Clostridium difficile binary toxin neutralizing antibodies

Abstract

The present invention provides isolated Clostridium difficile binary toxin antibodies that are capable of neutralizing binary toxin with high potency, polypeptides and nucleic acids encoding the same, and methods of use thereof.

Description

[0001] CLOSTRIDIUM DIFFICILE BINARY TOXIN NEUTRALIZING ANTIBODIES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Appl. No.:63 / 698,989, filed September 25, 2024. The content of the aforementioned application is relied upon and is incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under Grant Numbers AI152397 and GM152511 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY Incorporated by reference in its entirety herein is a computer-readable sequence listing submitted concurrently herewith and identified as follows: One 53,673 Byte xml file named “Sequence_Listing.xml,” created on September 19, 2025. FIELD OF THE INVENTION The field of the invention relates to medicine and infectious diseases, in particular therapeutics to treat or prevent Clostridium difficile infection. BACKGROUND OF THE INVENTION Clostridium difficile is a Gram-positive, spore-forming obligate anaerobe that can be found in the gastrointestinal tract of up to 15% of healthy adults (Schaffler et al., Front Microbiol (2018), 9:646). Its growth is held in check by indigenous microflora. Extended antibiotic prophylaxis could predispose the gut to growth of antibiotic-resistant C. difficile (Warren et al., Lancet, (2011), 377:8-9). Notably, C. difficile infection produces toxins that cause mucosal damage and inflammation, leading to symptoms ranging from diarrhea to pseudomembranous colitis, a life-threatening inflammation of the colon. CDAD is the fastest growing hospital-acquired infection and has surpassed staphylococcal infections in frequency and severity. There were over 500,000 cases of CDAD in the United States this year, up from 150,000 cases in 2001, with an annual death toll exceeding 15,000 according to the CDC reports. CDAD is now the most common cause of infectious diarrhea in hospitals and long-term care settings, leading to over 11,000 deaths each year and an annual economic burden of $3.2 billion in the U.S. (Hall et al., Clin Infect Dis, (2012), 55:216- 23; Dubberke et al., Clin Infect Dis, (2008), 46:497-504; O'Brien et al., Infect Control Hosp Epidemiol, (2007), 28:1219-27). Development of robust and effective therapeutics that can target C. difficile bacteria and / or its toxins in the gastrointestinal tract is critical. Two major toxins of C. difficile, TcdA and TcdB target gut epithelial cells by binding the putative carbohydrate receptor. Over the past decade, the number of patients with hypervirulent strains of C. difficile increased significantly (Deshpande et al., The Pediatric Infectious Disease Journal, (2013), 32:1138-1140; Deshpande et al., Infect Control Hosp Epidemiol, (2015), 36:452- 60). Vaccines provide efficacy against CDAD strains having the TcdA and TcdB toxins, but they work poorly, if at all, against hypervirulent strains, which harbor a third toxin termed the “binary toxin”, which is increasingly recognized being responsible for the enhanced virulence. The binary toxin has an enzymatic subunit, CDTa (47.4 kDa), with ribosyltransferase activity, and a cell-binding / pore-forming subunit, termed CDTb (Fig. 1, Fig. 2), which is initially produced and secreted as an inactive form, namely proCTDb (Gerding et al., Gut Microbes, (2014), 5:15-27). Upon secretion from the bacterium, a proteolytically activated 74 kDa CDTb subunit associates into a dimer of heptamers (> 1 MDa). CDTb binds host cell receptors such as the lipolysis-stimulated lipoprotein receptor (LSR) and / or CD44. CDTa / CDTb is reported to be internalized by endosomes. Followed by delivery into the cytoplasm, CDTa binds NAD+ and modifies G-actin via ADP- ribosylation (Fig. 1). This modification leads to F-actin filament dissociation, destruction of the cytoskeleton, microtubule protrusions, accelerated bacterial adhesion, and an accelerated “death spiral” for host cells. Critical functional domains of CDTa and CDTb contribute to the enhanced virulence mediated by binary toxin (Fig.2), as revealed by previous and ongoing structural and functional studies, including the CDTa D1 domain (CDTb binding domain) and D2 domain (active site) (Fig. 2A) as well as the CDTb receptor binding domain (RBD, Fig. 2B) (Roth et al., Biomol NMR Assign, (2016), 10:213-7; Roth et al., Biomol NMR Assign, (2016), 10:335-9). Conceptually, effective therapeutics (e.g. nAbs) should target these functional domains. For instance, a given nAb recognizing CDTb receptor binding domain (RBD) and blocking the initial attachment of binary toxin to host cell receptor LSR should prevent CDTa internalization to the host cell, thus it will abolish cytotoxicity. Currently, neutralizing antibodies to binary toxin are underdeveloped. There have been previously published two monoclonal antibodies that were isolated from immunized mice. These antibodies target the domain 3 (D3 & D3’) and the oligomer interface on the RBD2 of proCDTb, respectively, and show moderate toxin neutralizing potency. What is needed are new and effective therapies, including antibodies, to prevent or treat Clostridium difficile infections. The foregoing description of the background is provided to aid in understanding the invention, and is not admitted to be or to describe prior art to the invention. SUMMARY OF THE INVENTION It is to be understood that both the foregoing general description of the invention and the following detailed description are exemplary, and thus do not restrict the scope of the invention. Clostridium difficile, is an opportunistic pathogen that is asymptomatic in the context of healthy microflora. When symbiotic bacteria become depressed as a side effect of antibiotic treatment, C. difficile grows out of control and produces severe infection. Recently, hypervirulent, antibiotic-resistant C. difficile strains have emerged with increased mortality and recurrence (McDonald et al., N Engl J Med, (2005), 353:2433-41; Warny et al., Lancet, (2005), 366:1079-84). Notably, C. difficile infection produces toxins that cause mucosal damage and inflammation. Development of robust and effective therapeutics that can target C. difficile bacteria and toxins in the gastrointestinal tract is critical for Clostridium difficile-associated disease (CDAD) management. There are three major toxins that contribute to C. difficile virulence: TcdA and TcdB that target gut epithelial cells by binding to their putative carbohydrate receptor, and a third toxin termed the “binary toxin” consisting of two subunits, CTDa and CTDb which are produced and released by hypervirulent C. difficile strains and responsible for the enhanced virulence. While numerous studies demonstrated the efficacy of neutralizing monoclonal antibodies (nAbs) to TcdA (e.g. Actoxumab) and TcdB (e.g. Bezlotoxumab) in animal models and clinical trials, nAbs to binary toxin remain underdeveloped (Babcock et al., Infect Immun, (2006), 74:6339-47; Lowy et al., N Engl J Med, (2010), 362:197-205). Recently, we have isolated a panel of nAbs against C. difficile binary toxin from immunized Cynomolgus macaques that display potent in vitro toxin neutralization activities, which could be developed as therapeutic agents to cure CDAD. In one aspect, the invention provides an isolated Clostridium difficile binary toxin antibody that is capable of neutralizing binary toxin with an IC50 value of less than about 80 pM. In another aspect, the invention provides an isolated Clostridium difficile binary toxin antibody that is capable of neutralizing binary toxin with an IC50 value of from about 10 pM to about 80 pM. In some embodiments, the antibody is B2, B3 or B8, or an antigen binding fragment thereof. In some embodiments, the antibody comprises the VH and VL regions of antibody B2. In some embodiments, the antibody comprises the VH and VL regions of antibody B3. In some embodiments, the antibody comprises the VH and VL regions of antibody B8. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of antibody B2. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of antibody B3. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of antibody B8. In some embodiments, the Clostridium difficile binary toxin antibody is selected from the group consisting of: a. an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSFSSYW (SEQ ID NO:13), IRSGGSN (SEQ ID NO:14) and ARLRGYSNYAGFDY (SEQ ID NO:15); and a light chain variable region, wherein the CDRs comprise amino acid sequences SSNIGTNS (SEQ ID NO:16), YND and ATWDDSLSGYI (SEQ ID NO:17); b. an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSISDYYYW (SEQ ID NO:18), IYGDKTST (SEQ ID NO:19) and ARGVRDGTLKYNRFDV (SEQ ID NO:20); and a light chain variable region, wherein the CDRs comprise amino acid sequences QGISNA (SEQ ID NO:21), AAS and QQYNSYPLT (SEQ ID NO:22); and c. an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSISNNYW (SEQ ID NO:23), IFGSDGST (SEQ ID NO:24) and AREGRGYSDYSY (SEQ ID NO:25); and a light chain variable region, wherein the CDRs comprise amino acid sequences SGISVGGYR (SEQ ID NO:26), YHTDSDN (SEQ ID NO:27) and MIWLNNAGL (SEQ ID NO:28). In some embodiments, the Clostridium difficile binary toxin antibody is selected from the group consisting of: a. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:7 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:8 or an antigen binding fragment thereof; b. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:9 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:10 or an antigen binding fragment thereof; and c. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:11 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:12 or an antigen binding fragment thereof. In some embodiments, the antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain or antigen binding fragment thereof comprises a heavy chain variable (VH) region and the light chain or antigen binding fragment thereof comprises a light chain variable (VL) region; wherein the Clostridium difficile binary toxin antibody is selected from the group consisting of an antibody: a. wherein the VH region comprises SEQ ID NO:7 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:8 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; b. wherein the VH region comprises SEQ ID NO:9 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:10 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and c. wherein the VH region comprises SEQ ID NO:11 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:12 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions. In some embodiments, the antibody is humanized. In some embodiments, the antibody comprises human immunoglobulin heavy and light chain constant regions. In another aspect, the invention provides an isolated host cell expressing the antibody herein. In another aspect, the invention provides one or more vectors comprising a nucleic acid encoding the antibody herein. In some embodiments, one vector encodes a light chain sequence and another vector encodes a heavy chain sequence. In some embodiments, one vector encodes a light chain sequence and a heavy chain sequence. In another aspect, the invention provides a cell comprising the one or more vectors herein. In another aspect, the invention provides an engineered cell that expresses the antibody herein. In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a B cell. In another aspect, the invention provides a pharmaceutical composition comprising one or more antibodies and / or cells herein and a pharmaceutically acceptable carrier. In another aspect, the invention provides a method for treating or preventing Clostridium difficile infection or alleviating one or more symptoms thereof in a subject, comprising administering to the subject an effective amount of the composition herein. In some embodiments, the composition is administered in combination with another therapy. In some embodiments, the therapy is an antibiotic therapy. In some embodiments, the antibiotic is selected from metronidazole, vancomycin, fidaxomicin, and combinations thereof. Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE FIGURES The skilled artisan will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings in any way. FIG. 1. C. difficile infection and a model for “binary toxin (CDT)” action. C. difficile (i.e. NAP1 / BI / 027) binary toxin consists of CDTa(pink / blue) and CDTb (red). The binary toxin is thought to bind the host cell receptors (e.g. LSR) (step 1) and transported via receptor-mediated endocytosis into endosomes (step 2) with CDTa exiting endosomes via the pore-forming CDTb “channel” (step 3). CDTa binds NAD+ in the cytoplasm (step 4) and catalyzes the ribosylation of G-actin at Arg-177 (step 5), which results in actin capping & trapping of F-actin into nonfunctional entities (step 6) and the destruction of the actin cytoskeleton (step 7). Microtubules protrude from the host as a result (step 8), which facilitates bacterial colonization, bacterial resistance, and host cell death (step 9) (Kieckens et al., Vet Microbiol 202:29-37). FIG. 2. CDTa & CDTb functional domain scheme and structure. (A) Crystal structure ofFLCDTa determined in our lab showing domain 1 in red and domain 2 in blue. Note: Domain 1 (D1) contains the CDTb binding domain and Domain 2 (D2) contains the active site of CDTa. (B) CDTb (upper) Diagram of pro-CDTb showing its chymotrypsin cleavage site, ABD (CDTa binding domain), oligomerization and the receptor binding domain (RBD); (Lower) Cryo-EM 3-dimensional classification resulted in two structural families FIG.3. Characterization of binary toxin neutralizing antibodies. NHP animals were immunized with selected CDTa / CDTb immunogens at weeks 0, 2, and 6, followed by immune sera toxin neutralization assay and PBMC preparation. B cells from collected PBMC pool were stained with memory B cell marker cocktail in the presence of fluorescence-labeled CDTa / CDTb antigen probes, and sorted for Ig RT PCR & cloning to recover mAbs encoded by individual B cells. (A) Immunized NHP animal 171076 serum (1 week post the 3rd immunization, Imm3) showed toxin neutralization activity; CDT was incubated with serial dilutions (1:5) of NPH Sera #171076 (week 7) for 30 minutes at room temperature. Vero cells were then challenged with CDT (500 pM) and NHP sera #171076 for 1 hour at 37oC before fixing and staining with Alexa Fluor 488 Phalloidin, which preferentially stains F-actin. Greater Alexa Fluor 488 Phalloidin signal is indicative of diminished CDT toxicity. All data are plotted versus the normalized fluorescence of Alexa Fluor 488 Phalloidin. All experiments were performed in triplicate. (B) RBD2 binding mAbs, B2, B3 & B8, cloned from animal 171076 displayed potent neutralizing activity (IC50 pM scale) against binary toxin, in comparison with reference mAbs BINTOXB / 9 & BINTOXB / 22 published previously. CDT (1 CDTa: 7 CDTb) was challenged with serial dilutions of antibodies B2, B3, and B8 starting at 10 μg / mL (titration points: 10, 5, 2.5, 1.25, 0.75, 0.38, 0.19, 0 μg / mL) and compared to reference CDT-neutralizing antibodies BINTOXB / 22 and BINTOXB / 9 (Goldsmith et. al. 2023) following the same parameters. Vero cells were treated with 500 pM CDT and antibody dilutions for 2 hours at 37oC before fixing and staining with Alexa Fluor 488 Phalloidin, which preferentially stains F- actin. Greater Alexa Fluor 488 Phalloidin signal is indicative of diminished CDT toxicity. All data are plotted versus the normalized fluorescence of Alexa Fluor 488 Phalloidin. All experiments were performed in triplicate. (C) Antibody Cross-Competition Binding Assay Using Bio-Layer Interferometry (BLI). In-house NHP mAbs B3 and B8 target a novel epitope different from previously published mouse-origin RBD2-binding mAb, BINTOXb / 9, of which epitope overlaps with B2). To evaluate potential competition between antibodies for binding to RBD2, a cross-competition binding assay was performed using Bio-Layer Interferometry (BLI) on an Octet RED96 platform (ForteBio, Pall Life Sciences). Biotinylated proCDTb (100 nM) was immobilized onto pre-wetted Octet® SA Biosensors (Sartorius) for 3 minutes, followed by a washing step in 1× kinetics buffer (PBS, 0.02% Tween-20, 0.1% BSA) to remove unbound proteins. The biosensors were then incubated for 10 minutes with the ligand monoclonal antibody (mAb) at a concentration of 10 µg / mL in kinetics buffer, followed by a 60-second wash step in kinetics buffer. Subsequently, the biosensors were transferred to wells containing the analysate mAb (10 µg / mL) for an additional 10-minute incubation. A dissociation phase was then performed by transferring the biosensors to 1× kinetics buffer for 10 minutes. BLI signals were continuously recorded throughout the assay at 24°C, with orbital shaking at 1,000 rpm using 96-well black flat-bottom plates (Greiner, VWR). Maximum binding of the analyte mAb was determined in the absence of the ligand mAb (kinetics buffer only). Therelative binding of the analysate mAb was calculated as: Relative binding = 100 ∗^^^^^^ ^^ ^^^ ^^^^^^^^ ^^ ^^^^^^ ^^^ . ^^^^^^^ ^^^^^^ ^^ ^^^ ^^^^^^^ ^^ ^^^^^^ ^^^ FIG. 4. Epitope determination of binary toxin CDTb RBD-specific nAb B3 by competition binding assay and structural analysis of B3 complexed with RBD2. (A) BLI- based binding assay showing