[go: up one dir, main page]

WO2024211789A1 - Cross-flavivirus binding domains and uses thereof - Google Patents

Cross-flavivirus binding domains and uses thereof Download PDF

Info

Publication number
WO2024211789A1
WO2024211789A1 PCT/US2024/023379 US2024023379W WO2024211789A1 WO 2024211789 A1 WO2024211789 A1 WO 2024211789A1 US 2024023379 W US2024023379 W US 2024023379W WO 2024211789 A1 WO2024211789 A1 WO 2024211789A1
Authority
WO
WIPO (PCT)
Prior art keywords
sequence
seq
set forth
domain
binding domain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/023379
Other languages
French (fr)
Inventor
Leslie GOO
JR. David Jay LUBOW
IV Frederick MATSEN
Duncan RALPH
Lisa LEVOIR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fred Hutchinson Cancer Center
Original Assignee
Fred Hutchinson Cancer Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fred Hutchinson Cancer Center filed Critical Fred Hutchinson Cancer Center
Publication of WO2024211789A1 publication Critical patent/WO2024211789A1/en
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1081—Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Zika virus (ZIKV) and the four circulating serotypes of dengue virus (DENV1, DENV2, DENV3, and DENV4) are mosquito-borne flaviviruses with overlapping geographic distributions. climate change is predicted to further expand the geographic range of mosquito vectors, highlighting the need for effective clinical interventions to curb epidemics.
  • the complex antibody response to DENV1-4 has hampered the development of safe and effective vaccines. A first exposure to a given DENV serotype generates potently neutralizing antibodies that typically provide long-term, though sometimes incomplete protection against reinfection by that serotype.
  • ADE antibody-dependent enhancement
  • Fc ⁇ R Fc-Fc gamma receptor
  • a Category 1 binding domain binds DENV1, DENV2, DENV3, DENV4, and ZIKV.
  • a Category 1 binding domain includes binding domains from F25.S02, F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, or F02.S05.
  • a Category 2 binding domain binds DENV1, DENV2, DENV3, and DENV4.
  • the Category 2 binding domain includes binding domains from F09.S05, F05.S03, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, or F22.S01.
  • a binding domain from F25.S02 includes a variable heavy chain including a complementarity determining region (CDR) heavy (H)1 including the sequence as set forth in SEQ ID NO: 18, a CDRH2 including the sequence as set forth in SEQ ID NO: 19, and a CDRH3 including the sequence as set forth in SEQ ID NO: 20; and a variable light chain including a CDR light (L)1 including the sequence as set forth in SEQ ID NO: 21, a CDRL2 including the sequence as set forth in SEQ ID NO: 22, and a CDRL3 including the sequence as set forth in SEQ ID NO: 23.
  • CDR complementarity determining region
  • a binding domain from F25.S02 includes a variable heavy chain including the sequence as set forth in SEQ ID NO: 6 and a variable light chain including the sequence as set forth in SEQ ID NO: 7.
  • a binding domain from F09.S05 includes a variable heavy chain including a CDRH1 including the sequence as set forth in SEQ ID NO: 39, a CDRH2 including the sequence as set forth in SEQ ID NO: 40, and a CDRH3 including the sequence as set forth in SEQ ID NO: 41; and a variable light chain including a CDRL1 including the sequence as set forth in SEQ ID NO: 42, a CDRL2 including the sequence as set forth in SEQ ID NO: 43, and a CDRL3 including the sequence as set forth in SEQ ID NO: 44.
  • a binding domain from F09.S05 includes a variable heavy chain including the sequence as set forth in SEQ ID NO: 10 and a variable light chain including the sequence as set forth in SEQ ID NO: 11.
  • a binding domain from F053.S03 includes a variable heavy chain including a CDRH1 including the sequence as set forth in SEQ ID NO: 61, a CDRH2 F053-6006PCT / 23-211-WO-PCT including the sequence as set forth in SEQ ID NO: 62, and a CDRH3 including the sequence as set forth in SEQ ID NO: 63; and a variable light chain including a CDRL1 including the sequence as set forth in SEQ ID NO: 64, a CDRL2 including the sequence as set forth in SEQ ID NO: 65, and a CDRL3 including the sequence as set forth in SEQ ID NO: 66.
  • a binding domain from F05.S03 includes a variable heavy chain including the sequence as set forth in SEQ ID NO: 14 and a variable light chain including the sequence as set forth in SEQ ID NO: 15.
  • Additional binding domains are described in the Detailed Description.
  • the binding domains described herein can be used to neutralize DENV in a subject in need thereof.
  • the binding domains described herein can be used to neutralize DENV and ZIKV in a subject in need thereof.
  • FIGs. 1A-1F Workflow to identify broadly neutralizing antibodies (bnAbs) from donor samples.
  • bnAbs broadly neutralizing antibodies
  • B cells were isolated from the peripheral blood mononuclear cells (PBMCs) of donors selected in (FIG.1A) and processed for (1C) single-cell RNA sequencing of both global gene expression (GEX) and B cell receptor (BCR)-specific libraries.
  • GEX global gene expression
  • BCR B cell receptor
  • (1D) BCR libraries are analyzed by the software package partis (Ralph and Matsen, 4th (2022). PLoS Comput. Biol. 18 (“Ralph”)), which groups antibodies into clonal families and infers their shared ancestry.
  • (1E) Antibody sequences most likely to encode flavivirus-specific, high-affinity antibodies are bioinformatically down-selected for functional characterization.
  • FIG. 2 Serum neutralizing activity against flaviviruses. Serum samples from 38 cohort participants with the indicated age and DENV and/or ZIKV exposure histories collected at the time point(s) shown were diluted either 1:240 (expt1) or 1:300 (expt2) and tested for their ability to neutralize the indicated flaviviruses in two independent experiments.
  • Control antibodies which include human convalescent sera to DENV (BEI Resources NR-50232) or ZIKV F053-6006PCT / 23-211-WO-PCT (BEI Resources NR-50752) and monoclonal antibodies (mAb) E60134, ZV-67135, CR4354136, and EDE1 C1028.
  • the percent neutralizing activity shown under each virus column is normalized to infection in the absence of antibody.
  • Heatmap colors represent neutralizing activity of at least 50% as indicated in the key under the table.
  • Corresponding PBMC samples from the donors were selected and time points highlighted under the ‘Days post-fever’ column for single-cell RNA sequencing to isolate monoclonal antibodies. [0019] FIGs.3A, 3B.
  • B cell subsets and antibody isotypes within clonal families. Graphs depict the number of antibodies encoded (3A) by distinct B cell subsets and (3B) as various isotypes in clonal families of different sizes in each of the four donor samples analyzed. B cell subset and antibody isotype were determined by analysis of the cell’s transcriptome as captured by the gene expression library. Only B cells for which a corresponding antibody sequence was observed in the B cell receptor library were included. Sections without a symbol include multiple B cell subsets (3A) or multiple Ab isotypes (3B). [0020] FIG.4. Neutralization profiles of IgG1 transfection supernatants.
  • Heatmaps displaying the results of neutralization assays against DENV1-4 and ZIKV using 1/10 diluted ExpiCHO-S culture supernatant containing the antibodies indicated.
  • Antibodies were named based on the source of the antibody in the format DXX.FYY.SZZ, where XX is the donor number, YY is the clonal family within the donor ranked by decreasing size, and ZZ is assigned by the chronological order in which antibodies from the family were produced. The percent neutralization is calculated relative to infection in the absence of antibody. The final column displays the number of viruses that were neutralized by >50% by that antibody. The antibodies whose names were left were screened in round 1, which was intended to screen many different families.
  • FIG.5. Heatmaps of IC50 values obtained from dose-response neutralization assays using previously published bnAbs, novel category 1 bnAbs, which neutralize DENV1-4 and ZIKV, and novel category 2 novel bnAbs, which neutralize DENV1-4 but not ZIKV.
  • FIGs.6A-6D Neutralization profile of top bnAbs expressed as IgG1.
  • 6A Representative dose-response neutralization curves of each antibody against the indicated reporter virus particles F053-6006PCT / 23-211-WO-PCT performed in at least 3 biological replicates in duplicate wells. The data points represent the mean and the error bars represent the range of the duplicates.
  • 6B Mean IC50 values for antibody-virus pairs shown in (6A) and compiled from FIG. 5. The final column displays the geometric mean IC50 values against neutralized viruses.
  • Relative binding efficiency (measured by ELISA) by the indicated antibodies to (8A) E protein monomers (8B) or virus particles of DENV216681.
  • the results are from two independent experiments, each performed in duplicate wells. The absorbance of each duplicate, reported in arbitrary units (AU), was normalized to the wells that received positive control antibody B1039. HIV-specific antibody, PGT121133 was used as a negative control. Data points represent the normalized means of each experiment and the bars represent the means of the two experiments.
