55-74, wherein the K pneumoniae infection is an infection caused by exposure to a f/efc/e//a-contaminated medical device.

76. The method of any one of claims 55-75, wherein the K pneumoniae infection comprises antibiotic-resistant K pneumoniae.

77. The method of any one of claims 55-76, wherein the subject is a surgical subject.

78. The method of any one of claims 55-77, wherein the subject is human.

79. The method of any one of claims 55-78, wherein the antibody or antigen-binding fragment thereof inhibits the growth of Klebsiella or reduces the number of Klebsiella in the subject.

80. A method for detecting K. pneumoniae or K. pneumoniae LPS in a sample comprising contacting said sample with the antibody or antigen-binding fragment thereof of any one of claims 1-45 or 53.