that the in-house NHP nAb B3 mediates the blockage of CDTb binding to receptor LSR. Biotin-labeled proCDTb was initially captured by BLI SA- probe followed by immersing into wells containing test antibodies (PBS as negative control) and wells containing soluble form of recombinant human LSR protein subsequently to collect LSR binding signal. In-house RBD-specific nAb B3 inhibits CDTb- LSR binding, while reference mAb BINTOXb / 9 shows no inhibition. (B) Representative CryoEM 2D class of the B3 Fab-RBD2 complex. (C) Crystal structure of the B3 Fab-RBD2 complex. (Left) overall complex structure: B3 heavy chain (cyan), light chain (magenta), RBD (green); (Right) Detailed protein-protein interface showing contact residues that define antibody-antigen recognition. The heavy chain CDR1 (CDRH1) of nAb B3 makes direct contact with residue F774 on RBD, a putative receptor LSR contact residue identified by previous mutagenesis study. FIG. 5. In vivo efficacy of C. difficile binary toxin RBD-binding nAbs. (A) Combination treatment with anti-TcdA (Actoxumab), anti-TcdB (Bezlotoxumab), and binary toxin nAb-B2 or B3 provided 100% protection in C. difficile-challenged mice. Six- week-old C57BL / 6 mice (N=5 / group) were challenged with a ribotype 027 C. difficile strain expressing TcdA, TcdB, and binary toxin. Treatment was administered via intraperitoneal injection (IP) four hours post-challenge. PBS and an irrelevant human IgG antibody served as negative controls. Survival was analyzed using the Mantel-Cox log- rank test; *p<0.05 indicates statistical significance compared to controls, while "n.s." denotes no significant difference relative to the PBS-treated group. (B) Effect of combination treatment with antibodies on hamsters challenged with C. difficile. (left panel) anti-TcdA (Actoxumab), anti-TcdB (Bezlotoxumab), and binary toxin nAb-B2 or B3 also extend the survival time in C. difficile-challenged hamsters compared to the animals treated with negative control human IgG or anti-TcdA / TcdB only, (right panel) anti-TcdA (Actoxumab), anti-TcdB (Bezlotoxumab), and binary toxin nAb-B2 or B3 reduced body weight decrease of C. difficile-challenged hamster on day 1 post infection. Body weight change was analyzed using Mann-Whitney U test, *p<0.05 indicates statistical significance compared to controls. DETAILED DESCRIPTION OF THE INVENTION The present disclosure provides a panel of C. difficile binary toxin neutralizing antibodies from non-human primates and characterizes the mechanism underlying the toxin neutralization and protection. Due to the high degree of structural and functional similarity with human IgG molecules, neutralizing antibodies of non-human primate origin are more amenable for developing therapeutic antibodies than those derived from other animal species like mice. Reference will now be made in detail to the presently preferred embodiments of the invention which, together with the drawings and the following examples, serve to explain the principles of the invention. These embodiments describe in sufficient detail to enable those skilled in the art to practice the invention, and it is understood that other embodiments may be utilized, and that structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. The practice of the present invention employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual, 2ndedition (1989); Current Protocols in Molecular Biology (F. M. Ausubel et al. eds. (1987)); the series Methods in Enzymology (Academic Press, Inc.); PCR: A Practical Approach (M. MacPherson et al. IRL Press at Oxford University Press (1991)); PCR 2: A Practical Approach (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)); Antibodies, A Laboratory Manual (Harlow and Lane eds. (1988)); Using Antibodies, A Laboratory Manual (Harlow and Lane eds. (1999)); and Animal Cell Culture (R. I. Freshney ed. (1987)).Definitions of common terms in molecular biology may be found, for example, in Benjamin Lewin, Genes VII, published by Oxford University Press, 2000 (ISBN 019879276X); Kendrew et al. (eds.); The Encyclopedia of Molecular Biology, published by Blackwell Publishers, 1994 (ISBN 0632021829); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by Wiley, John & Sons, Inc., 1995 (ISBN 0471186341). For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with the usage of that word in any other document, including any document incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and its associated claims unless a contrary meaning is clearly intended (for example in the document where the term is originally used). The use of "or" means "and / or" unless stated otherwise. As used in the specification and claims, the singular form "a," "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” and “including” are interchangeable and not intended to be limiting. Furthermore, where the description of one or more embodiments uses the term “comprising,” those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language “consisting essentially of” and / or “consisting of.” Abbreviations for amino acids are used throughout this disclosure and follow the standard nomenclature known in the art. For example, as would be understood by those of ordinary skill in the art, Alanine is Ala or A; Arginine is Arg or R; Asparagine is Asn or N; Aspartic Acid is Asp or D; Cysteine is Cys or C; Glutamic acid is Glu or E; Glutamine is Gln or Q; Glycine is Gly or G; Histidine is His or H; Isoleucine is Ile or I; Leucine is Leu or L; Lysine is Lys or K; Methionine is Met or M; Phenylalanine is Phe or F; Proline is Pro or P; Serine is Ser or S; Threonine is Thr or T; Tryptophan is Trp or W; Tyrosine is Tyr or Y; and Valine is Val or V. As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. 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, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments, dual affinity retargeting antibodies (DART)), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific and trispecific antibodies generated from at least two intact 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. In some embodiments, an antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. IgG1, IgG2, IgG3, IgG4, IgA1 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. The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 basic heterotetramer units along with an additional polypeptide called J chain, and therefore contain 10 antigen binding sites, while secreted IgA antibodies can polymerize to form polyvalent assemblages comprising 2-5 of the basic 4-chain units along with J chain. In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable region (VH) followed by three constant domains (CH) for each of the α and γ chains and four CHdomains for µ and ε isotypes. Each L chain has at the N-terminus, a variable region (VL) followed by a constant domain (CL) at its other end. The VLis aligned with the VHand the CLis aligned with the first constant domain of the heavy chain (CH1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable regions. The pairing of a VHand VLtogether forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, Conn., 1994, page 71, and Chapter 6. The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains (CL). Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (µ) respectively. The γ and α classes are further divided into subclasses on the basis of relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The terms "antigen" or "immunogen" are used interchangeably to refer to a substance, typically a protein, which is capable of inducing an immune response in a subject. The term also refers to proteins that are immunologically active in the sense that once administered to a subject (either directly or by administering to the subject a nucleotide sequence or vector that encodes the protein) is able to evoke an immune response of the humoral and / or cellular type directed against that protein. The term "antigen binding fragment" or antibody fragment refers to a portion of an intact antibody and comprises the antigenic determining variable regions of an intact antibody. Examples of antigen binding fragment include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies formed from antibody fragments. A "monoclonal antibody" refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term "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. Furthermore, "monoclonal antibody" refers to such antibodies made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals. The term "humanized antibody" refers to forms of non-human (e.g. murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g. mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (Jones et al., 1986, Nature, 321:522-525; Riechmann et al., 1988, Nature, 332:323-327; Verhoeyen et al., 1988, Science, 239:1534-1536). In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and capability. The humanized antibody can be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and / or capability. In general, the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat. No. 5,225,539 or 5,639,641. A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen- binding site of antibodies. The term "hypervariable region" when used herein refers to the amino acid residues of an antibody that are responsible for antigen binding. The hypervariable region generally comprises amino acid residues from a "complementarity determining region" or "CDR" (e.g., around about residues 24-34 (L1), 50-56 (L2) and 89- 97 (L3) in the VL, and around about 31-35 (H1), 50-65 (H2) and 95-102 (H3) in the VH when numbered in accordance with the Kabat numbering system; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)); and / or those residues from a "hypervariable loop" (e.g., residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the VL, and 26-32 (H1), 52-56 (H2) and 95-101 (H3) in the VH when numbered in accordance with the Chothia numbering system; Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); and / or those residues from a "hypervariable loop" / CDR (e.g., residues 27-38 (L1), 56-65 (L2) and 105-120 (L3) in the VL, and 27-38 (H1), 56-65 (H2) and 105-120 (H3) in the VHwhen numbered in accordance with the IMGT numbering system; Lefranc, M. P. et al. Nucl. Acids Res. 27:209-212 (1999), Ruiz, M. e al. Nucl. Acids Res. 28:219-221 (2000)). The IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species (Lefranc M.-P., Immunology Today 18, 509 (1997) / Lefranc M.-P., The Immunologist, 7, 132-136 (1999) / Lefranc, M.- P., Pommie, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, Dev. Comp. Immunol., 27, 55-77 (2003). In the IMGT unique numbering, the conserved amino acids always have the same position, for instance cysteine 23 (1st-CYS), tryptophan 41 (CONSERVED-TRP), hydrophobic amino acid 89, cysteine 104 (2nd- CYS), phenylalanine or tryptophan 118 (J-PHE or J-TRP). The IMGT unique numbering provides a standardized delimitation of the framework regions (FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. As gaps represent unoccupied positions, the CDR-IMGT lengths (shown between brackets and separated by dots, e.g. [8.8.13]) become crucial information. The IMGT unique numbering is used in 2D graphical representations, designated as IMGT Colliers de Perles (Ruiz, M. and Lefranc, M.-P., Immunogenetics, 53, 857-883 (2002) / Kaas, Q. and Lefranc, M.-P., Current Bioinformatics, 2, 21-30 (2007)), and in 3D structures in IMGT / 3Dstructure-DB (Kaas, Q., Ruiz, M. and Lefranc, M.-P., T cell receptor and MHC structural data. Nucl. Acids. Res., 32, D208-D210 (2004)). In some embodiments, CDRs are determined based on cross-species sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md.)). In some embodiments, CDRs are determined based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al (1997) J. Molec. Biol. 273:927-948)). In addition, combinations of these two approaches can be used to determine CDRs. In some embodiments, the CDRs are determined based on AHo (Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670; 2001). In some embodiments, CDRs are determined based on the IMGT system. The term "human antibody" means an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human made using any technique known in the art. This definition of a human antibody includes intact or full-length antibodies, fragments thereof, and / or antibodies comprising at least one human heavy and / or light chain polypeptide such as, for example, an antibody comprising murine light chain and human heavy chain polypeptides. An "intact" antibody is one that comprises an antigen-binding site as well as a CL and at least heavy chain constant domains, CH1, CH2 and CH3. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. The term "chimeric antibodies" refers to antibodies wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species. Typically, the variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g. mouse, rat, rabbit, etc) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies derived from another (usually human) to avoid eliciting an immune response in that species. The antibodies herein also include antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies belonging to a particular antibody class or subclass, while the remainder of the chain(s) is 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. In some embodiments, the antibody comprises variable region antigen-binding sequences derived from human antibodies (e.g., CDRs) and containing one or more sequences derived from a non-human antibody, e.g., an FR or C region sequence. In some embodiments, the antibody includes those comprising a human variable region antigen binding sequence of one antibody class or subclass and another sequence, e.g., FR or C region sequence, derived from another antibody class or subclass. In some embodiments, chimeric antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. In some embodiments, modifications are made to further refine antibody performance. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). The term "epitope" or "antigenic determinant" are used interchangeably herein and refer to that portion of an antigen capable of being recognized and specifically bound by a particular antibody. When the antigen is a polypeptide, epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding are typically lost upon protein denaturing. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. "Binding affinity" generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method well known in the art, e.g. flow cytometry, enzyme-linked immunoabsorbent assay (ELISA), or radioimmunoassay (RIA), or kinetics (e.g., BIACORETManalysis). Direct binding assays as well as competitive binding assay formats can be readily employed. (See, for example, Berzofsky, et al., "Antibody-Antigen Interactions," In Fundamental Immunology, Paul, W. E., Ed., Raven Press: New York, N.Y. (1984); Kuby, Janis Immunology, W.H. Freeman and Company: New York, N.Y. (1992); and methods described herein. The measured affinity of a particular antibody- antigen interaction can vary if measured under different conditions (e.g., salt concentration, pH, temperature). Thus, measurements of affinity and other antigen-binding parameters (e.g., KD or Kd, Kon, Koff) are made with standardized solutions of antibody and antigen, and a standardized buffer, as known in the art and such as the buffer described herein. The phrase "substantially similar," or "substantially the same", as used herein, denotes a sufficiently high degree of similarity between two numeric values (generally one associated with an antibody of the invention and the other associated with a reference / comparator antibody) such that one of skill in the art would consider the difference between the two values to be of little or no biological and / or statistical significance within the context of the biological characteristics measured by said values (e.g., Kd values). The difference between said two values is less than about 500%, less than about 40%, less than about 300%, less than about 200%, or less than about 10% as a function of the value for the reference / comparator antibody. A polypeptide, antibody, polynucleotide, vector, cell, or composition which is "isolated" is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cell or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature. In some embodiments, an antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure. An "isolated nucleic acid" is a nucleic acid that is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term embraces a nucleic acid sequence that has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by heterologous systems. A substantially pure nucleic acid includes isolated forms of the nucleic acid. Of course, this refers to the nucleic acid as originally isolated and does not exclude genes or sequences later added to the isolated nucleic acid by the hand of man. An "isolated polypeptide" is one that has been identified and separated and / or recovered from a component of its natural environment. In preferred embodiments, the isolated polypeptide will be purified (1) to greater than 95% by weight of polypeptide as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. A "native sequence" polynucleotide is one that has the same nucleotide sequence as a polynucleotide derived from nature. A "native sequence" polypeptide is one that has the same amino acid sequence as a polypeptide (e.g., antibody) derived from nature (e.g., from any species). Such native sequence polynucleotides and polypeptides can be isolated from nature. A polynucleotide "variant," as the term is used herein, is a polynucleotide that typically differs from a polynucleotide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants may be naturally occurring or may be synthetically generated, for example, by modifying one or more of the polynucleotide sequences of the invention and evaluating one or more biological activities of the encoded polypeptide as described herein and / or using any of a number of techniques well known in the art. A polypeptide "variant," as the term is used herein, is a polypeptide that typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants may be naturally occurring or may be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptide as described herein and / or using any of a number of techniques well known in the art. or can be produced by recombinant or synthetic means. As used herein, "substantially pure" refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure. The term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject. Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order. The term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulation can be sterile. An "effective amount" of an antibody as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" can be determined empirically and in a routine manner, in relation to the stated purpose. The term "therapeutically effective amount" refers to an amount of an antibody or other drug effective to "treat" or prevent a disease or disorder in a subject or mammal. Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and 2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. "Polynucleotide," or "nucleic acid," as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, cabamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars can be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or can be conjugated to solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages can be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), "(O)NR2 ("amidate"), P(O)R, P(O)OR', CO or CH2("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (--O--) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA. The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is understood that, because the polypeptides of this invention are based upon antibodies, in certain embodiments, the polypeptides can occur as single chains or associated chains. The terms "identical" or percent "identity" in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software are known in the art that can be used to obtain alignments of amino acid or nucleotide sequences. One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al, 1990, Proc. Natl. Acad. Sci., 87:2264-2268, as modified in Karlin et al., 1993, Proc. Natl. Acad. Sci., 90:5873-5877, and incorporated into the NBLAST and XBLAST programs (Altschul et al., 1991, Nucleic Acids Res., 25:3389-3402). In certain embodiments, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. BLAST-2, WU-BLAST-2 (Altschul et al., 1996, Methods in Enzymology, 266:460-480), ALIGN, ALIGN-2 (Genentech, South San Francisco, Calif.) or Megalign (DNASTAR) are additional publicly available software programs that can be used to align sequences. In certain embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in GCG software (e.g., using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 90 and a length weight of 1, 2, 3, 4, 5, or 6). In certain alternative embodiments, the GAP program in the GCG software package, which incorporates the algorithm of Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) can be used to determine the percent identity between two amino acid sequences (e.g., using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5). Alternatively, in certain embodiments, the percent identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4:11-17 (1989)). For example, the percent identity can be determined using the ALIGN program (version 2.0) and using a PAM120 with residue table, a gap length penalty of 12 and a gap penalty of 4. Appropriate parameters for maximal alignment by particular alignment software can be determined by one skilled in the art. In certain embodiments, the default parameters of the alignment software are used. In certain embodiments, the percentage identity "X" of a first amino acid sequence to a second sequence amino acid is calculated as 100 x (Y / Z), where Y is the number of amino acid residues scored as identical matches in the alignment of the first and second sequences (as aligned by visual inspection or a particular sequence alignment program) and Z is the total number of residues in the second sequence. If the length of a first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence will be longer than the percent identity of the second sequence to the first sequence. As a non-limiting example, whether any particular polynucleotide has a certain percentage sequence identity (e.g., is at least 80% identical, at least 85% identical, at least 90% identical, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% identical) to a reference sequence can, in certain embodiments, be determined using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711). Bestfit uses the local homology algorithm of Smith and Waterman. Advances in Applied Mathematics 2: 482489 (1981), to find the best segment of homology between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is, for instance, 95% identical to a reference sequence according to the present invention, the parameters are set such that the percentage of identity is calculated over the full length of the reference nucleotide sequence and that gaps in homology of up to 5% of the total number of nucleotides in the reference sequence are allowed. In some embodiments, two nucleic acids or polypeptides of the invention are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In certain embodiments, identity exists over a region of the sequences that is at least about 10, about 20, about 40-60 residues in length or any integral value therebetween, or over a longer region than 60-80 residues, at least about 90-100 residues, or the sequences are substantially identical over the full length of the sequences being compared, such as the coding region of a nucleotide sequence for example. A "conservative amino acid substitution" is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is a conservative substitution. In certain embodiments, conservative substitutions in the sequences of the polypeptides and antibodies of the invention do not abrogate the binding of the polypeptide or antibody containing the amino acid sequence, to the antigen(s), i.e., the gp120 to which the polypeptide or antibody binds. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate antigen binding are well-known in the art (see, e.g., Brummell et al., Biochem. 32: 1180-1187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:412-417 (1997)). Clostridium difficile binary toxin neutralizing antibodies In some embodiments, the invention provides antibodies that are neutralizing antibodies against Clostridium difficile binary toxin. In some embodiments, the invention provides antibodies that are neutralizing against Clostridium difficile binary toxin. In some embodiments, the antibody has a particularly high potency in neutralizing Clostridium difficile binary toxin. Such antibodies are desirable, as only low concentrations are required in order to neutralize a given amount of Clostridium difficile. This facilitates higher levels of protection while administering lower amounts of antibody. In one embodiment, the invention provides an isolated Clostridium difficile binary toxin antibody, wherein the antibody is capable of neutralizing Clostridium difficile binary toxin with an IC50 value ranging from about 10 to about 80 pM. In some embodiments, the antibody is selected from the group consisting of a. B2 or an antigen binding fragment thereof; b. B3 or an antigen binding fragment thereof; and c. B8 or an antigen binding fragment thereof. In some embodiments, the antibody comprises the VH and VL regions of B2, B3, or B8 as described herein. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of B2, B3, or B8 as described herein. In some embodiments, the Clostridium difficile binary toxin antibody neutralizes binary toxin with an IC50 value of less than about 80 pM. In some embodiments, the antibody is B2 or an antigen binding fragment thereof. In some embodiments, the antibody comprises the VH and VL regions of B2 as described herein. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of B2 as described herein. In some embodiments, the Clostridium difficile binary toxin antibody neutralizes binary toxin with an IC50 value of less than about 10 pM. In some embodiments, the antibody is B3 or an antigen binding fragment thereof. In some embodiments, the antibody comprises the VH and VL regions of B3 as described herein. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of B3 as described herein. In some embodiments, the Clostridium difficile binary toxin antibody neutralizes binary toxin with an IC50 value of less than about 50 pM. In some embodiments, the antibody is B8 or an antigen binding fragment thereof. In some embodiments, the antibody comprises the VH and VL regions of B8 as described herein. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of B8 as described herein. In some embodiments, the neutralization can be performed according to the examples herein (see FIG. 3). In some embodiments, the Clostridium difficile binary toxin antibody binds to a CDTb epitope comprising F774 on the receptor binding domain (RBD) of CDTb, wherein binding of the antibody to the RBD prevents CDTb from binding to the lipolysis-stimulated lipoprotein receptor. In some embodiments, the antibody comprises antibody B3, the VH and VL regions of B3 as described herein, or the CDRs of the VH and VL regions of B3 as described herein. In some embodiments, the antibody comprises CDR1 of the heavy chain of antibody B3 which contacts residue F774. Methods for producing antibodies, such as those disclosed herein, are known in the art. For example, DNA molecules encoding light chain variable regions and / or heavy chain variable regions can be chemically synthesized using the sequence information provided herein. Synthetic DNA molecules can be ligated to other appropriate nucleotide sequences, including, e.g., expression control sequences, to produce conventional gene expression constructs encoding the desired antibodies. Production of defined gene constructs is within routine skill in the art. Alternatively, the sequences provided herein can be cloned out of hybridomas by conventional hybridization techniques or polymerase chain reaction (PCR) techniques, using synthetic nucleic acid probes whose sequences are based on sequence information provided herein, or prior art sequence information regarding genes encoding the heavy and light chains. Standard techniques of molecular biology may be used to prepare DNA sequences coding for the antibodies or fragments of the antibodies of the present invention. Desired DNA sequences may be synthesized completely or in part using oligonucleotide synthesis techniques. Site-directed mutagenesis and polymerase chain reaction (PCR) techniques may be used as appropriate. Any suitable host cell / vector system may be used for expression of the DNA sequences encoding the antibody molecules of the present invention or fragments thereof. Bacterial, for example E. coli, and other microbial systems may be used, in part, for expression of antibody fragments such as Fab and F(ab')2 fragments, and especially Fv fragments and single chain antibody fragments, for example, single chain Fvs. Eukaryotic, e.g. mammalian, host cell expression systems may be used for production of larger antibody molecules, including complete antibody molecules. Suitable mammalian host cells include CHO, HEK293T, PER.C6, myeloma or hybridoma cells. In some embodiments, antibodies according to the invention may be produced by i) expressing a nucleic acid sequence according to the invention in a cell, and ii) isolating the expressed antibody product. Additionally, the method may include iii) purifying the antibody. For the antibodies of the present invention to be expressed, the protein coding sequence should be "operably linked" to regulatory or nucleic acid control sequences that direct transcription and translation of the protein. As used herein, a coding sequence and a nucleic acid control sequence or promoter are said to be "operably linked" when they are covalently linked in such a way as to place the expression or transcription and / or translation of the coding sequence under the influence or control of the nucleic acid control sequence. The "nucleic acid control sequence" can be any nucleic acid element, such as, but not limited to promoters, enhancers, IRES, introns, and other elements described herein that direct the expression of a nucleic acid sequence or coding sequence that is operably linked thereto. The term "promoter" will be used herein to refer to a group of transcriptional control modules that are clustered around the initiation site for RNA polymerase II and that when operationally linked to the protein coding sequences of the invention lead to the expression of the encoded protein. The expression of the antibodies of the present invention can be under the control of a constitutive promoter or of an inducible promoter, which initiates transcription only when exposed to some particular external stimulus, such as, without limitation, antibiotics such as tetracycline, hormones such as ecdysone, or heavy metals. The promoter can also be specific to a particular cell-type, tissue or organ. Many suitable promoters and enhancers are known in the art, and any such suitable promoter or enhancer may be used for expression of the antibodies of the invention. For example, suitable promoters and / or enhancers can be selected from the Eukaryotic Promoter Database (EPDB). Nucleic acids encoding desired antibodies can be incorporated (ligated) into expression vectors, which can be introduced into host cells through conventional transfection or transformation techniques. Exemplary host cells are E. coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells that do not otherwise produce IgG protein. Transformed host cells can be grown under conditions that permit the host cells to express the genes that encode the immunoglobulin light and / or heavy chain variable regions. Specific expression and purification conditions will vary depending upon the expression system employed. Following expression, the antibodies and / or antigens of the invention can be isolated and / or purified or concentrated using any suitable technique known in the art. For example, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, immuno-affinity chromatography, hydroxyapatite chromatography, lectin chromatography, molecular sieve chromatography, isoelectric focusing, gel electrophoresis, or any other suitable method or combination of methods can be used. In some embodiments, the antibodies can be made using recombinant DNA methods as described in U.S. Pat. No. 4,816,567. The polynucleotides encoding a monoclonal antibody can be isolated from mature B-cells or hybridoma cell, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using conventional procedures. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors, which when transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, monoclonal antibodies are generated by the host cells. The antibodies can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues. It should be understood that the antibodies of the invention may differ from the exact sequences illustrated and described herein. Thus, the invention contemplates deletions, additions and substitutions to the sequences shown, so long as the sequences function in accordance with the methods of the invention. In this regard, particularly preferred substitutions will generally be conservative in nature, i.e., those substitutions that take place within a family of amino acids. For example, amino acids are generally divided into four families: (1) acidic--aspartate and glutamate; (2) basic--lysine, arginine, histidine; (3) non-polar-- alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar--glycine, asparagine, glutamine, cystine, serine threonine, tyrosine. Phenylalanine, tryptophan, and tyrosine are sometimes classified as aromatic amino acids. For example, leucine can be replaced with isoleucine or valine, or vice versa; an aspartate with a glutamate or vice versa; a threonine with a serine or vice versa; or a similar conservative replacement of an amino acid with a structurally related amino acid can be made. The polynucleotide(s) encoding a monoclonal antibody can further be modified in a number of different manners using recombinant DNA technology to generate alternative antibodies. In some embodiments, the constant domains of the light and heavy chains of, for example, a mouse monoclonal antibody can be substituted 1) for those regions of, for example, a human antibody to generate a chimeric antibody or 2) for a non- immunoglobulin polypeptide to generate a fusion antibody. In some embodiments, the constant regions are truncated or removed to generate the desired antibody fragment of a monoclonal antibody. Site-directed or high-density mutagenesis of the variable region can be used to optimize specificity, affinity, etc. of a monoclonal antibody. For the purposes of the present invention, it should be appreciated that modified antibodies can comprise any type of variable region that provides for the association of the antibody with the binary toxin of Clostridium difficile, or to individual subunits of the binary toxin or fragments thereof. In some embodiments, the variable regions or domains in both the heavy and light chains are altered by at least partial replacement of one or more CDRs and, if necessary, by partial framework region replacement and sequence changing. Although the CDRs can be derived from an antibody of the same class or even subclass as the antibody from which the framework regions are derived, in some embodiments the CDRs will be derived from an antibody of different class. Alterations to the variable region notwithstanding, those skilled in the art will appreciate that the modified antibodies of this invention can comprise antibodies (e.g., full- length antibodies or immunoreactive fragments thereof) in which at least a fraction of one or more of the constant region domains has been deleted or otherwise altered so as to provide desired biochemical characteristics such as increased localization, increased serum half-life or reduced serum half-life when compared with an antibody of approximately the same immunogenicity comprising a native or unaltered constant region. In some embodiments, the constant region of the modified antibodies will comprise a human constant region. Modifications to the constant region compatible with this invention comprise additions, deletions or substitutions of one or more amino acids in one or more domains. That is, the modified antibodies disclosed herein can comprise alterations or modifications to one or more of the three heavy chain constant domains (CH1, CH2 or CH3) and / or to the light chain constant domain (CL). In some embodiments, modified constant regions wherein one or more domains are partially or entirely deleted are contemplated. In some embodiments, the modified antibodies will comprise domain deleted constructs or variants wherein the entire CH2 domain has been removed (ΔCH2 constructs). In some embodiments, the omitted constant region domain will be replaced by a short amino acid spacer (e.g.10 residues) that provides some of the molecular flexibility typically imparted by the absent constant region. Besides their configuration, it is known in the art that the constant region mediates several effector functions. For example, binding of the C1 component of complement to antibodies activates the complement system. Activation of complement is important in the opsonisation and lysis of cell pathogens. The activation of complement also stimulates the inflammatory response and can also be involved in autoimmune hypersensitivity. Further, antibodies bind to cells via the Fc region, with a Fc receptor site on the antibody Fc region binding to a Fc receptor (FcR) on a cell. There are a number of Fc receptors which are specific for different classes of antibody, including IgG (gamma receptors), IgE (eta receptors), IgA (alpha receptors) and IgM (mu receptors). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (called antibody-dependent cell-mediated cytotoxicity, or ADCC), release of inflammatory mediators, placental transfer and control of immunoglobulin production. In certain embodiments, the binary toxin antibodies provide for altered effector functions that, in turn, affect the biological profile of the administered antibody. For example, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating modified antibody. In other cases it may be that constant region modifications, consistent with this invention, moderate complement binding and thus reduce the serum half life and nonspecific association of a conjugated cytotoxin. Yet other modifications of the constant region can be used to eliminate disulfide linkages or oligosaccharide moieties that allow for enhanced localization due to increased antigen specificity or antibody flexibility. Similarly, modifications to the constant region in accordance with this invention can easily be made using well known biochemical or molecular engineering techniques well within the purview of the skilled artisan. In certain embodiments, the invention provides antibodies or antigen binding fragments that specifically bind to Clostridium difficile binary toxin. In some embodiments, the invention is directed to a neutralizing antibody against Clostridium difficile binary toxin wherein the antibody binds a novel epitope. In some embodiments, the Clostridium difficile binary toxin antibody is an antibody that binds to the same epitope as antibody B2, B3 and / or B8 or antigen binding fragments thereof. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:7, 9, and 11. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain comprising an amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS:7, 9, and 11. In some embodiments, the Clostridium difficile binary toxin antibody comprises an antigen binding fragment of an amino acid sequence selected from the group consisting of SEQ ID NOS:7, 9, and 11. In some embodiments, the Clostridium difficile binary toxin antibody comprises an antigen binding fragment of an amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS:7, 9, and 11. In some embodiments, the Clostridium difficile binary toxin antibody comprises a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:8, 10, and 12. In some embodiments, the Clostridium difficile binary toxin antibody comprises a light chain comprising an amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS:8, 10, and 12. In some embodiments, the Clostridium difficile binary toxin antibody comprises an antigen binding fragment of an amino acid sequence selected from the group consisting of SEQ ID NOS:8, 10, and 12. In some embodiments, the Clostridium difficile binary toxin antibody comprises an antigen binding fragment of an amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOS:8, 10, and 12. In some embodiments, the Clostridium difficile binary toxin antibody is selected from the group consisting of: a. an antibody comprising a heavy chain amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:7 or an antigen binding fragment thereof and a light chain amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:8 or an antigen binding fragment thereof; b. an antibody comprising a heavy chain amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:9 or an antigen binding fragment thereof and a light chain amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:10 or an antigen binding fragment thereof; and c. an antibody comprising a heavy chain amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:11 or an antigen binding fragment thereof and a light chain amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:12 or an antigen binding fragment thereof. In some embodiments, the Clostridium difficile binary toxin antibody is selected from the group consisting of: a. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:7 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:8 or an antigen binding fragment thereof; b. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:9 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:10 or an antigen binding fragment thereof; and c. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:11 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:12 or an antigen binding fragment thereof. In some embodiments, the Clostridium difficile binary toxin antibody comprises an amino acid sequence comprising a heavy chain constant region. In some embodiments, the heavy chain constant region is from a human sequence. In some embodiments, the heavy chain constant region is selected from γ, α, δ, μ and ε heavy chains. In some embodiments, the Clostridium difficile binary toxin antibody comprises an amino acid sequence comprising a light chain constant region. In some embodiments, the light chain constant region is from a human sequence. In some embodiments, the light chain constant region is selected from κ and λ light chains. In some embodiments, the antibody has a human IgG1 heavy chain constant region encoded by SEQ ID NO:29 and / or having an amino acid sequence of SEQ ID NO:30. >human IgG1 (ch1-ch2-ch3) (SEQ ID NO:29) GCGTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAA TCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCA ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACC GTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGG TAAA >human IgG1 (ch1-ch2-ch3) (SEQ ID NO:30) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK In some embodiments, the antibody has a human κ light chain constant region encoded by SEQ ID NO:31 and / or having an amino acid sequence of SEQ ID NO:32. In some embodiments, antibody B3 has a human κ light chain encoded by SEQ ID NO:31 and / or having an amino acid sequence of SEQ ID NO:32. >human kappa (B3_K) (SEQ ID NO:31) CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTACCCC AGAGAAGCCAAAGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGAAAC AGCCAGGAAAGCGTGACAGAGCAGGATTCCAAGGATTCCACATACAGCCTG AGCAGCACACTGACACTGTCCAAGGCCGACTACGAGAAGCACAAGGTGTAC GCCTGCGAAGTGACACACCAGGGACTGTCCTCCCCTGTGACAAAGAGCTTCA ACAGAGGAGAATGC >human kappa (B3_K) (SEQ ID NO:32) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC In some embodiments, the antibody has a human λ light chain constant region encoded by SEQ ID NO:33 and / or having an amino acid sequence of SEQ ID NO:34. In some embodiments, antibodies B2 or B8 have a human κ light chain encoded by SEQ ID NO:33 and / or having an amino acid sequence of SEQ ID NO:34. >human lambda (B2_L, B8_L) (SEQ ID NO:33) ggtcagcccaaggccaaccccactgtcactctgttcccgccctcctctgaggagctccaagccaacaaggccacac tagtgtgtctgatcagtgacttctacccgggagctgtgacagtggcctggaaggcagatggcagccccgtcaaggcgggagtg gagaccaccaaaccctccaaacagagcaacaacaagtacgcggccagcagctacctgagcctgacgcccgagcagtggaa gtcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgttcatag >human lambda (B2_L, B8_L) (SEQ ID NO:34) GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVK AGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS In some embodiments, the Clostridium difficile binary toxin antibody is isolated and / or substantially pure. In some embodiments, the Clostridium difficile binary toxin antibody is non-naturally occurring. In some embodiments, the Clostridium difficile binary toxin antibody is non-naturally occurring and is humanized. For example, in some embodiments, the antibodies can comprise chimeric antibodies comprising a human constant region in the heavy and light chains and a variable region from any of antibodies B2, B3 or B8. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain comprises a heavy chain variable (VH) region and the light chain comprises a light chain variable (VL) region; wherein the VL region comprises one or more VL complementary determining regions (CDRs) and wherein the VH region comprises one or more VH complementary determining regions (CDRs), wherein the VL CDRs correspond to the CDRs found within any of SEQ ID NOS:8, 10 and 12. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain comprises a heavy chain variable (VH) region and the light chain comprises a light chain variable (VL) region; wherein the VL region comprises one or more VL complementary determining regions (CDRs) and wherein the VH region comprises one or more VH complementary determining regions (CDRs), wherein the VH CDRs correspond to the CDRs found within any of SEQ ID NOS:7, 9 and 11. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain comprises a heavy chain variable (VH) region comprising an amino acid sequence selected from SEQ ID NOS:7, 9, and 11 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions, and the light chain comprises a light chain variable (VL) region comprising an amino acid sequence selected from SEQ ID NOS:8, 10, and 12 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain comprises a heavy chain variable (VH) region and the light chain comprises a light chain variable (VL) region; wherein the VL region comprises one or more VL complementary determining regions (CDRs) and wherein the VH region comprises one or more VH complementary determining regions (CDRs), wherein the VL CDRs correspond to the CDRs found within any of SEQ ID NOS:8, 10 or 12 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions, and wherein the VH CDRs correspond to the CDRs found within any of SEQ ID NOS:7, 9, or 11 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain or antigen binding fragment thereof comprises a heavy chain variable (VH) region and the light chain or antigen binding fragment thereof comprises a light chain variable (VL) region; wherein the Clostridium difficile binary toxin antibody is selected from the group consisting of an antibody: i) wherein the VH region comprises SEQ ID NO:7 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:8 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; ii) wherein the VH region comprises SEQ ID NO:9 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:10 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and iii) wherein the VH region comprises SEQ ID NO:11 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:12 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions. In some embodiments, the Clostridium difficile binary toxin antibody is selected from the group consisting of: i) an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSFSSYW (SEQ ID NO:13), IRSGGSN (SEQ ID NO:14) and ARLRGYSNYAGFDY (SEQ ID NO:15); and a light chain variable region, wherein the CDRs comprise amino acid sequences SSNIGTNS (SEQ ID NO:16), YND and ATWDDSLSGYI (SEQ ID NO:17); ii) an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSISDYYYW (SEQ ID NO:18), IYGDKTST (SEQ ID NO:19) and ARGVRDGTLKYNRFDV (SEQ ID NO:20); and a light chain variable region, wherein the CDRs comprise amino acid sequences QGISNA (SEQ ID NO:21), AAS and QQYNSYPLT (SEQ ID NO:22); and iii) an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSISNNYW (SEQ ID NO:23), IFGSDGST (SEQ ID NO:24) and AREGRGYSDYSY (SEQ ID NO:25); and a light chain variable region, wherein the CDRs comprise amino acid sequences SGISVGGYR (SEQ ID NO:26), YHTDSDN (SEQ ID NO:27) and MIWLNNAGL (SEQ ID NO:28). In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain and a light chain, wherein the antibody is selected from the group consisting of: i) an antibody comprising a heavy chain having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:35; and a light chain having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:36; ii) an antibody comprising a heavy chain having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:37; and a light chain having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:38; and iii) an antibody comprising a heavy chain having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:39; and a light chain having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:40. In some embodiments, the Clostridium difficile binary toxin antibody comprises a heavy chain and a light chain, wherein the antibody is selected from the group consisting of: i) an antibody comprising a heavy chain comprising SEQ ID NO:35 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and a light chain comprising SEQ ID NO:36 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; ii) an antibody comprising a heavy chain comprising SEQ ID NO:37 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and a light chain comprising SEQ ID NO:38 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and iii) an antibody comprising a heavy chain comprising SEQ ID NO:39 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and a light chain comprising SEQ ID NO:40 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions. In some embodiments, the Clostridium difficile binary toxin antibody is a non- naturally occurring antibody. In some embodiments, the invention provides antibodies or antigen binding fragments comprising the CDRs as described herein with up to four (i.e. 0, 1, 2, 3, or 4) conservative amino acid substitutions per CDR. Table 1. Amino acid sequence of variable regions of Clostridium difficile binary toxin antibodies. Heavy chain is shown first (above solid line), followed by the light chain (below solid line). Antibody Amino acid sequence (variable region)B2 SEQ ID NO:7 DIQMTQSPSSLSASVGDSVTITCRASQGISNALAWYQQKPGKAPE NSYPLTFGGGTKVEIK SEQ ID NO:10 B8Heavy (VH) EWIGRIFGSDGSTDYNPSLKSRVTISTDTSKNQFSLKLSSVTAADT AVYYCAREGRGYSDYSYWGQGVLVTVSS SEQ ID NO:11 toxin antibodies. Heavy chain is shown first (above solid line), followed by the light chain (below solid line). Antibody Nucleotide sequence B2 GCATATCCGTAGTGGTGGGAGCAACTATGTTAACCCGTCCCTCAAGAGT CGAGTCACCCTGTCAGCAGACACGTCCAAGAACCAGTTCTCCCTGAAGC TGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGACT ACGTGGATACAGTAACTACGCCGGCTTTGACTACTGGGGCCAGGGAGT CCTGGTCACCGTCTCCTCA SEQ ID NO:1 Light Chain (VL) CAGTCTGTGCTGACTCAGCCTCCCTCAGCGTCTGAGGCCGCCAGGAAGA GTGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACATCGGAACTAATAG TGTATCCTGGTACCAGCAGCTCCCAGGAACGGCTCCCAAACTCCTCATC TCTTATAATGATCAACGAGCCTCAGGTGTCTCTGACCGATTCTCTGGCTC CAAGTCTGGCACGTCAGCCTCCCTGGCCATCAGTGGGCTCCAGACCGAG GATGAGGCTGATTATTACTGCGCAACATGGGATGATAGCCTGAGCGGTT ACATCTTCGGTGCTGGGACCCGGCTCACCGTCCTA SEQ ID NO:2B3Heavy Chain (VH)