  • (8C-8F) DENV2 16681 E protein sites important for binding by antibody (8C) F25.S02 or (8E) F05.S03 are shown on the ribbon structure of the DENV2 E dimer (PDB: 1OAN) and labeled on one monomer.
  • FIGs.9A-9F E protein residues critical for neutralization by bnAbs.
  • Bar graphs show the mean IC50 fold change for antibodies (9A) F09.S05, (9B) F25.S02, (9C) F05.S03, (9D) EDE1- F053-6006PCT / 23-211-WO-PCT C10, and (9E) J9 against DENV216681 reporter virus particles encoding E protein variants relative to wild type (WT) DENV2. Values of 1, >1, and ⁇ 1 indicate no change, decreased sensitivity, and increased sensitivity of mutant relative to WT DENV2, respectively. Mean values were obtained from at least 2 independent experiments shown as individual data points in which WT and mutant DENV2 were tested in parallel. WT ZIKV H/PF/2013 (first sample) was included as a control.
  • Each half also has a well containing IgA1 monomers of the indicated antibody that was produced as monomers, i.e., in the absence of a J chain expression plasmid (Mono) in addition to a well containing monomers that were purified via SEC (S-Mono).
  • the two sources of monomers appear identical on the gel, but for simplicity only the ones produced in the absence of a J chain expression plasmid were used for experiments.
  • FIGs.12A, 12B Neutralization profiles of antibodies expressed as IgA1.
  • IgG open circles
  • monomeric IgA1 triangle
  • polymeric IgA1 star versions of F25.S02 (top row), EDE1-C10 (middle row), and SIgN-3C (bottom row) were tested for their ability to neutralize reporter virus particles indicated in each column.
  • Dose-response curves are representative of 3 independent experiments, each tested in duplicate wells. Data points and error bars represent F053-6006PCT / 23-211-WO-PCT the mean and range of the duplicates, respectively.
  • FIG. 13 Antibody dependent enhancement (ADE) profile of IgG1 bnAbs in K562 cells. Serial dilutions of antibodies indicated in the key were complexed with reporter virus particles shown above graphs prior to infection of K562 cells.
  • ADE antibody dependent enhancement
  • FIG.14 Fc receptor expression profile of K562 and U937 cells. Histograms display the fluorescence intensity of K562 (top row) or U937 (bottom row) cells stained for the indicated Fc receptors. Histograms are normalized to the modal cell count. The isotype control was conjugated to the same fluorophore and used at the same concentration as anti-Fc ⁇ RIIa or anti-Fc ⁇ R1 antibody on the same population of cells.
  • FIGs.15A-15C Effect of antibody isotype on ADE.
  • DENV1 left panel
  • DENV4 right panel
  • reporter virus particles were pre-incubated with serial dilutions of IgG1 and/or IgA1 forms of the indicated antibodies prior to infection of target cells expressing Fc receptor for IgG and/or IgA.
  • Dose-response ADE assays in K562 cells, which express Fc ⁇ RII but not Fc ⁇ RI. IgG1 and IgA1 antibodies were tested individually. The data points and error bars represent the means and range of duplicate infection, respectively.
  • Sequences supporting the disclosure including F25.S03 variable heavy chain (SEQ ID NO: 335) and encoding sequence (SEQ ID NO: 336); F25.S03 variable light chain (SEQ ID NO: 337) and encoding sequence (SEQ ID NO: 338); F25.S04 variable heavy chain (SEQ ID NO: 339) and encoding sequence (SEQ ID NO: 340); F25.S04 variable light chain (SEQ ID NO: 341) and encoding sequence (SEQ ID NO: 342); F25.S06 variable heavy chain (SEQ ID NO: 343) and encoding sequence (SEQ ID NO: 344); F25.S06 variable light chain (SEQ ID NO: 345) and encoding sequence (SEQ ID NO: 346); 4UT9_1 (SEQ ID NO: 347); 4UT9_2 (SEQ ID NO: 348); 4UT9_3 (SEQ ID NO: 349); 4UTA_1 (SEQ ID NO: 350); 4UTA_2 (SEQ ID NO: 35
  • Dengue virus is a positive-sense RNA virus of the Flavivirus genus of the Flaviviridae family, which also includes West Nile virus, Yellow Fever Virus, and Japanese Encephalitis virus. It is transmitted to humans through Stegomyia aegypti (formerly Aedes) mosquito vectors and is mainly found in the tropical and semitropical areas of the world, where it is endemic.
  • Stegomyia aegypti (formerly Aedes) mosquito vectors and is mainly found in the tropical and semitropical areas of the world, where it is endemic.
  • There are four serotypes of DENV including DENV1, DENV2, DENV3, and DENV4. The four serotypes show immunological cross-reactivity, but are distinguishable in plaque reduction neutralization tests and by their respective monoclonal antibodies.
  • the DENV envelope (E) protein is composed of three domains: E protein domain I (ED1) is the central domain, ED2 is the dimerization domain and contains the conserved fusion loop, and ED3 is the putative receptor- binding domain (Modis et al., Proc Natl Acad Sci U S A 100, 2003, p6986-6991).
  • E protein occupies the majority of the viral surface and is the primary antigen targeted by the humoral immune response (Kuhn et al., Cell 108, 2002, p717–725; and Pierson et al., Expert Rev Mol Med 10, 2008, e12).
  • Zika virus is a member of the Flaviviridae virus family and the flavivirus genus. In humans, it causes a disease known as Zika fever. It is related to dengue, and like dengue, ZIKV is spread to people through mosquito bites. The most common symptoms of Zika fever are fever, rash, joint pain, and red eye. The illness is usually mild with symptoms lasting from several days to a week. There is no vaccine to prevent, or medicine to treat, Zika virus. F053-6006PCT / 23-211-WO-PCT [0037] The complex antibody response to DENV1-4 has hampered the development of safe and effective vaccines.
  • a first exposure to a given DENV serotype generates potently neutralizing antibodies that typically provide long-term, though sometimes incomplete protection against reinfection by that serotype.
  • antibodies that are cross-reactive in binding but not neutralizing activity against other DENV serotypes are also elicited and pre-existing non- neutralizing antibodies predict the risk of severe disease following secondary exposure to a different DENV serotypes.
  • This phenomenon is attributed to a process called antibody-dependent enhancement (ADE), in which non-neutralizing IgG antibodies facilitate the uptake of bound DENV particles into relevant myeloid target cells via Fc-Fc gamma receptor (Fc ⁇ R)-dependent pathways.
  • ADE antibody-dependent enhancement
  • the binding domains disclosed herein bind the E protein of DENV.
  • binding domains also bind the E protein of ZIKV.
  • the binding domains disclosed herein bind quaternary epitopes of the E protein.
  • the E protein of DENV1 includes the sequence MRCVGIGNRDFVEGLSGATWVDVVLEHGSCVTTMAKNKPTLDIELLKTEVTNPAVLRKLCIEAKI SNTTTDSRCPTQGEATLVEEQDANFVCRRTFVDRGWGNGCGLFGKGSLLTCAKFKCVTKLEG KIVQYENLKYSVIVTVHTGDQHQVGNETTEHGTIATITPQAPTSEIQLTDYGALTLDCSPRTGLD FNEMVLLTMKEKSWLVHKQWFLDLPLPWTSGASTSHETWNRQDLLVTFKTAHAKKQEVVVLG SQEGAMHTALTGATEIQMSGTTTIFAGHLKCRLKMDKLTLKGVSYVMCTGSFKLEKEVAETQH GTVLVQVKYEGTDAPCKIPFSIQDEKGVTQNGRLITANPIATDKEKPVNIETEPPFGESYIVIGAG EKALKLSWFKKGSSIGKMFEATARGARRMAILGDTAW
  • the E protein of DENV2 includes the sequence: MDKLQLKGMSYSMCTGKFKVVKEIAETQHGTIVIRVQYEGDGSPCKIPFEIMDLEKRHVLGRLIT VNPIVTEKDSPVNIEAEPPFGDSYIIIGVEP (SEQ ID NO: 2).
  • the E protein of DENV3 includes the sequence: LEHGGCVTTMAKNKPTLDIELQKTEATQLATLRKLCIEGKITNVTTDSRCPTQGEAILPEEQDQN (SEQ ID NO: 3).
  • the E protein of DENV4 includes the sequence: MRCVGVGNRDFVEGVSGGAWVDLVLEHGGCVTTMAQGKPTLDFELIKTTAKEVALLRTYCIEA SISNITTATRCPTQGEPYLKEEQDQQYICRRDMVDRGWGNGCGLFGKGGVVTCAKFSCSGKIT GNLVQIENLEYTVVVTVHNGDTHAVGNDTSNHGETATITPRSPSVEVKLPDYGELTLDCEPRSG IDFNEMILMKMKTKTWLVHKQWFLDLPLPWTAGADTSEVHWNHKERMVTFKVPHAKRQDVTV F053-6006PCT / 23-211-WO-PCT LGSQEGAMHSALAGATEVDSGDGNHMFAGHLKCKVRMEKLRIKGMSYTMCSGKFSIDKEMAE TQHGTTVVKVKYEGTGAPCKVPIEIRDVNKEKVVGRIISSTPFAENTNSVTNIELEPPFGDSYIVI
  • the E protein of ZIKV includes the sequence IRCIGVSNRDFVEGMSGGTWVDVVLEHGGCVTVMAQDKPTVDIELVTTTVSNMAEVRSYCYEA SISDMASDSRCPTQGEAYLDKQSDTQYVCKRTLVDRGWGNGCGLFGKGSLVTCAKFACSKK MTGKSIQPENLEYRIMLSVHGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL DCEPRTGLDFSDLYYLTMNNKHWLVHKEWFHDIPLPWHAGADTGTPHWNNKEALVEFKDAHA KRQTVVVLGSQEGAVHTALAGALEAEMDGAKGRLSSGHLKCRLKMDKLRLKGVSYSLCTAAF TFTKIPAETLHGTVTVEVQYAGTDGPCKVPAQMAVDMQTLTPVGRLITANPVITESTENSKMML ELDPPFGDSYIVIGVGEKKITHHWHRSGSTIGKAFEATVRGAK
  • a Category 1 binding domain binds DENV1, DENV2, DENV3, DENV4, and ZIKV.
  • a Category 1 binding domain includes binding domains from F25.S02, F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, or F02.S05.
  • a Category 2 binding domain binds DENV1, DENV2, DENV3, and DENV4.
  • the Category 2 binding domain includes binding domains from F09.S05, F05.S03, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, or F22.S01.
  • a binding domain from F25.S02 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSAKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIMPIFGTVNYAQ KFQGRVTITADESTSTAYMELSRLRSEDTAVYFCARGWGGNYRSADLWIYFDLWGQGTLVTV SS (SEQ ID NO: 6) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKAPKLMIYDVTKRPSGVPD RFSGSKSGNTASLTISGLQADDEADYYCCSYAGSYTHVVFGGGTKLTVL (SEQ ID NO: 7).
  • a binding domain from F25.S02 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGCGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAAGTATCATGCCTATCTTTGGTACAGTAAACTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTAC F053-6006PCT / 23-211-WO-PCT ATGGAGTTGAGCAGACTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGAGGATGG GGTGGGAACTACAGGTCTGCGGATTTGTGGATCTACTTTGACTTATGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAG (SEQ ID NO: 8) and a variable light chain encoded by the sequence:
  • F25.S02 is derived from an IgA1 isotype as opposed to an IgG1 isotype (other binding domains are derived from IgG1 isotype). F25.S02 is beneficial because it has limited potential for antibody-dependent enhancement of infection in vitro. Furthermore, F25.S02 potently and broadly neutralizes DENV1-4 and ZIKV; it has greater geometric mean potency against DENV1-4 compared to previously described EDE1 antibody of similar breadth (FIG.6B).
  • a binding domain from F09.S05 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVRVSCKASGYTFTSYGISWVRQAPGQGLEWMGWIGTYNGNTNYA PKFHGRVTMTTDTPTSTAYMDLRGLRSDDTAVYYCARDTRHFYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 10) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLVWYQQKPGQAPRLLIHDASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 11).
  • a binding domain from F09.S05 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGT CTCCTGCAAGGCTTCTGGTTACACCTTTACCAGTTATGGTATCAGTTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGATCGGCACTTACAATGGAAACACAAACTAT GCACCGAAATTCCACGGCAGAGTCACCATGACCACAGACACACCCACGAGTACAGCCTAC ATGGACCTGAGGGGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATACC CGCCATTTTTATGATACAAGTGGTTATTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 12) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACC
  • a binding domain from F05.S03 includes a variable heavy chain including the sequence: VQQLVESGGGLVKPGGSLRLSCAASGITFSTYTMNWVRQAPGKGLEWISSINGGSSNIYYADS VEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRGHYYDSSGYFQMGEIDYWGQGTLVS VSS (SEQ ID NO: 14) and a variable light chain including the sequence: DIQMTQSPSTLSASVGDRVTITCRASQSITNWLAWYQQKPGKAPRLLIYKASSLEGGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQQYKTYSRTFGQGTKVEIK (SEQ ID NO: 15).
  • a binding domain from F05.S03 includes a variable heavy chain encoded by the sequence: GTGCAGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGAATCACCTTCAGTACCTATACCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGATCTCATCCATTAATGGTGGTAGTAGTAACATATATTACG CAGACTCAGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTACC TGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAGATAGGG GCCATTACTATGATAGTAGTGGTTATTTCCAAATGGGGGAAATTGACTACTGGGGGG AACCCTGGTCTCCGTCTCCTCAG (SEQ ID NO: 16) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCCTTCCACCCTG
  • CDRs for binding domains of F25.S02, F09.S05, and F05.S03 are in Table 1. [0053] Table 1. CDR sequences for F25.S02, F09.S05, and F05.S03.
  • a binding domain from F25.S06 includes a variable heavy chain encoded by the sequence: CAGGGGCAGCTGGTGCAGTCTGGGGCTGAGGTGAGGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTGCTGGAGGCACCTTCAGCACCTATGGTGTCAGCTGGGTGCGACTGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTTACTTCGGTACCACGAACTA CGCACAGAAGTTTCACGGTAGAGTCACGATAACCGCCGACGAATCCACGAGCACAGTCTA CATGGAACTGCGCAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCGAGAGGATG GGGTGGGAACTACAGGAATATGGATTTGTGGATCTACTTTGACTATTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCAG (SEQ ID NO: 84) and a variable light chain encoded by the sequence
  • a binding domain from F25.S03 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYAVSWVRQAPGQGLEWMGGIIPFFGTTNYA QRFQGRITITADESTGTAYMELRSLRSEDTAVYYCARGWGGNYRNADLWIYFDSWGQGTLVT VSS (SEQ ID NO: 86) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKAPKLMIYDVSKRPSGVPD RYSGSKSGNTASLTISGLQAEDEADYYCCSYADSFTHVIFGGGTKLTVL (SEQ ID NO: 87).
  • a binding domain from F25.S03 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGGTATGCTGTCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTTTTTTTGGTACAACGAATTAC GCACAGAGGTTCCAGGGCAGAATCACAATTACCGCGGACGAATCCACGGGCACAGCCTAC ATGGAGTTGAGGAGTCTCAGATCTGAAGACACGGCCGTGTATTACTGTGCGAGAGGATGG GGTGGGAATTATAGGAATGCGGATTTGTGGATCTACTTTGACTCCTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAG (SEQ ID NO: 88) and a variable light chain encoded by the sequence: CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCG
  • a binding domain from F25.S05 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTVSSYAISWVRQAPGQGLEWMGGILPLFDTRNFAQ KFQGRVTITADESTSTAYMELNSLRYEDTAVYYCARGWGGNYRTADLWIYFDSWGQGTLVTV SS (SEQ ID NO: 90) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKVPKLMIYDVNRRPSGVPD RFSGSKSGNTASLTISGLQAEDEANYYCCSYAGTYTHVLFGGGTKLTVL (SEQ ID NO: 91).
  • a binding domain from F25.S05 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCGTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCCTCCCTCTGTTTGACACAAGAAACTT CGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTA CATGGAGCTGAACAGCCTGAGATATGAGGACACGGCCGTGTATTACTGTGCGCGAGGATG GGGTGGGAACTACAGGACTGCGGATTTGTGGATCTACTTTGACTCCTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCAG (SEQ ID NO: 92) and a variable light chain encoded by the sequence: CAGTCTGCCCTGACTCAGCCTCGCTCAGTG
  • a binding domain from F02.S30 includes a variable heavy chain including the sequence: EVQLVESGGGLVKPGGSLRLSCAGSGFTFSGYSMNWVRQAPGKGLEWVSSLSSSRTYMYYA DSVRGRFTISRDNAENSLFLQMNSLRAEDTAVYYCTRGAPLDDNSGYFVPWYFDLWGRGALV TVSS (SEQ ID NO: 94) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIHGASTRATGIPARFS F053-6006PCT / 23-211-WO-PCT GSGSGTEFTLTISSLQSEDLAVYYCQQYNDWPPETFGQGTKVEIK (SEQ ID NO: 95).
  • a binding domain from F02.S30 includes a variable heavy chain encoded by the sequence: GAGGTGCAGCTGGTGGAATCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGGCTCTGGATTCACCTTCAGTGGCTACAGCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCATCCCTTAGTAGTAGTCGTACTTACATGTACTAC GCAGACTCAGTGAGGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACTCACTGTTT CTCCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTACGAGAGGCGCC CCTCGATGACAATAGTGGTTATTTCGTCCCCTGGTACTTCGATCTGGGGCCGTGGC GCCCTAGTCACTGTCTCCTCAG (SEQ ID NO: 96) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTG
  • a binding domain from F25.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGGIIPIFGTTNYAQ KFQGRVTITADESTNTAYMELSSLRSEDTAVYYCAKGWGGNYRTADLWIYFDLWGQGTLVTV SS (SEQ ID NO: 98) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKAPKLMIYDVTKRPSGVPA RFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHVVFGGGTKLTVL (SEQ ID NO: 99).