[0002] GGATCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAG ATTTTGCAACTTATTACTGTCAACAGTATAATAGTTACCCTCTCACTTTC Table 3. Amino acid sequences of full length Clostridium difficile binary toxin antibodies. Heavy chain is shown first (above solid line), followed by the light chain (below solid line). Antibody Amino acid sequence (full length)B2Heavy QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK SEQ ID NO:35 Light QSVLTQPPSASEAARKSVTISCSGSSSNIGTNSVSWYQQLPGTAPK LLISYNDQRASGVSDRFSGSKSGTSASLAISGLQTEDEADYYCAT WDDSLSGYIFGAGTRLTVLGQPKANPTVTLFPPSSEELQANKATL VCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO:36B3Heavy PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK SEQ ID NO:37 EWIGRIFGSDGSTDYNPSLKSRVTISTDTSKNQFSLKLSSVTAADT AVYYCAREGRGYSDYSYWGQGVLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP Table 4. Nucleotide sequences of full length Clostridium difficile binary toxin antibodies. Heavy chain is shown first (above solid line), followed by the light chain (below solid line). Antibody Nucleotide sequence (full length)B2Heavy GGGACTGGAGTGGATTGGGCATATCCGTAGTGGTGGGAGCAA CTATGTTAACCCGTCCCTCAAGAGTCGAGTCACCCTGTCAGCA GACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGA CCGCCGCGGACACGGCCGTGTATTACTGTGCGAGACTACGTGG ATACAGTAACTACGCCGGCTTTGACTACTGGGGCCAGGGAGTC CTGGTCACCGTCTCCTCAgcgtcgaccaagggcccatcggtcttccccctggcaccct cctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagt cctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctac atctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccc cccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtga gccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagac aaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgaga aaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccggg atgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgcc gtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactcc gacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtctt ctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccggg taaa SEQ ID NO:41 Light CAGTCTGTGCTGACTCAGCCTCCCTCAGCGTCTGAGGCCGCCA GGAAGAGTGTCACCATCTCCTGTTCTGGAAGCAGCTCCAACAT CGGAACTAATAGTGTATCCTGGTACCAGCAGCTCCCAGGAAC GGCTCCCAAACTCCTCATCTCTTATAATGATCAACGAGCCTCA GGTGTCTCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAG CCTCCCTGGCCATCAGTGGGCTCCAGACCGAGGATGAGGCTG ATTATTACTGCGCAACATGGGATGATAGCCTGAGCGGTTACAT CTTCGGTGCTGGGACCCGGCTCACCGTCCTAggtcagcccaaggccaac cccactgtcactctgttcccgccctcctctgaggagctccaagccaacaaggccacactagtgtgtctga tcagtgacttctacccgggagctgtgacagtggcctggaaggcagatggcagccccgtcaaggcggg agtggagaccaccaaaccctccaaacagagcaacaacaagtacgcggccagcagctacctgagcctB3 caaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcac accttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaa agttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggg gaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgt ggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaag ccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgta caccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggc ttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagacca cgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggt ggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaag agcctctccctgtctccgggtaaa SEQ ID NO:43 Light AGGAGACTCAGTCACCATCACTTGCCGGGCAAGTCAGGGCAT TAGCAATGCTTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTGAGCTCCTGATCTATGCTGCATCCGGTTTGCAGAGTGGG GTCCCATCAGGGTTCAGCGGCAGTGGATCTGGGACAGACTTCA CTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTA TTACTGTCAACAGTATAATAGTTACCCTCTCACTTTCGGCGGAg ggaccaaggtggaaatcaaaCGTACGGTGGCTGCACCATCTGTCTTCATC TTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTG TTGTGTGCCTGCTGAATAACTTCTACCCCAGAGAAGCCAAAGT GCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGAAACAGCCA GGAAAGCGTGACAGAGCAGGATTCCAAGGATTCCACATACAG SEQ ID NO:44 B8Heavy TCGGAGACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCA TCAGCAATAACTACTGGAGCTGGATCCGCCAGGCCCCAGGGA AGGGACTGGAGTGGATTGGACGTATCTTTGGTAGTGATGGGA GCACCGACTACAACCCCTCCCTCAAGAGTCGAGTCACCATTTC AACAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCT GTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAG GGGCGTGGATACAGTGACTACAGTTACTGGGGCCAGGGAGTC CTGGTCACCGTCTCCTCAgcgtcgaccaagggcccatcggtcttccccctggcaccct cctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagt cctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctac atctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccc aaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgaga aaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccggg atgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgcc gtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactcc gacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtctt ctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccggg taaa SEQ ID NO:45 Light CAGCCTGTGCTGACTCAGCCAACCTCCCTCTCAGCATCTCCTGGAGC ATCAGCCAGACTCACCTGCACCTTGCGCAGTGGCATCAGTGTTGGTG GTTACAGGATGTTCTGGTACCAGCAGAAGCCAGGGAGTCCTCCCCG GTATCTTCTGAACTACCACACAGACTCAGATAACCACCAGGGCTCTG GAGTCCCCAGCCGCTTCTCTGGATCCAAAGATGCTTCGGCCAATGCA GGGATTTTACTCATCTCTGGGCTCCAGTCTGAGGATGAGGCTGACTA TTACTGTATGATTTGGCTCAACAATGCTGGCTTATTCGGAGGAGGGA CCCGGCTGACCGTCggtcagcccaaggccaaccccactgtcactctgttcccgccctcctctgagga gctccaagccaacaaggccacactagtgtgtctgatcagtgacttctacccgggagctgtgacagtggcctggaa ggcagatggcagccccgtcaaggcgggagtggagaccaccaaaccctccaaacagagcaacaacaagtacg cggccagcagctacctgagcctgacgcccgagcagtggaagtcccacagaagctacagctgccaggtcacgc atgaagggagcaccgtggagaagacagtggcccctacagaatgttcatag SEQ ID NO:46 Polypeptides In some embodiments, the invention provides isolated polypeptides comprising an individual light chain or heavy chain sequence of variable region described herein as well as antigen binding fragments thereof. Polypeptides (e.g., intact antibodies) comprising both a light chain and a heavy chain are also provided. Also provided are polypeptides that comprise a polypeptide comprising SEQ ID NOS:7, 8, 9, 10, 11, 12, 35, 36, 37, 38, 39, or 40 or an antigen binding fragment thereof. Also provided are polypeptides that comprise a polypeptide having at least about 90% sequence identity to SEQ ID NOS: 7, 8, 9, 10, 11, 12, 35, 36, 37, 38, 39, or 40. In some embodiments, the polypeptide comprises a polypeptide having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NOS: 7, 8, 9, 10, 11, 12, 35, 36, 37, 38, 39, or 40. Polynucleotides In some embodiments, the invention encompasses polynucleotides comprising polynucleotides that encode a polypeptide as described herein, such as a heavy chain or light chain sequence of an antibody or a fragment of such a polypeptide. For example, the invention provides a polynucleotide comprising a nucleic acid sequence that encodes a Clostridium difficile antibody to binary toxin or encodes a fragment of such an antibody. The polynucleotides of the invention can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA; and can be double-stranded or single-stranded, and if single stranded can be the coding strand or non-coding (anti-sense) strand. In some embodiments, the polynucleotides are isolated. In certain embodiments, the polynucleotides are substantially pure. In some embodiments, the invention provides a polynucleotide comprising a polynucleotide encoding a polypeptide comprising a sequence selected from the group consisting of SEQ ID NOS:1, 2, 3, 4, 5, 6, 41, 42, 43, 44, 45 and 46. In some embodiments, the invention provides a polynucleotide comprising a polynucleotide encoding a polypeptide comprising the heavy or light chain variable region found within a sequence selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 41, 42, 43, 44, 45 and 46. Also provided is a polynucleotide encoding a polypeptide having at least about 70%, 75%, 80%, 85%, 90% 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NOS: 1, 2, 3, 4, 5, 6, 41, 42, 43, 44, 45 and 46. In some embodiments the polynucleotides comprise the coding sequence for the mature polypeptide fused in the same reading frame to a polynucleotide which aids, for example, in expression and secretion of a polypeptide from a host cell (e.g. a leader sequence which functions as a secretory sequence for controlling transport of a polypeptide from the cell). The polypeptide having a leader sequence is a preprotein and can have the leader sequence cleaved by the host cell to form the mature form of the polypeptide. The polynucleotides can also encode for a proprotein which is the mature protein plus additional 5' amino acid residues. A mature protein having a prosequence is a proprotein and is an inactive form of the protein. Once the prosequence is cleaved an active mature protein remains. In certain embodiments the polynucleotides comprise the coding sequence for the mature polypeptide fused in the same reading frame to a marker sequence that allows, for example, for purification of the encoded polypeptide. For example, the marker sequence can be a hexa-histidine tag supplied by a pQE-9 vector to provide for purification of the mature polypeptide fused to the marker in the case of a bacterial host, or the marker sequence can be a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host (e.g. COS-7 cells) is used. The present invention further relates to variants of the hereinabove described polynucleotides encoding, for example, fragments, analogs, and derivatives. The polynucleotide variants can contain alterations in the coding regions, non- coding regions, or both. In some embodiments the polynucleotide variants contain alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. In some embodiments, nucleotide variants are produced by silent substitutions due to the degeneracy of the genetic code. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host such as E. coli). Vectors and cells comprising the polynucleotides described herein are also provided. The term "vector" means a construct, which is capable of delivering, and expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells. "Vector" also includes shuttle and expression vectors. In some embodiments, the vector is a plasmid construct and also includes an origin of replication (e.g., the ColE1 origin of replication) and a selectable marker (e.g., ampicillin or tetracycline resistance), for replication and selection, respectively. An "expression vector" refers to a vector that contains the necessary control sequences or regulatory elements for expression of the antibodies including antibody fragments of the invention, in bacterial or eukaryotic cells. Methods The antibodies of the invention are useful in a variety of applications including, but not limited to, therapeutic treatment methods, such as the treatment of Clostridium difficile infection. The methods of use may be in vitro, ex vivo, or in vivo methods. In some embodiments, the antibodies disclosed herein may be used as neutralizing antibodies, passively administered or given via gene therapies. In one aspect, the antibodies are useful for detecting the presence of Clostridium difficile or the binary toxin in a biological sample. The term "detecting" as used herein encompasses quantitative or qualitative detection. In certain embodiments, a biological sample comprises a cell or tissue. Certain other methods can be used to detect binding of antibodies to antigens such as Clostridium difficile binary toxin or a subunit thereof. Such methods include, but are not limited to, antigen-binding assays that are well known in the art, such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoprecipitation assays, fluorescent immunoassays, protein A immunoassays, and immunohistochemistry (IHC). In certain embodiments, the antibodies are labeled. Labels include, but are not limited to, labels or moieties that are detected directly (such as fluorescent, chromophoric, electron-dense, chemiluminescent, and radioactive labels), as well as moieties, such as enzymes or ligands, that are detected indirectly, e.g., through an enzymatic reaction or molecular interaction. In certain embodiments, the antibodies are immobilized on an insoluble matrix. Immobilization entails separating the antibody from any antigen that remains free in solution. This conventionally is accomplished by either insolubilizing the antibody before the assay procedure, as by adsorption to a water-insoluble matrix or surface (Bennich et al., U.S. Pat. No. 3,720,760), or by covalent coupling (for example, using glutaraldehyde cross-linking), or by insolubilizing the antibody after formation of a complex between the antibody and antigen, e.g., by immunoprecipitation. The present invention provides for methods of treating or preventing Clostridium difficile infection comprising administering a therapeutically effective amount of an antibody as described herein to a subject (e.g., a subject in need of treatment). In some embodiments, the subject is a human. Administration of a prophylactic agent such as the antibody herein can occur prior to the manifestation of symptoms characteristic of Clostridium difficile infection, such that the infection or symptoms thereof are prevented or, alternatively, delayed in their progression. In some embodiments of the present invention, the subject is administered effective amounts of more than one Clostridium difficile binary toxin antibodies of the invention. In some embodiments, the subject is administered a pharmaceutical composition comprising a combination of antibodies of the invention, in order to treat or prevent Clostridium difficile infection. In some embodiments, a combination of antibodies are administered, which can include a combination comprising any one or more of the antibodies herein. In some embodiments, the antibody comprises the VH and VL regions of B2, B3, or B8 as described herein. In some embodiments, the antibody comprises the CDRs of the VH and VL regions of B2, B3, or B8 as described herein. In some embodiments, the combination comprises i) B2 or an antigen binding fragment thereof, ii) B3 or an antigen binding fragment thereof and iii) B8 or an antigen binding fragment thereof. In some embodiments, the subject is administered a polyclonal composition of antibodies comprising any one of i) B2 or an antigen binding fragment thereof, ii) B3 or an antigen binding fragment thereof and / or iii) B8 or an antigen binding fragment thereof in combination with one or more natural or variant antibodies as described herein. Such combinations can be