  • a binding domain from F25.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTTTCAGCTGGGTGCGACAGGC CCCTGGACAAGGACTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAACAAACTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAACACAGCCTAC ATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTATATTACTGTGCGAAAGGATGG GGTGGGAACTACAGGACTGCGGATTTGTGGATCTACTTTGACCTCTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAG (SEQ ID NO: 100) and a variable light chain encoded by the sequence: F053-6006PCT / 23-211-WO-PCT CAGT
  • a binding domain from F02.S27 includes a variable heavy chain including the sequence: EVQLVESGGGLVKPGGSLRLSCAGSGFTFSSYTMNWVRQAPGKGLEWVSSLSSSRSYMFYA DSVKGRFTISRDNAENSLSLRMNSLRGEDTAVYYCARGAPLDENSGYFVPWYFDLWGRGTLV TVSS (SEQ ID NO: 102) and a variable light chain including the sequence: EIVMTQSPATLSASPGERVTLSCRASQSVSSKLAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYFCQQYNKWPPETFGQGTKVEIK (SEQ ID NO: 103).
  • a binding domain from F02.S27 includes a variable heavy chain encoded by the sequence: GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGGGTCCCTGAGAC TCTCCTGTGCAGGCTCTGGATTCACCTTCAGTTCCTATACCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGTTGGAGTGGGTCTCATCCCTTAGTAGTAGTCGCAGTTACATGTTCTAC GCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAAAATTCATTGTCTT TGCGAATGAACTCCCTGAGAGGCGAGGACACGGCTGTGTATTACTGTGCGAGGGGCGCC CCCCTCGATGAAAACAGTGGTTATTTCGTCCCCTGGTACTTCGATCTGGGGCCGTGGCA CCCTGGTCACTGTCTCGTCAG (SEQ ID NO: 104) and a variable light chain encoded by the sequence: GAAATAGTAATGACGCAGTCTCCAGCCACC
  • a binding domain from F02.S05 includes a variable heavy chain including the sequence: EVQMVESGGGLVKPGGSLRLSCAASGFTFSGYTMNWVRQAPGKGLEWVSSLSSSRSYMYYA DSVKGRFTISRDNAENSLYLQMNSLTAEDTAVYYCARGAPLDENSGFFVPWYFDLWGRGTLV TVSS (SEQ ID NO: 106) and a variable light chain including the sequence: F053-6006PCT / 23-211-WO-PCT EIVMTQSPATLSVSPGERATLSCRASQSISSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPETFGQGTKVEIK (SEQ ID NO: 107).
  • a binding domain from F02.S05 includes a variable heavy chain encoded by the sequence: GAGGTGCAGATGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGGTTATACCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTCTCATCCCTTAGTAGTAGTAGGAGTTACATGTACTAC GCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACTCACTGTAT CTGCAAATGAACAGCCTGACAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGCGCC CCCCTCGATGAAAATAGTGGATTTTTCGTCCCCTGGTACTTCGATCTGGGGCCGTGGCA CCCTGGTCACTGTCTCCTCAG (SEQ ID NO: 108) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCAG (SEQ ID NO: 108)
  • a binding domain from F09.S07 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYGISWVRQAPGQGLEWMGWIGTYNYNTNYA PKFQDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDTRHYYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 110) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSITNNYLTWYQQKPGQPPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGTSLITFGQGTRLAIK (SEQ ID NO: 111).
  • a binding domain from F09.S07 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAAGT CTCCTGTAAGGCTTCTGGTTACACCTTTACCACCTATGGTATCAGTTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGATCGGCACTTACAATTATAATACAAACTATG CACCGAAGTTCCAGGACAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACA TGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTTTACTACTGTGCGAGAGATACGC GGCATTACTATGATACTAGTGGTTATTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAGG GAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 112) and a variable light chain encoded by F053-6006PCT / 23-211-WO-PCT the sequence: GAA
  • a binding domain from F27.S01 includes a variable heavy chain including the sequence: QVQLIQSGAEVKKPGSSVKVSCKASGGTFNSYTINWVRQAPGQGLEWMGNIIPVLGTTNYAEK YQGRVTITADESTSTVYLDLSSLRSGDTAVYYCARGINFYDSSNYFSANWFDPWGQGTLVTVT S (SEQ ID NO: 114) and a variable light chain including the sequence: EIVMTQSPATLSVSPGETATLSCRTSQSVNNNLVWYQQKPGQAPRLLIYAASSRVTGVPARFS GSGSGTEFTLTISSLQSEDSAVYYCQQYKNWPATFGPGTKVDLK (SEQ ID NO: 115).
  • a binding domain from F27.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGTTGATTCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTC TCCTGTAAGGCGTCTGGAGGCACATTCAACAGTTATACTATCAACTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGAAACATCATCCCTGTCCTTGGTACAACAAATTACG CAGAGAAGTACCAGGGCAGAGTCACGATTACCGCGGACGAATCCACCAGTACAGTCTACT TGGACCTGAGCAGTCTGAGATCTGGGGACACGGCCGTCTATTATTGTGCGAGAGGGATCA ACTTCTATGACAGCTCCAACTATTTTTCGGCCAACTGGTTCGACCCCTGGGGCCAGGGAAC CCTGGTCACCGTCACCTCAG (SEQ ID NO: 116) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCAG (SEQ ID NO: 11
  • a binding domain from F09.S08 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYGISWVRQAPGQGPEWMAWISTYNGNTNFA PKFQGRVTMTTDTSTSTAYLELRSLRSDDTAVYYCARDTRHFYDTSGYYLGGWFAPWGPGTQ F053-6006PCT / 23-211-WO-PCT VTVSS (SEQ ID NO: 118) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQAPRLVIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 119).
  • a binding domain from F09.S08 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGTTACTCCTTTACCAGTTATGGTATCAGCTGGGTGCGACAGGCC CCTGGACAAGGGCCTGAGTGGATGGCATGGATCAGCACTTACAATGGTAACACAAACTTT GCACCGAAGTTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC TTGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTACTGTGCGCGAGATACC CGTCATTTCTATGATACTAGTGGTTACTACTTGGGGGGGTGGTTCGCCCTGGGGCCCG GGAACCCAGGTCACCGTCTCCTCAG (SEQ ID NO: 120) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACC
  • a binding domain from F09.S02 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVKVSCKTSGYTFTSYGISWLRQAPGQGLEWIGWIGTYNGNTNYAP KFQGTVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDTRHYYDTSGYYLGGWFAPWGQGTL VTVSS (SEQ ID NO: 122) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GWGSGTDFTLTISRLEPEDFALYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 123).
  • a binding domain from F09.S02 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGACCTCTGGTTACACCTTTACCAGTTATGGTATCAGCTGGTTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATTGGATGGATCGGCACTTACAATGGTAACACAAACTATG CACCGAAGTTCCAGGGCACAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACA TGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGGGATACCC GGCATTACTATGATACTAGTGGTTACTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAGG F053-6006PCT / 23-211-WO-PCT GAACCCTGGTCACCGTCCTCA (SEQ ID NO: 124) and a variable light chain encoded by the sequence:
  • a binding domain from F09.S06 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASLKVSCKASGYTFTSYGISWLRQAPGQGLEWMGWSSPYNGNTHYA PKFQGRVTMTTDTSTSTAYMDLRSLRSDDTAVYYCARDTRHFYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 126) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFITFGQGTRLEIK (SEQ ID NO: 127).
  • a binding domain from F09.S06 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCCGAGGTGAAGAAGCCTGGGGCCTCACTGAAGGT CTCCTGCAAGGCTTCTGGTTACACTTTTACCAGTTATGGTATCAGCTGGCTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGAGCAGCCCTTACAATGGTAACACACATTAC GCACCGAAGTTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC ATGGACCTGAGGAGCCTGAGATCTGACGACACGGCCGTCTATTATTGTGCGAGAGATACC CGGCATTTCTATGATACTAGTGGTTATTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 128) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAATCTCCAGGCACCCTG
  • a binding domain from F05.S01 includes a variable heavy chain including the sequence: VQQLVESGGGLVKPGGSLRLSCAASGITFSTYTMNWVRQAPGKGLEWISSINGGSTNIYYADS F053-6006PCT / 23-211-WO-PCT VEGRFTISRDNAKNSLYLQMNSLRAEETAVYYCARDRGHYYDSSGYFHMGEIDYWGQGTLVS VSS (SEQ ID NO: 130) and a variable light chain including the sequence: DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQQYKTYSRTFGQGTKVEIK (SEQ ID NO: 131).
  • a binding domain from F05.S01 includes a variable heavy chain encoded by the sequence: GTGCAGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGAATCACCTTCAGTACCTATACCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGATCTCATCCATTAATGGTGGTAGTACTAACATATACTACG CAGACTCAGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACGGCTGTATATTACTGTGCGAGAGATAGGG GCCATTATTATGATAGTAGTGGTTATTTCCATATGGGGGAAATTGACTACTGGGGCCAGGG AACCCTGGTCTCCGTCCTCAG (SEQ ID NO: 132) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCCTTCCACCCTG
  • a binding domain from F10.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGSYSSYRISWVRQAPGQGLEWMGRIVPFFGTVDYA EKFQGRVTITADESTSTVYMELTSLRSEDTAVYYCARDINYFDSSYYHSGWWFDPWGQGTLV TVSS (SEQ ID NO: 134) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSSNLVWYQQKPGQAPRLLIYGASTRVTGIPARFTG SGSGTEFTLTISSLQSEDFAVYYCQQYYSWRPITFGQGTRLEIK (SEQ ID NO: 135).
  • a binding domain from F10.S01 includes a variable heavy chain encoded by the sequence: CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT GTCCTGTAAGGCTTCTGGAGGCTCCTACAGCAGCTATAGGATCAGTTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCGTCCCTTTCTTTGGTACAGTAGACTA CGCAGAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGTACAGTGTA TATGGAGCTGACCAGCCTGAGATCTGAGGACACGGCCGTGTATTATTGTGCGAGAGACAT F053-6006PCT / 23-211-WO-PCT AAACTACTTTGATAGTAGTTATTATCATTCTGGTTGGTGGTTCGACCCCTGGGGCCAGGGA ACCCTGGTCACCGTCTCTTCAG (SEQ ID NO: 136) and a variable light chain encoded by the sequence: G
  • a binding domain from F09.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVRVSCKASGYTFTTYGISWVRQAPGQGLEWMGWIGTYNGNTIYA QKFQGRVTMTTDTSTSTAYMELRSLRFDDTAVYYCARDTRHYYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 138) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERASLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 139).
  • a binding domain from F09.S01 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGT CTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTATGGTATTAGCTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGATCGGCACTTACAATGGTAACACAATCTAT GCACAGAAATTTCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC ATGGAGCTGAGGAGCCTGAGATTTGACGACACGGCCGTGTATTACTGTGCGAGAGATACC CGGCATTACTATGATACTAGTGGTTATTACTTAGGGGGGTGGTTCGCCCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 140) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTGTCTGTCTGTCTGGGG
  • a binding domain from F02.S13 includes a variable heavy chain including the sequence: F053-6006PCT / 23-211-WO-PCT EVQLEESGGGLVKPGGSLRLSCAGSGFTFRSYTMNWVRQAPGKGLEWVSSLSSSRSYMFYA DSVRGRFTISRDNAQNSLYLQMRSLRAEDTAVYYCARGAPLDDNSDYFVPWYFDLWGRGTLV TVSS (SEQ ID NO: 142) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPETFGQGTKVEIK (SEQ ID NO: 143).
  • a binding domain from F02.S13 includes a variable heavy chain encoded by the sequence: GAGGTGCAGCTGGAGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGGGTCCCTGAGAC TCTCTTGTGCAGGCTCTGGGTTCACCTTCAGGAGTTACACCATGAACTGGGTCCGTCAGG CTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCCTTAGTAGTAGCCGCTCTTACATGTTCT ACGCAGACTCAGTGAGGGGCCGATTCACCATCTCCAGAGACAACGCCCAGAACTCACTGT ATCTGCAAATGCGCAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGCG CCCCTCGATGATAACAGCGATTATTTCGTCCCCTGGTATTTCGATCTCTGGGGCCGTGG CACCCTGGTCACTGTCTCCTCAG (SEQ ID NO: 144) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCAAGCCGGGGGGGTCCCTG
  • a binding domain from F28.S01 includes a variable heavy chain including the sequence: QVQLQESGPGLVRPSETLSLTCTVSGGSIDGHYWSWIRQPPGKGLEWIGFMFYRGGTNFNPS LKSRVTISVETSKSQFSLKLTSVTAADTAMYYCARGVIRDYGLRFDYWGQGSLVTVSS (SEQ ID NO: 146) and a variable light chain including the sequence: DIQMTQSPSSVSASVGDRVTITCRASQDINSWLAWYQQKPGKAPKLLIYAASNLQNGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQGNSFGVTFGQGTRLEIK (SEQ ID NO: 147).
  • a binding domain from F28.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAGGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCGATGGTCACTACTGGAGCTGGATCCGGCAGCC CCCAGGTAAGGGACTGGAGTGGATTGGCTTTATGTTTTACAGGGGGGGCACCAACTTCAA CCCCTCAAGAGTCGAGTCACCATATCAGTCGAGACGTCCAAGAGTCAGTTCTCCCTG F053-6006PCT / 23-211-WO-PCT AAACTGACATCTGTGACCGCTGCGGACACGGCCATGTATTACTGTGCGAGAGGAGTCATT CGTGACTACGGTCTTCGATTTGACTACTGGGGCCAGGGATCCCTGGTCACCGTCTCCTCA G (SEQ ID NO: 148) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCC
  • a binding domain from F15.S01 includes a variable heavy chain including the sequence: QLHLQESGPGLAKPSETLSLTCTVSRGSIDTATYYWAWIRQTPGKGLEWIGSIYLSADTYYNPS LKSRVSISMDTSTNQFSLKLSSVTAADTAVYYCARQLGNYFDSWGQGTLVTVSS (SEQ ID NO: 150) and a variable light chain including the sequence: AIQLTQSPSSLSASVGDRVTITCRASQGIASYLAWYQQKPGQAPKLLIHTASTLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLSAYLFTFGQGTRLEIK (SEQ ID NO: 151).
  • a binding domain from F15.S01 includes a variable heavy chain encoded by the sequence: CAACTGCATCTTCAGGAGTCGGGCCCAGGGCTGGCGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTGTCTCGTGGCTCCATCGACACTGCAACTTACTACTGGGCCTGGATACG CCAGACCCCCGGGAAGGGACTGGAGTGGATTGGGAGTATCTATCTCAGTGCGGATACCTA CTACAACCCGTCCCTCAAGAGTCGAGTCTCCATATCCATGGACACGTCTACGAACCAGTTC TCCCTGAAGCTGAGCTCAGTCACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGACAG CTGGGTAACTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCCG (SEQ ID NO: 152) and a variable light chain encoded by the sequence: GCCATCCAGTTGACCCAGTCTCCATCGTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCA
  • a binding domain from F13.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGDTFSSYFFTWVRQAPGQGLEWMGGIIPMYGTRNYA F053-6006PCT / 23-211-WO-PCT QKFQGRVTITADESTSTAYMELSSLRSDDTAVYYCARVKFGDFGAYYYYYGMDVWGQGTTVT VSS (SEQ ID NO: 154) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERVTLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFS GSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPAFTFGPGTKVDIK (SEQ ID NO: 155).
  • a binding domain from F13.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGACACCTTCAGCAGTTATTTTTTCACGTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATGTATGGTACAAGAAATTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTAC ATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTATATTACTGTGCGAGAGTGAAG TTCGGTGACTTCGGGGCCTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACC ACGGTCACCGTCCTCAN (SEQ ID NO: 156) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTGTCCTCAN (SEQ ID NO
  • a binding domain from F22.S01 includes a variable heavy chain including the sequence: QVHLVQSGAEVKKPGSSVKVSCKASGGTLSNYAISWVRQAPGQGLEWMGGIIPVFTTGVYAQ SFQGRVTITADESTGTAYMELSSLRSEDTAIYYCATEPQSGVSGRYFDSWGQGTLVTVSS (SEQ ID NO: 158) and a variable light chain including the sequence: DIQMTQSPSTLSPSVGDRVTITCRASQSISSWLAWYQQKPGKAPNLLIYKASTLQSGVPSRFSG SGSGTEFTLTISSLQPDDVATYYCQQYESHPTFGQGTKVEIK (SEQ ID NO: 159).
  • a binding domain from F22.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCACCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGCGGCACCCTCAGCAACTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCAGTCTTTACTACAGGAGTCTA CGCACAGAGCTTCCAGGGCAGAGTCACCATTACCGCGGACGAGTCCACGGGGACAGCCT ACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCATTTATTACTGTGCGACGGAGC F053-6006PCT / 23-211-WO-PCT CCCAGTCGGGTGTCTCGGGGCGCTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACC GTCTCCTCAG (SEQ ID NO: 160) and a variable light chain encoded by the sequence: GACATCCAGATGACCCA
  • CDRs for binding domains of F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, F02.S05, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, and F22.S01 are provided in Table 2. [0095] Table 2.