selected according to the desired immunity. The composition can further include one or more other neutralizing antibodies. For in vivo treatment of human patients, the patient is usually administered or provided a pharmaceutical formulation including a Clostridium difficile binary toxin antibody of the invention. When used for in vivo therapy, the antibodies of the invention are administered to the patient in therapeutically effective amounts (i.e., amounts that eliminate or reduce the patient's viral burden). The antibodies can be administered to a human patient, in accord with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. The antibodies may be administered parenterally, when possible, at the target cell site, or intravenously. Intravenous or subcutaneous administration of the antibody is preferred in certain embodiments. Therapeutic compositions of the invention are administered to a patient or subject systemically, parenterally, or locally. For parenteral administration, the antibodies can be formulated in a unit dosage injectable form (solution, suspension, emulsion) in association with a pharmaceutically acceptable, parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate are also used. Liposomes are used as carriers. The vehicle contains minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. The antibodies are typically formulated in such vehicles at concentrations of about 1 mg / ml to 10 mg / ml. The dose and dosage regimen depends upon a variety of factors readily determined by a physician, such as the nature of the infection and the characteristics of the particular cytotoxic agent or growth inhibitory agent conjugated to the antibody (when used), e.g., its therapeutic index, the patient, and the patient's history. Generally, a therapeutically effective amount of an antibody is administered to a patient. In particular embodiments, the amount of antibody administered is in the range of about 0.1 mg / kg to about 20 mg / kg of patient body weight. Depending on the type and severity of the infection, about 0.1 mg / kg to about 20 mg / kg body weight (e.g., about 0.1-15 mg / kg / dose) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. The progress of this therapy is readily monitored by conventional methods and assays and based on criteria known to the physician or other persons of skill in the art. Antibodies of the invention can be coupled to a drug for delivery to a treatment site or coupled to a detectable label to facilitate imaging of a site comprising cells of interest, such as cells infected with Clostridium difficile. Methods for coupling antibodies to drugs and detectable labels are well known in the art, as are methods for imaging using detectable labels. Labeled antibodies may be employed in a wide variety of assays, employing a wide variety of labels. Detection of the formation of an antibody-antigen complex between an antibody of the invention and an epitope of interest can be facilitated by attaching a detectable substance to the antibody. Suitable detection means include the use of labels such as radionucleotides, enzymes, coenzymes, fluorescers, chemiluminescers, chromogens, enzyme substrates or co-factors, enzyme inhibitors, prosthetic group complexes, free radicals, particles, dyes, and the like. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material is luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include125I,131I,35S, or .sup.3H. Such labeled reagents may be used in a variety of well-known assays, such as radioimmunoassays, enzyme immunoassays, e.g., ELISA, fluorescent immunoassays, and the like. The antibodies can be tagged with such labels by known methods. For instance, coupling agents such as aldehydes, carbodiimides, dimaleimide, imidates, succinimides, bid-diazotized benzadine and the like are used to tag the antibodies with the above- described fluorescent, chemiluminescent, and enzyme labels. An enzyme is typically combined with an antibody using bridging molecules such as carbodiimides, periodate, diisocyanates, glutaraldehyde and the like. Various labeling techniques are described in Morrison, Methods in Enzymology 32b, 103 (1974), Syvanen et al., J. Biol. Chem. 284, 3762 (1973) and Bolton and Hunter, Biochem J. 133, 529(1973). In one embodiment, the antibodies can be administered as immunoconjugates, conjugated to a second molecule. For example, the second molecule can be a toxin, a label, a radioisotope, a drug, or a chemical compound. An antibody according to the invention may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent, or a radioactive metal ion or radioisotope. Examples of radioisotopes include, but are not limited to, I-131, I-123, I-125, Y-90, Re- 188, Re-186, At-211, Cu-67, Bi-212, Bi-213, Pd-109, Tc-99, In-111, and the like. Such antibody conjugates can be used for modifying a given biological response; the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin, TLR agonists (such as TLR7 agonist), or monomethylauristatin E. In some embodiments, the methods further comprise administering to the subject an effective amount of one or more additional therapeutic agents. The combined administration of the Clostridium difficile binary toxin antibody includes co- administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities. Preferably such combined therapy results in a synergistic therapeutic effect. For any application, the antibody, antigen binding fragment, or nucleic acid encoding the antibody or antigen binding fragment can be combined with antibiotic therapy, such as metronidazole, vancomycin, or fidaxomicin. In some embodiments, the one or more additional therapeutic agents is an antibody. In some embodiments, the antibody is an anti-TcdA or an anti-TcdB antibody. In some embodiments, the anti-TcdA antibody is actoxumab. In some embodiments, the anti-TcdB antibody is bezlotoxumab. In some embodiments, the one or more additional therapeutic agents is an anti- TcdA antibody and an anti-TcdB antibody. In some embodiments, the anti-TcdA antibody is actoxumab and the anti-TcdB antibody is bezlotoxumab. Single or multiple administrations of the compositions including the antibody, antigen binding fragment, or nucleic acid encoding the antibody or antigen binding fragment, that are disclosed herein, are administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of at least one of the antibodies disclosed herein to effectively treat the patient. The dosage can be administered once, but may be applied periodically until either a therapeutic result is achieved or until side effects warrant discontinuation of therapy. One approach to administration of nucleic acids is direct administration with plasmid DNA, such as with a mammalian expression plasmid. The nucleotide sequence encoding the disclosed antibody, or antibody binding fragments thereof, can be placed under the control of a promoter to increase expression. Another approach is to administer the nucleic acids in the form of mRNA. In some embodiments, the subject is administered cells that are engineered to express the Clostridium difficile binary toxin antibody. In some embodiments, the cells are engineered immune cells, such as B cells. In some embodiments, the cells are engineered, autologous cells. In another approach to using nucleic acids, a Clostridium difficile binary toxin antibody, or antibody binding fragment thereof can also be expressed by attenuated viral hosts or vectors or bacterial vectors. Recombinant vaccinia virus, adeno-associated virus (AAV), herpes virus, retrovirus, cytomegalovirus or other viral vectors can be used to express the antibody. For example, vaccinia vectors and methods useful protocols are described in U.S. Pat. No. 4,722,848. BCG (Bacillus Calmette Guerin) provides another vector for expression of the disclosed antibodies (see Stover, Nature 351:456-460, 1991). Compositions The present invention also encompasses compositions comprising one or more antibodies of the invention. In certain embodiments, the compositions are pharmaceutical compositions. In some embodiments, formulations are prepared for storage and use by combining an antibody with a pharmaceutically acceptable vehicle (e.g. carrier, excipient) (Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000). Suitable pharmaceutically acceptable vehicles include, but are not limited to, nontoxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (e.g. less than about 10 amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates such as monosacchandes, disaccharides, glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn- protein complexes); and non-ionic surfactants such as TWEEN or polyethylene glycol (PEG). For the treatment or prevention of infection by Clostridium difficile, the appropriate dosage of an antibody or combination of antibodies of the present invention can depend on a variety of factors, such as the severity and course of the disease, the responsiveness of the disease, whether the antibody or agent is administered for therapeutic or preventative purposes, previous therapy, patient's clinical history, and so on all at the discretion of the treating physician. The antibody or agent can be administered one time or over a series of treatments lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. The administering physician can easily determine optimum dosages, dosing methodologies and repetition rates. In certain embodiments, dosage is from 0.01 µg to 100 mg per kg of body weight, and can be given once or more daily, weekly, monthly or yearly. In certain embodiments, the antibody or combination of antibodies is given once every two weeks or once every three weeks. In certain embodiments, the dosage of the antibody is from about 0.1 mg to about 20 mg per kg of body weight. The treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Effective dosages and schedules for administering embodiments of the present invention can be determined empirically. In some embodiments, and effective amount of one or more antibodies are administered to neutralize, treat, prevent or eradicate Clostridium difficile infection. In some embodiments, compositions comprising one or more nucleic acid molecules of the invention are administered to the subject. In some embodiments, genetic constructs capable of inducing production of antibodies of the present invention may be administered to a patient in need thereof. Controlled-release parenteral formulations can be made as implants, oily injections, or as particulate systems. For a broad overview of protein delivery systems see, Banga, A. J., Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, Technomic Publishing Company, Inc., Lancaster, Pa., (1995). Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles. Microcapsules contain the therapeutic protein, such as a cytotoxin or a drug, as a central core. In microspheres the therapeutic is dispersed throughout the particle. Particles, microspheres, and microcapsules smaller than about 1 µm are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively. Capillaries have a diameter of approximately 5 .mu.m so that only nanoparticles are administered intravenously. Microparticles are typically around 100 µm in diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, J., Colloidal Drug Delivery Systems, J. Kreuter, ed., Marcel Dekker, Inc., New York, N.Y., pp. 219- 342 (1994); and Tice & Tabibi, Treatise on Controlled Drug Delivery, A. Kydonieus, ed., Marcel Dekker, Inc. New York, N.Y., pp. 315-339, (1992). Polymers can be used for ion-controlled release of the antibody compositions disclosed herein. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, Accounts Chem. Res. 26:537-542, 1993). For example, the block copolymer, polaxamer 407, exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has been shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin-2 and urease (Johnston et al., Pharm. Res. 9:425-434, 1992; and Pec et al., J. Parent. Sci. Tech. 44(2):58-65, 1990). Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm. 112:215-224, 1994). In yet another aspect, liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems, Technomic Publishing Co., Inc., Lancaster, Pa. (1993)). Numerous additional systems for controlled delivery of therapeutic proteins are known (see U.S. Pat. No. 5,055,303; U.S. Pat. No. 5,188,837; U.S. Pat. No. 4,235,871; U.S. Pat. No. 4,501,728; U.S. Pat. No. 4,837,028; U.S. Pat. No.4,957,735; U.S. Pat. No.5,019,369; U.S. Pat. No.5,055,303; U.S. Pat. No. 5,514,670; U.S. Pat. No. 5,413,797; U.S. Pat. No. 5,268,164; U.S. Pat. No. 5,004,697; U.S. Pat. No.4,902,505; U.S. Pat. No.5,506,206; U.S. Pat. No.5,271,961; U.S. Pat. No. 5,254,342 and U.S. Pat. No. 5,534,496). In some embodiments, the compositions of the invention may be injectable suspensions, solutions, sprays, lyophilized powders, syrups, elixirs and the like. Any suitable form of composition may be used. To prepare such a composition, a nucleic acid or vector of the invention, having the desired degree of purity, is mixed with one or more pharmaceutically acceptable carriers and / or excipients. The carriers and excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, or combinations thereof, buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); 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, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEENTMPLURONICSTMor polyethylene glycol (PEG). The compositions can be designed to introduce the antibodies, nucleic acids or expression vectors to a desired site of action and release it at an appropriate and controllable rate. Methods of preparing controlled-release formulations are known in the art. For example, controlled release preparations can be produced by the use of polymers to complex or absorb the immunogen and / or immunogenic composition. A controlled-release formulations can be prepared using appropriate macromolecules (for example, polyesters, polyamino acids, polyvinyl, pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, or protamine sulfate) known to provide the desired controlled release characteristics or release profile. Another possible method to control the duration of action by a controlled-release preparation is to incorporate the active ingredients into particles of a polymeric material such as, for example, polyesters, polyamino acids, hydrogels, polylactic acid, polyglycolic acid, copolymers