  • the binding domains described herein can be used to F053-6006PCT / 23-211-WO-PCT neutralize DENV1-4 and ZIKV.
  • Aspects of the current disclosure are now described in more supporting detail as follows: (I) Antibodies; (II) Antibody Variants; (III) Multi-Domain Binding Molecules; (IV) Recombinant Production; (V) Antibody Conjugates; (VI) Compositions or Formulations for Administration; (VII) Methods of Use; (VIII) Kits; (IX) Exemplary Embodiments; (X) Experimental Example; and (XI) Closing Paragraphs.
  • Naturally occurring antibody structural units include a tetramer. Each tetramer includes two pairs of polypeptide chains, each pair having one light chain and one heavy chain. The amino-terminal portion of each chain includes a variable region that is responsible for antigen recognition and epitope binding. The variable regions exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called complementarity determining regions (CDRs). The CDRs from the two chains of each pair are aligned by the framework regions, which enables binding to a specific epitope.
  • FR relatively conserved framework regions
  • CDRs complementarity determining regions
  • both light and heavy chain variable regions include the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the assignment of amino acids to each domain can be in accordance with Kabat numbering (Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.
  • Definitive delineation of a CDR and identification of residues including the binding site of an antibody can be accomplished by solving the structure of the antibody and/or solving the structure of the antibody-epitope complex. In particular embodiments, this can be accomplished by methods such as X-ray crystallography and cryoelectron microscopy.
  • CDRs are F053-6006PCT / 23-211-WO-PCT determined by comparison to known antibodies (linear sequence) and without resorting to solving a crystal structure.
  • a co-crystal structure of the Fab (antibody fragment) bound to the target can optionally be determined.
  • Software programs and bioinformatical tools, such as ABodyBuilder and Paratome can also be used to determine CDR sequences.
  • the carboxy-terminal portion of each chain defines a constant region, which can be responsible for effector function particularly in the heavy chain (the Fc). Examples of effector functions include: C1q binding and complement dependent cytotoxicity (CDC); antibody- dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B-cell receptors); and B-cell activation.
  • variable and constant regions are joined by a “J” region of amino acids, with the heavy chain also including a “D” region of amino acids. See, e.g., Fundamental Immunology, Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).
  • Human light chains are classified as kappa and lambda light chains.
  • a human kappa light chain (Ig ⁇ ) constant region includes the sequence: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 250).
  • a human lambda light chain (Ig ⁇ ) constant region includes the sequence: GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 251).
  • Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • IgG has several subclasses, including, IgG1, IgG2, IgG3, and IgG4.
  • IgM has subclasses including IgM1 and IgM2.
  • IgA is similarly subdivided into subclasses including IgA1 and IgA2.
  • IgG causes opsonization and cellular cytotoxicity and crosses the placenta
  • IgA functions on the mucosal surface
  • IgM is most effective in complement fixation
  • IgE mediates degranulation of mast cells and basophils.
  • the function of IgD is still not well understood.
  • Resting B cells which are immunocompetent but not yet activated, express IgM and IgD. Once activated and committed to secrete antibodies these B cells can express any of the five isotypes.
  • the heavy chain isotypes of IgG, IgA, IgM, IgD and IgE are respectively designated the ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ chains.
  • the constant region of the antibody with multiple binding domains may be of any suitable immunoglobulin subtype.
  • the subtype of the antibody may be of the class IgG, IgD, IgE, IgA, or IgM.
  • Such an antibody may further belong to any subclass, e.g., IgG1, IgG2a, IgG2b, IgG3 and IgG4.
  • a constant region includes a light chain F053-6006PCT / 23-211-WO-PCT constant region and a heavy chain constant region.
  • a “functional constant heavy chain” or “functional CH” activates an aspect of the immune response.
  • a human IgG1 Fc region includes the sequence: THTCPPCPAPEFFGGPSVFFFPPKPKDTFMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVETVFHQDWENGKEYKCKVSNKAFPVPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 252).
  • a human IgG2 Fc region includes the amino acid sequence: PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 253) [0109]
  • a human IgG3 Fc region includes the amino acid sequence: PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPR EEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKG
  • a human IgG4 Fc region includes the amino acid sequence: PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 255).
  • the human IgD constant region typically includes the amino acid sequence: APTKAPDVFPIISGCRHPKDNSPVVLACLITGYHPTSVTVTWYMGTQSQPQRTFPEIQRRDSYY MTSSQLSTPLQQWRQGEYKCVVQHTASKSKKEIFRWPESPKAQASSVPTAQPQAEGSLAKAT TAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFT CFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTL NHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQRE VNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSY VTDHGPMK (SEQ ID NO: 256).
  • the human IgE constant region typically includes the amino acid sequence: ASTQSPSVFPLTRCCKNIPSNATSVTLGCLATGYFPEPVMVTWDTGSLNGTTMTLPATTLTLSG HYATISLLTVSGAWAKQMFTCRVAHTPSSTDWVDNKTFSVCSRDFTPPTVKILQSSCDGGGHF PPTIQLLCLVSGYTPGTINITWLEDGQVMDVDLSTASTTQEGELASTQSELTLSQKHWLSDRTY F053-6006PCT / 23-211-WO-PCT TCQVTYQGHTFEDSTKKCADSNPRGVSAYLSRPSPFDLFIRKSPTITCLVVDLAPSKGTVNLTW SRASGKPVNHSTRKEEKQRNGTLTVTSTLPVGTRDWIEGETYQCRVTHPHLPRALMRSTTKTS GPRAAPEVYAFATPEWPGSRDKRTLACLIQNFMPEDISVQWLHNEVQLPDARHSTTQPRKTK GSGFFVFSR
  • the human IgA1 constant region typically includes the amino acid sequence: ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDL YTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPR LSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVL PGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLAR GFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMV GHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY (SEQ ID NO: 258).
  • the human IgA2 constant region typically includes the amino acid sequence ASPTSPKVFPLSLDSTPQDGNVVVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDASGD LYTTSSQLTLPATQCPDGKSVTCHVKHYTNPSQDVTVPCPVPPPPPCCHPRLSLHRPALEDLL LGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHG ETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRW LQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQK TIDRLAGKPTHVNVSVVMAEVDGTCY (SEQ ID NO: 259).
  • the human IgM constant region typically includes the amino acid sequence GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALP
  • the human C ⁇ 1 region ranges from amino acid 5 to amino acid 102; the human C ⁇ 2 region ranges from amino acid 114 to amino acid 205, the human C ⁇ 3 region ranges from amino acid 224 to amino acid 319, the C ⁇ 4 region ranges from amino acid 329 to amino acid 430, and the tailpiece ranges from amino acid 431 to amino acid 453.
  • an IgM heavy chain constant region includes the sequence: GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK F053-6006PCT / 23-211-WO-PCT YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL GQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDS VTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTI SRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSA PMPEP
  • This sequence differs from SEQ ID NO: 260 by one amino acid at position 191.
  • the Kabat numbering system for the human IgM constant domain can be found in Kabat, et. al. “Tabulation and Analysis of Amino acid and nucleic acid Sequences of Precursors, V- Regions, C-Regions, J-Chain, T-Cell Receptors for Antigen, T-Cell Surface Antigens, b-2 Microglobulins, Major Histocompatibility Antigens, Thy-l, Complement, C-Reactive Protein, Thymopoietin, Integrins, Post-gamma Globulin, a-2 Macroglobulins, and Other Related Proteins,” U.S.
  • IgM constant regions can be numbered sequentially (i.e., amino acid #1 starting with the first amino acid of the constant region) or by using the Kabat numbering scheme.
  • human IgM constant regions, and also certain non-human primate IgM constant regions, as provided herein typically include five (5) naturally-occurring asparagine (N)-linked glycosylation motifs or sites.
  • N-linked glycosylation motif includes the amino acid sequence N-X1-S/T, wherein N is asparagine, X1 is any amino acid except proline (P), and S/T is serine (S) or threonine (T).
  • the glycan is attached to the nitrogen atom of the asparagine residue. See, e.g., Drickamer K, Taylor ME (2006), Introduction to Glycobiology (2nd ed.). Oxford University Press, USA.
  • N- linked glycosylation motifs occur in the human IgM heavy chain constant regions of SEQ ID NO: 260 or SEQ ID NO: 258 starting at positions 46 (“Nl”), 209 (“N2”), 272 (“N3”), 279 (“N4”), and 440 (“N5”). These five motifs are conserved in non-human primate IgM heavy chain constant regions, and four of the five are conserved in the mouse IgM heavy chain constant region.
  • a variant human IgM constant region includes an amino acid substitution corresponding to the wild-type human IgM constant region at position P311, P313, R344, E345, S401, E402, and/or E403 the corresponding IgM sequence in SEQ ID NO: 260.
  • antigen refers to a molecule or a portion of a molecule that is bound by an antibody when in the non-blocked presence of the antibody.
  • An epitope is a region of an antigen that is bound by the variable region of an antibody. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three- dimensional structural characteristics, and/or specific charge characteristics.
  • the antigen is a protein or peptide
  • the epitope includes specific amino acids within that protein or peptide that contact the variable region of an antibody.
  • an epitope denotes the binding site on a viral peptide, bacterial peptide, cancer protein, or other antigen bound by a corresponding variable region of an antibody.
  • the variable region either binds to a linear epitope, (e.g., an epitope including a stretch of 5 to 12 consecutive amino acids), or the variable region binds to a three-dimensional structure formed by the spatial arrangement of several short stretches of the protein target.
  • Three-dimensional epitopes recognized by a variable region e.g., by the epitope recognition site or paratope of an antibody or antibody fragment, can be thought of as three-dimensional surface features of an epitope molecule.
  • an epitope can be considered to have two levels: (i) the “covered patch” which can be thought of as the shadow an antibody variable region would cast on the antigen to which it binds; and (ii) the individual participating side chains and backbone residues that facilitate binding. Binding is then due to the aggregate of ionic interactions, hydrogen bonds, and hydrophobic interactions.
  • Epitopes of the currently disclosed antibodies can be found on a virus (e.g., dengue virus (DENV) or zika virus (ZIKV)).
  • “bind” means that the variable regions that form a binding domain associate with their target epitope with a dissociation constant (Kd or KD) of 10 -8 M or less, in particular embodiments of from 10 -5 M to 10 -13 M, in particular embodiments of from 10 -5 M to 10 -10 M, in particular embodiments of from 10 -5 M to 10 -7 M, in particular embodiments of from 10 -8 M to 10 -13 M, or in particular embodiments of from 10 -9 M to 10 -13 M.
  • Kd or KD dissociation constant
  • variable regions do not bind to other biomolecules present (e.g., it binds F053-6006PCT / 23-211-WO-PCT to other biomolecules with a dissociation constant (Kd) of 10 -4 M or more, in particular embodiments of from 10 -4 M to 1 M).
  • Kd dissociation constant
  • a “functional antigen binding domain” is a binding domain that binds its intended antigen.
  • Kd can be characterized using BIAcore.
  • Kd can be measured using surface plasmon resonance assays using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25°C with immobilized antigen CM5 chips at 10 response units (RU).
  • BIACORE®-2000 or a BIACORE®-3000 BIAcore, Inc., Piscataway, N.J.
  • immobilized antigen CM5 chips at 10 response units (RU).
  • RU response units
  • antibodies can include monoclonal antibodies (mAbs), human or humanized antibodies, multi-specific antibodies, bi-specific antibodies, tri-specific antibodies, tetra-specific antibodies, penta-specific antibodies, polyclonal antibodies, linear antibodies, minibodies, domain antibodies, synthetic antibodies, chimeric antibodies, antibody fusions, single chain variable fragments (scFvs), polyclonal antibodies, and fragments thereof, respectively.
  • mAbs monoclonal antibodies
  • human or humanized antibodies multi-specific antibodies, bi-specific antibodies, tri-specific antibodies, tetra-specific antibodies, penta-specific antibodies, polyclonal antibodies, linear antibodies, minibodies, domain antibodies, synthetic antibodies, chimeric antibodies, antibody fusions, single chain variable fragments (scFvs), polyclonal antibodies, and fragments thereof, respectively.
  • scFvs single chain variable fragments
  • polyclonal antibodies and fragments thereof, respectively.
  • antibodies can include oligomers or multiplexed versions of the antibodies disclosed herein.
  • a monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies including the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations which include different antibodies directed against different epitopes
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method.
  • monoclonal antibodies can be made by a variety of techniques, including the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.
  • a “human antibody” is one which includes an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences.
  • a “human consensus framework” is a framework that represents the most commonly F053-6006PCT / 23-211-WO-PCT occurring amino acid residues in a selection of human immunoglobulin V L or V H framework sequences.
  • the selection of human immunoglobulin V L or V H sequences is from a subgroup of variable domain sequences.
  • the subgroup of sequences can be a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91- 3242, Bethesda Md. (1991), vols. 1-3.
  • the subgroup is subgroup kappa I as in Kabat et al. (supra).
  • the subgroup is subgroup III as in Kabat et al. (supra).
  • a neutralizing antibody is an antibody that is responsible for blocking the entry of a pathogen into a cell so that it is firstly unable to infect healthy cells, and secondly, it is unable to replicate and cause severe infection.
  • the binding domains disclosed herein are part of a full antibody.
  • the antibody is an IgG antibody, an IgA antibody, an IgM antibody, an IgE antibody, or an IgD antibody.
  • the IgG antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.
  • the IgG antibody is an IgG1 antibody.
  • the IgA antibody is an IgA1 antibody or an IgA2 antibody.
  • the IgA antibody is an IgA1 antibody.
  • the IgA antibody is monomeric, dimeric, or polymeric. [0131] (II) Antibody Variants. Binding domains disclosed herein can be utilized to prepare various forms of relevant binding domain molecules.
  • particular embodiments can include binding fragments of an antibody, e.g., Fv, Fab, Fab', F(ab')2, and single chain Fv fragments (scFvs) or any biologically effective fragments of an immunoglobulin that bind specifically to an epitope described herein.
  • an antibody fragment is used.
  • An “antibody fragment” denotes a portion of a full-length antibody that retains the ability to bind to an epitope.
  • Antibody fragments can be made by various techniques, including proteolytic digestion of an intact antibody as well as production by recombinant host-cells (e.g., mammalian suspension cell lines, E. coli or phage), as described herein.
  • Antibody fragments can be screened for their binding properties in the same manner as intact antibodies.
  • Examples of antibody fragments include Fv, scFv, Fab, Fab', Fab'- SH, F(ab') 2 ; diabodies; and linear antibodies.
  • a single chain variable fragment (scFv) is a fusion protein of the variable regions of the heavy and light chains of immunoglobulins connected with a short linker peptide. Fv fragments include the V L and V H domains of a single arm of an antibody but lack the constant regions.
  • V L and V H are coded by separate genes, they can be joined, using, for example, recombinant methods, by a synthetic linker that enables them to be F053-6006PCT / 23-211-WO-PCT made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (single chain Fv (scFv)).
  • a synthetic linker that enables them to be F053-6006PCT / 23-211-WO-PCT made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (single chain Fv (scFv)).
  • scFv single chain Fv
  • Linker sequences that are used to connect the VL and VH of an scFv are generally five to 35 amino acids in length.
  • a VL-VH linker includes from five to 35, ten to 30 amino acids or from 15 to 25 amino acids. Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies.
  • Linker sequences of scFv are commonly Gly-Ser linkers, described in more detail elsewhere herein.
  • Additional examples of antibody-based binding domain formats include scFv-based grababodies and soluble VH domain antibodies. These antibodies form binding regions using only heavy chain variable regions. See, for example, Jespers et al., Nat. Biotechnol.22:1161, 2004; Cortez-Retamozo et al., Cancer Res.64:2853, 2004; Baral et al., Nature Med.12:580, 2006; and Barthelemy et al., J. Biol. Chem.283:3639, 2008.
  • a Fab fragment is a monovalent antibody fragment including VL, VH, CL and CH1 domains.
  • a F(ab')2 fragment is a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region.
  • Diabodies include two epitope-binding sites that may be bivalent. See, for example, EP 0404097; WO1993/01161; and Holliger, et al., Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993.
  • Dual affinity retargeting antibodies (DARTTM; based on the diabody format but featuring a C-terminal disulfide bridge for additional stabilization (Moore et al., Blood 117:4542-51, 2011)) can also be used.
  • Antibody fragments can also include isolated CDRs. For a review of antibody fragments, see Hudson, et al., Nat. Med. 9:129-134, 2003.
  • the binding domains disclosed herein are expressed as a Fab.
  • one or more amino acid modifications may be introduced into the Fc region of an antibody, thereby generating an Fc region variant.
  • the Fc region variant may include a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) including an amino acid modification (e.g., a substitution) at one or more amino acid positions.
  • a human Fc region sequence e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region
  • an amino acid modification e.g., a substitution
  • Exemplary administration benefits can F053-6006PCT / 23-211-WO-PCT include (1) reduced susceptibility to proteolysis, (2) reduced susceptibility to oxidation, (3) altered binding affinity for forming protein complexes, (4) altered binding affinities, (5) reduced immunogenicity; and/or (6) extended half-live. While the disclosure below describes these modifications in terms of their application to antibodies, when applicable to another particular anti- CD45 binding domain format (e.g., bispecific antibodies), the modifications can also be applied to these other formats. [0139] In particular embodiments, the Fc moiety of an antibody includes a substitution at positions CH2 4, CH25, or both.
  • the amino acid at positions 4 and 5 of CH2 of the wild-type IgG1 and IgG3 is a leucine ("L").