of these acids, or ethylene vinylacetate copolymers. Alternatively, instead of incorporating these active ingredients into polymeric particles, it is possible to entrap these materials into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacrylate) microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in New Trends and Developments in Vaccines, Voller et al. (eds.), University Park Press, Baltimore, Md., 1978 and Remington's Pharmaceutical Sciences, 16th edition. The compositions can be administered using any suitable delivery method including, but not limited to, intramuscular, intravenous, intradermal, mucosal, and topical delivery. Such techniques are well known to those of skill in the art. More specific examples of delivery methods are intramuscular injection, intradermal injection, and subcutaneous injection. However, delivery need not be limited to injection methods. Further, delivery of DNA to animal tissue has been achieved by cationic liposomes (Watanabe et al., (1994) Mol. Reprod. Dev. 38:268-274; and WO 96 / 20013), direct injection of naked DNA into animal muscle tissue (Robinson et al., (1993) Vaccine 11:957- 960; Hoffman et al., (1994) Vaccine 12: 1529-1533; Xiang et al., (1994) Virology 199: 132-140; Webster et al., (1994) Vaccine 12: 1495-1498; Davis et al., (1994) Vaccine 12: 1503-1509; and Davis et al., (1993) Hum. Mol. Gen. 2: 1847-1851), or intradermal injection of DNA using "gene gun" technology (Johnston et al., (1994) Meth. Cell Biol. 43:353-365). Alternatively, delivery routes can be oral, intranasal or by any other suitable route. Delivery also be accomplished via a mucosal surface such as the anal, vaginal or oral mucosa. Dosing schedules (or regimens) can be readily determined for the particular subject and composition. Hence, the composition can be administered one or more times to the subject. Preferably, there is a set time interval between separate administrations of the composition. While this interval varies for every subject, typically it can range from 10 days to several weeks, and is often 2, 4, 6 or 8 weeks. In some embodiments, the interval can be typically from 2 to 6 weeks. The compositions of the invention can be administered alone, or can be co- administered, or sequentially administered, with other Clostridium difficile immunogens and / or Clostridium difficile immunogenic compositions, e.g., with "other" immunological, antigenic or vaccine or therapeutic compositions thereby providing multivalent or "cocktail" or combination compositions of the invention and methods of employing them. Again, the ingredients and manner (sequential or co-administration) of administration, as well as dosages can be determined taking into consideration such factors as the age, sex, weight, species and condition of the particular subject, and the route of administration. Kits The present invention also includes kits useful in performing diagnostic and prognostic assays using the antibodies of the present invention. Kits of the invention include a suitable container comprising a Clostridium difficile antibody of the invention in either labeled or unlabeled form. In addition, when the antibody is supplied in a labeled form suitable for an indirect binding assay, the kit further includes reagents for performing the appropriate indirect assay. For example, the kit includes one or more suitable containers including enzyme substrates or derivatizing agents, depending on the nature of the label. Control samples and / or instructions are also included. Application of the teachings of the present invention to a specific problem is within the capabilities of one having ordinary skill in the art in light of the teaching contained herein. Examples of the compositions and methods of the invention appear in the following non-limiting Examples. EXAMPLES Example 1. Elicitation of potent neutralizing antibody response to C. difficile binary toxins in non-human primates We have immunized two non-human primate Cynomolgus macaques with selected C. difficile binary toxin variants to generate polyclonal nAb response against binary toxins followed by isolating monoclonal nAbs from the immunized animals by our in-house memory B cell sorting and cloning platform (Fig. 3). We used selected binary toxin constructs designed and produced in the Weber / Pozharskiy lab as immunization antigens, including the full-length CDTa carrying 4 mutations in the CDTa-D2 domain, the catalytic CDTa-D2 domain, the inactive proCDTb, the D3 &D3’ domains of proCDTb (also called RBD1), and the D4 domain of proCDTb (also called RBD2) which is involved engagement with host receptor LSR protein. This panel of antigens present varieties of cognate functional epitopes for neutralizing antibodies (Fig. 2) to generate binary toxin specific B cell repertoires in NHP animals. After three immunizations, the sera from these two immunized macaques displayed potent binary toxin neutralization activities. As shown in Fig.3A, immune serum from one of the macaques, namely NHP 171076 showed ID50 value above 12,500 against binary toxin assessed in a validated in vitro binary toxin toxicity assay, suggesting that the immunization had elicited memory B cells capable of producing binary toxin-specific neutralizing antibodies. We then applied an in-house (Li Laboratory) well-established FACS-based antigen-specific memory B cell sorting and mAb cloning platform to enrich binary toxin epitope-specific memory B cells and clone the mAb-encoding genes to reconstitute full- length IgG molecule (Wu et al., Science, (2010) 329:856-61;Zhao et al. Cell, (2017), 169:891-904.e15). The recent initial effort using proCDTb-RBD2 domain as sorting antigen, we have isolated three nAbs, namely B2, B3, and B8, which showed potent neutralization activities against binary toxin (Fig. 3B), with IC50 values ranging from 10- 80 pM (Fig. 3B). Our in-house NHP-derived binary toxin nAbs possess superior neutralization potency and target novel epitope compared with previously published mouse-derived nAbs Our most potent antibody, nAb-B3 (nAb-B3IC50 = 10±1 pM), is >5 to >20-fold superior to any binary toxin neutralizing antibodies (nAb) reported so far (Fig. 3B), as we tested all 5 of these antibodies in side-by-side Vero cell toxicity assays (BINTOXB / 9IC50 = 57±4 pM; BINTOXB / 22IC50 = 211±54 pM) (Goldsmith et al. J Bacteriol, (2023), 205:e0045622). We next showed that two of our nAbs (nAb-B3 & nAb-B8) have distinct binding epitopes from nAbs reported previously (Fig. 3C) (Goldsmith et al. J Bacteriol, (2023), 205:e0045622). Thus, our in-house nAbs of NHP-origin possess superior neutralization potency and target novel epitope compared with previously published mouse-derived nAbs, which are more amenable for developing therapeutic antibodies to cure CDAD than those nAbs published previously (Goldsmith et al. J Bacteriol, (2023), 205:e0045622). Example 2. Nucleotide (nt) and amino acid (aa) sequences of Clostridium difficile binary toxin neutralizing antibodies. >B2_H_nt (SEQ ID NO:1) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCC TGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCTTCAGCAGTTACTGGTGGGGC TGGATCCGCCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGCATATCCGTA GTGGTGGGAGCAACTATGTTAACCCGTCCCTCAAGAGTCGAGTCACCCTGTC AGCAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCC GCGGACACGGCCGTGTATTACTGTGCGAGACTACGTGGATACAGTAACTACG CCGGCTTTGACTACTGGGGCCAGGGAGTCCTGGTCACCGTCTCCTCA >B2_L_nt (SEQ ID NO:2) CAGTCTGTGCTGACTCAGCCTCCCTCAGCGTCTGAGGCCGCCAGGAAGAGTG TCACCATCTCCTGTTCTGGAAGCAGCTCCAACATCGGAACTAATAGTGTATCC TGGTACCAGCAGCTCCCAGGAACGGCTCCCAAACTCCTCATCTCTTATAATGA TCAACGAGCCTCAGGTGTCTCTGACCGATTCTCTGGCTCCAAGTCTGGCACGT CAGCCTCCCTGGCCATCAGTGGGCTCCAGACCGAGGATGAGGCTGATTATTA CTGCGCAACATGGGATGATAGCCTGAGCGGTTACATCTTCGGTGCTGGGACC CGGCTCACCGTCCTA >B3_H_nt (SEQ ID NO:3) CAGGTGCAGCTGCAGgAGTGGGGCGAAGGACTGGTGAAGCCTTCGGAGACCC TGTCCCTCAGCTGCGCTGTCTATGGTGGCTCCATAAGCGATTACTACTACTGG AGCTGGATCCGCCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATTT ATGGTGATAAGACGAGCACCAACTACAACCCCTCCCTCAAGGATCGAGTCAC CATTTCAAAAGAGACGTCCAAGAACCTGTTCTCCCTGAAGCTGACCTCTGTGA CCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGGGGTTCGTGACGGCAC GCTTAAGTACAACCGGTTCGATGTCTGGGGCCCGGGAGTCCTGGTCACCGTCT CCTCA >B3_K_nt (SEQ ID NO:4) GACATTCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACTC AGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAATGCTTTAGCCTGG TATCAGCAGAAACCAGGGAAAGCCCCTGAGCTCCTGATCTATGCTGCATCCG GTTTGCAGAGTGGGGTCCCATCAGGGTTCAGCGGCAGTGGATCTGGGACAGA CTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACT GTCAACAGTATAATAGTTACCCTCTCACTTTCGGCGGAgggaccaaggtggaaatcaaa >B8_H_nt (SEQ ID NO:5) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCC TGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAATAACTACTGGAGC TGGATCCGCCAGGCCCCAGGGAAGGGACTGGAGTGGATTGGACGTATCTTTG GTAGTGATGGGAGCACCGACTACAACCCCTCCCTCAAGAGTCGAGTCACCAT TTCAACAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACC GCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAGGGGCGTGGATACAGTG ACTACAGTTACTGGGGCCAGGGAGTCCTGGTCACCGTCTCCTCA >B8_L_nt (SEQ ID NO:6) CAGCCTGTGCTGACTCAGCCAACCTCCCTCTCAGCATCTCCTGGAGCATCAGC CAGACTCACCTGCACCTTGCGCAGTGGCATCAGTGTTGGTGGTTACAGGATGT TCTGGTACCAGCAGAAGCCAGGGAGTCCTCCCCGGTATCTTCTGAACTACCA CACAGACTCAGATAACCACCAGGGCTCTGGAGTCCCCAGCCGCTTCTCTGGA TCCAAAGATGCTTCGGCCAATGCAGGGATTTTACTCATCTCTGGGCTCCAGTC TGAGGATGAGGCTGACTATTACTGTATGATTTGGCTCAACAATGCTGGCTTAT TCGGAGGAGGGACCCGGCTGACCGTC >B2_H_aa (SEQ ID NO:7) QVQLQESGPGLVKPSETLSLTCAVSGGSFSSYWWGWIRQPPGKGLEWIGHIRSG GSNYVNPSLKSRVTLSADTSKNQFSLKLSSVTAADTAVYYCARLRGYSNYAGFD YWGQGVLVTVSS >B2_L_aa (SEQ ID NO:8) QSVLTQPPSASEAARKSVTISCSGSSSNIGTNSVSWYQQLPGTAPKLLISYNDQRA SGVSDRFSGSKSGTSASLAISGLQTEDEADYYCATWDDSLSGYIFGAGTRLTVL >B3_H_aa (SEQ ID NO:9) QVQLQEWGEGLVKPSETLSLSCAVYGGSISDYYYWSWIRQPPGKGLEWIGYIYG DKTSTNYNPSLKDRVTISKETSKNLFSLKLTSVTAADTAVYYCARGVRDGTLKY NRFDVWGPGVLVTVSS >B3_K_aa (SEQ ID NO:10) DIQMTQSPSSLSASVGDSVTITCRASQGISNALAWYQQKPGKAPELLIYAASGLQ SGVPSGFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK >B8_H_aa (SEQ ID NO:11) QVQLQESGPGLVKPSETLSLTCAVSGGSISNNYWSWIRQAPGKGLEWIGRIFGSD GSTDYNPSLKSRVTISTDTSKNQFSLKLSSVTAADTAVYYCAREGRGYSDYSYW GQGVLVTVSS >B8_L_aa (SEQ ID NO:12) QPVLTQPTSLSASPGASARLTCTLRSGISVGGYRMFWYQQKPGSPPRYLLNYHTD SDNHQGSGVPSRFSGSKDASANAGILLISGLQSEDEADYYCMIWLNNAGLFGGG TRLTV CDR sequences of the antibodies are shown below: CDR1 CDR2 CDR3 DV Example 3. Epitope Mapping Reveals a Novel Site on CDTb RBD2 Targeted by the Binary Toxin CDTb RBD-Specific Neutralizing Antibody B3. We tested if nAb B3 blocks binary toxin binding to cell receptor LSR using a BLI- based CDTb binding assay shown in Fig. 4A. Biotin-labeled proCDTb was initially captured by BLI SA-probe followed by immersing into wells containing test antibodies (PBS as negative control) and wells containing soluble form of recombinant human LSR protein subsequently to collect LSR binding signal. RBD-specific nAb B3 inhibits CDTb- LSR binding, while reference mAb BINTOXb / 9 shows no inhibition, suggesting that nAb B3 mediates the blockage of CDTb binding to receptor LSR. Furthermore, we investigated the epitope targeted by nAb B3 in more details via structural analysis (Figs. 4B & 4C). Specifically, we pursued the structure determination for the B3 Fab in complex with the toxin. Low resolution single particle reconstruction by cryoEM confirmed that the antibody targets the RBD component of CDTb (Fig. 4B). We then focused on crystallizing the B3 Fab complex with the RBD domain of CDTb to obtain a high-resolution structure (Fig. 4C, left), which revealed details of the B3 CDR conformation in the context of antigen binding. Notably, nAb B3 appears to block CDTb binding to the receptor LSR directly. As shown in Fig.4C (right panel), the heavy chain of nAb B3 contacts residue F774 on RBD^ previously identified by mutagenesis as a critical site for LSR binding (Anderson DM et al., Nat Microbiol, (2020), 5:102-107). This structural finding is consistent with the functional data demonstrating that nAb B3 prevents CDTb from binding to a soluble form of receptor LSR (Fig. 4A). Example 4. Protective efficacy conferred by binary toxin nAbs against primary CDI in mouse and hamster models In this example, we examined if the RBD-specific nAbs we have isolated in could confer protection against primary CDI in mice (Fig. 5A). 6–8-week-old female C57BL / 6 mice, N=5 / group were administered daily for 3 days with an antibiotic cocktail via oral gavage and consist of kanamycin, gentamicin, colistin, metronidazole, and vancomycin. On the day prior to infection, mice were administered one dose of clindamycin intraperitoneally (IP). The next day mice were infected by gavage with a hypervirulent C. difficile strain (Ribotype 027, ATCC BAA 1803 expressing TcdA & B and binary toxin) in vegetative form with an optimized dose (2.5 X 104CFU) for inducing primary CDI. The mice then received antibody treatment intraperitoneally (10 mg / kg for each antibody) 4 hours post-infection, with PBS or an irrelevant human IgG antibody treatment as negative control. Combination of treatment with α-TcdA (Actoxumab), α-TcdB (Bezlotoxumab), and binary toxin nAb-B2 or B3 provided 100% protection in C. difficile-challenged mice, while mice treated with α-TcdA / TcdB only showed partial protection (Fig. 5A). This result is consistent with an independent study in hamsters (Fig. 5B), in which male hamsters received IP injection of clindamycin (20 mg / kg) one day prior to a high lethal dose C. difficile infection (106CFU) with the same strain via oral gavage. Antibody treatment was administered at 4- hours post-infection. We have similar observation that hamsters received combination treatment with α-TcdA / TcdB, and binary toxin nAb-B2 or B3 showed extended survival time (increased median survival, Fig. 5B, left panel) compared to those treated with the negative control human IgG or α-TcdA / TcdB only. Additionally, α-TcdA / TcdB, and binary toxin nAb-B2 or B3 reduced body weight decrease of C. difficile-challenged hamster on day 1 post infection (Fig. 5B, right panel). In summary, our protective efficacy studies in mice and hamsters demonstrated that selected binary toxin nAbs, when combined with anti-TcdA / TcdB antibodies, provided better protection compared to treatment with anti-TcdA / TcdB antibodies alone. These findings warrant further investigation. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.

Claims

WHAT IS CLAIMED IS:

1. An isolated Clostridium difficile binary toxin antibody that is capable of neutralizing binary toxin with an IC50 value of less than about 80 pM.

2. An isolated Clostridium difficile binary toxin antibody that is capable of neutralizing binary toxin with an IC50 value of from about 10 pM to about 80 pM.

3. The isolated Clostridium difficile binary toxin antibody of claims 1 or 2, wherein the antibody is B2, B3 or B8, or an antigen binding fragment thereof.

4. The isolated Clostridium difficile binary toxin antibody of any of claims 1-3, wherein the antibody comprises heavy chain variable (VH) and light chain variable (VL) regions of antibody B2.

5. The isolated Clostridium difficile binary toxin antibody of any of claims 1-3, wherein the antibody comprises VH and VL regions of antibody B3.

6. The isolated Clostridium difficile binary toxin antibody of any of claims 1-3, wherein the antibody comprises VH and VL regions of antibody B8.

7. The isolated Clostridium difficile binary toxin antibody of any of claims 1-3, wherein the antibody comprises complementarity determining regions (CDRs) of the VH and VL regions of antibody B2.

8. The isolated Clostridium difficile binary toxin antibody of any of claims 1-3, wherein the antibody comprises CDRs of the VH and VL regions of antibody B3.

9. The isolated Clostridium difficile binary toxin antibody of any of claims 1-3, wherein the antibody comprises CDRs of the VH and VL regions of antibody B8.

10. The isolated Clostridium difficile binary toxin antibody of any of claims 1-9, wherein Clostridium difficile binary toxin antibody is selected from the group consisting of: a. an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSFSSYW (SEQ ID NO:13), IRSGGSN (SEQ ID NO:14) and ARLRGYSNYAGFDY (SEQ IDNO:15); and a light chain variable region, wherein the CDRs comprise amino acid sequences SSNIGTNS (SEQ ID NO:16), YND and ATWDDSLSGYI (SEQ ID NO:17); b. an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSISDYYYW (SEQ ID NO:18), IYGDKTST (SEQ ID NO:19) and ARGVRDGTLKYNRFDV (SEQ ID NO:20); and a light chain variable region, wherein the CDRs comprise amino acid sequences QGISNA (SEQ ID NO:21), AAS and QQYNSYPLT (SEQ ID NO:22); and c. an antibody comprising a heavy chain variable region, wherein the CDRs comprise amino acid sequences GGSISNNYW (SEQ ID NO:23), IFGSDGST (SEQ ID NO:24) and AREGRGYSDYSY (SEQ ID NO:25); and a light chain variable region, wherein the CDRs comprise amino acid sequences SGISVGGYR (SEQ ID NO:26), YHTDSDN (SEQ ID NO:27) and MIWLNNAGL (SEQ ID NO:28).

11. The isolated Clostridium difficile binary toxin antibody of any of claims 1-9, wherein Clostridium difficile binary toxin antibody is selected from the group consisting of: a. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:7 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:8 or an antigen binding fragment thereof; b. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:9 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:10 or an antigen binding fragment thereof; and c. an antibody comprising a heavy chain amino acid sequence comprising SEQ ID NO:11 or an antigen binding fragment thereof and a light chain amino acid sequence comprising SEQ ID NO:12 or an antigen binding fragment thereof.

12. The isolated Clostridium difficile binary toxin antibody of any of claims 1-9, wherein the antibody comprises a heavy chain or an antigen binding fragment thereof and a light chain or an antigen binding fragment thereof, wherein the heavy chain or antigen binding fragment thereof comprises a heavy chain variable (VH) region and the light chain or antigen binding fragment thereof comprises a light chain variable (VL) region; wherein the Clostridium difficile binary toxin antibody is selected from the group consisting of an antibody: a. wherein the VH region comprises SEQ ID NO:7 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:8 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; b. wherein the VH region comprises SEQ ID NO:9 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:10 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; and c. wherein the VH region comprises SEQ ID NO:11 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL region comprises SEQ ID NO:12 or a variant thereof comprising 1, 2, 3, or 4 conservative amino acid substitutions.

13. The isolated Clostridium difficile binary toxin antibody of any of claims 1-12, wherein the antibody is humanized.

14. The isolated Clostridium difficile binary toxin antibody of any of claims 1-13, wherein the antibody comprises human immunoglobulin heavy and light chain constant regions.

15. An isolated host cell expressing the antibody of any of claims 1-14.

16. One or more vectors comprising a nucleic acid encoding the antibody of any of claims 1-14.

17. The one or more vectors of claim 16, wherein a first vector encodes a light chain sequence and a second vector encodes a heavy chain sequence.

18. The one or more vectors of claim 16, wherein a single vector encodes a light chain sequence and a heavy chain sequence.

19. A cell comprising the one or more vectors of any of claims 16-18.

20. An engineered cell that expresses the antibody of any of claims 1-14.

21. The cell of claim 20, wherein the cell is an immune cell.

22. The cell of claim 21, wherein the immune cell is a B cell.

23. A pharmaceutical composition comprising one or more antibodies of any of claims 1-14 and / or cells of any of claims 19-22 and a pharmaceutically acceptable carrier.

24. A method for treating or preventing Clostridium difficile infection or alleviating one or more symptoms thereof in a subject, comprising administering to the subject an effective amount of the composition of claim 23.

25. The method of claim 24, wherein the method further comprises administering to the subject an effective amount of one or more additional therapeutic agents.

26. The method of claim 25, wherein the one or more additional therapeutic agents is an antibiotic.

27. The method of claim 26, wherein the antibiotic is selected from metronidazole, vancomycin, fidaxomicin, and combinations thereof.

28. The method of claim 25, wherein the one or more additional therapeutic agents is an antibody.

29. The method of claim 28, wherein the antibody is an anti-TcdA or an anti-TcdB antibody.

30. The method of claim 29, wherein the anti-TcdA antibody is actoxumab.

31. The method of claim 29, wherein the anti-TcdB antibody is bezlotoxumab.

32. The method of claim 25, wherein the one or more additional therapeutic agents is an anti-TcdA antibody and an anti-TcdB antibody.

33. The method of claim 32, wherein the anti-TcdA antibody is actoxumab and the anti-TcdB antibody is bezlotoxumab.

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