  • the antibody includes an amino acid at position CH24, CH25, or both, that is not an L.
  • an antibody includes an alanine ("A") at position CH24, or CH25, or both.
  • the antibody includes both, a CH2 L4A and a CH2 L5A substitution.
  • Such antibodies are referred to herein as a "LALA” variant.
  • ADE antibody-dependent enhancement
  • an IgG4 Fc region is mutated to form the IgG4_S228P Fc region.
  • IgG4 antibodies can undergo a process called Fab arm exchange which results in functionally monovalent, bispecific antibodies with unknown specificity and thus potentially reduced therapeutic efficacy. Mutating the wildtype IgG4 serine at position 228 within the core- hinge region to a proline creates the IgG4_S228P mutant. In particular embodiments, the IgG4_S228P mutant prevents Fab arm exchange.
  • the antibodies can be mutated to increase their affinity for Fc receptors.
  • an antibody variant includes an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • alterations are made in the Fc region that result in altered C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat.
  • cysteine engineered antibodies e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues.
  • the substituted residues occur at accessible sites of the antibody.
  • residues By substituting those residues with cysteine, reactive thiol groups are thereby positioned F053-6006PCT / 23-211-WO-PCT at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further below.
  • residue 5400 EU numbering
  • Cysteine engineered antibodies may be generated as described, e.g., in U.S. Pat. No. 7,521,541.
  • Antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
  • the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
  • the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example.
  • Asn297 refers to the asparagine residue located at position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function.
  • Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys.249:533-545, 1986, and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614, 2004; Kanda et al., Biotechnol. Bioeng., 94(4):680-688, 2006; and WO2003/085107).
  • modified antibodies include those wherein one or more amino acids have been replaced with a non-amino acid component, or where the amino acid has been conjugated to a functional group or a functional group has been otherwise associated with an amino acid.
  • the modified amino acid may be, e.g., a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, or an amino acid conjugated to an organic derivatizing agent.
  • Amino acid(s) can be modified, for example, co-translationally or post-translationally during recombinant production (e.g., N-linked glycosylation at N-X-S/T motifs during expression in mammalian cells) or modified by synthetic means.
  • the modified amino acid can be within the F053-6006PCT / 23-211-WO-PCT sequence or at the terminal end of a sequence.
  • Modifications also include nitrited constructs.
  • variants include glycosylation variants wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a reference sequence.
  • glycosylation variants include a greater or a lesser number of N-linked glycosylation sites than the reference sequence.
  • An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X can be any amino acid residue except proline.
  • the substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (e.g., those that are naturally occurring) are eliminated and one or more new N-linked sites are created.
  • Additional antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the reference sequence. These cysteine variants can be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. These cysteine variants generally have fewer cysteine residues than the reference sequence, and typically have an even number to minimize interactions resulting from unpaired cysteines.
  • PEGylation particularly is a process by which polyethylene glycol (PEG) polymer chains are covalently conjugated to other molecules such as proteins. Several methods of PEGylating proteins have been reported in the literature.
  • N-hydroxy succinimide (NHS)-PEG was used to PEGylate the free amine groups of lysine residues and N-terminus of proteins; PEGs bearing aldehyde groups have been used to PEGylate the amino-termini of proteins in the presence of a reducing reagent; PEGs with maleimide functional groups have been used for selectively PEGylating the free thiol groups of cysteine residues in proteins; and site-specific PEGylation of acetyl-phenylalanine residues can be performed. [0147] Covalent attachment of proteins to PEG has proven to be a useful method to increase the half-lives of proteins in the body (Abuchowski, A. et al., Cancer Biochem.
  • PEGylation can also decrease protein aggregation (Suzuki et al., Biochem. Bioph. Acta 788:248, 1984), alter protein immunogenicity (Abuchowski et al., J. Biol. Chem.252: 3582, 1977), and increase protein solubility as described, for example, in PCT Publication No. WO 92/16221).
  • PEGs are commercially available (Nektar Advanced PEGylation Catalog 2005-2006; and NOF DDS Catalogue Ver 7.1), which are suitable for producing proteins with targeted circulating half-lives.
  • active PEGs have been used including mPEG succinimidyl succinate, mPEG succinimidyl carbonate, and PEG aldehydes, such as mPEG- propionaldehyde.
  • the antibody can be fused or coupled to an Fc polypeptide that includes amino acid alterations that extend the in vivo half-life of an antibody that contains the altered Fc polypeptide as compared to the half-life of a similar antibody containing the same Fc polypeptide without the amino acid alterations.
  • Fc polypeptide amino acid alterations can include M252Y, S254T, T256E, M428L, and/or N434S and can be used together, separately or in any combination.
  • M428L/N434S is a pair of mutations that increase the half-life of antibodies in serum, as described in Zalevsky et al., Nature Biotechnology 28, 157-159, 2010.
  • any substitution at one of the following amino acid positions in an Fc polypeptide can be considered an Fc alteration that extends half-life: 250, 251, 252, 259, 307, 308, 332, 378, 380, 428, 430, 434, 436.
  • Each of these alterations or combinations of these alterations can be used to extend the half-life of a bispecific antibody as described herein.
  • Fc modifications include huIgG4 ProAlaAla, huIgG2m4, and/or huIgG2sigma mutations.
  • one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain may be missing or derivatized in a proportion or all of the molecules. Substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No.5,624,821; Tso et al., US Patent No.
  • Multi-domain binding molecules include at least two binding domains, wherein at least one binding domain includes a binding domain disclosed herein.
  • a multi-domain binding molecule includes at least one, at least two, at least, three, at least four binding domains that bind an epitope on DENV and/or ZIKV.
  • all of the binding domains of a multi-domain binding molecule bind DENV and/or ZIKV.
  • Multi-domain binding molecules include bispecific antibodies which bind at least two epitopes wherein at least one of the epitopes is located on DENV and/or ZIKV.
  • Multi-domain binding molecules include trispecific antibodies which binds at least 3 epitopes, wherein at least one of the epitopes is located on DENV and/or ZIKV, and so on.
  • Bispecific antibodies can be prepared utilizing antibody fragments (for example, F(ab')2 bispecific antibodies).
  • WO 1996/016673 describes a bispecific anti-ErbB2/anti-Fc gamma RIII antibody; US Pat.
  • No.5,837,234 describes a bispecific anti-ErbB2/anti-Fc gamma RI antibody
  • WO 1998/002463 describes a bispecific anti-ErbB2/Fc alpha antibody
  • US 5,821,337 describes a bispecific anti-ErbB2/anti-CD3 antibody.
  • Some additional exemplary bispecific antibodies have two heavy chains (each having three heavy chain CDRs, followed by (N-terminal to C-terminal) a CH1 domain, a hinge, a CH2 domain, and a CH3 domain), and two immunoglobulin light chains that confer antigen-binding specificity through association with each heavy chain.
  • bi-specific antibodies in which the light chain(s) associate with each heavy chain but do not (or minimally) contribute to antigen-binding specificity, or that can bind one or more of the epitopes bound by the heavy chain antigen-binding regions, or that can associate with each heavy chain and enable binding of one or both of the heavy chains to one or both epitopes.
  • Two antibodies or fragments thereof can be linked through a linker to form a bispecific antibody.
  • the two antibodies or fragments thereof can bind the same epitope or different epitopes. Examples of linkers can be found in Chen et al., Adv Drug Deliv Rev. 2013 Oct 15; 65(10): 1357–1369.
  • Linkers can be flexible, rigid, or semi-rigid, depending on the desired functional domain presentation to a target.
  • Commonly used flexible linkers include a linker sequence with the amino acids glycine and serine (Gly-Ser linkers).
  • the linker sequence includes sets of glycine and serine repeats such as from one to ten repeats of (Gly x Ser y ) n , wherein x and y are independently an integer from 0 to 10 provided that x and y are not both 0 and wherein n is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).
  • Particular examples include (Gly 4 Ser) n (SEQ ID NO: 262), F053-6006PCT / 23-211-WO-PCT (Gly 3 Ser) n (Gly 4 Ser) n (SEQ ID NO: 263), (Gly 3 Ser) n (Gly 2 Ser) n (SEQ ID NO: 264), and (Gly 3 Ser) n (Gly 4 Ser) 1 (SEQ ID NO: 265).
  • the linker is (Gly 4 Ser) 4 (SEQ ID NO: 266), (Gly 4 Ser) 3 (SEQ ID NO: 267), (Gly 4 Ser) 2 (SEQ ID NO: 268), (Gly 4 Ser) 1 (SEQ ID NO: 269), (Gly 3 Ser) 2 (SEQ ID NO: 270), (Gly 3 Ser) 1 (SEQ ID NO: 271), (Gly 2 Ser) 2 (SEQ ID NO: 272) or (Gly2Ser)1, GGSGGGSGGSG (SEQ ID NO: 273), GGSGGGSGSG (SEQ ID NO: 274), or GGSGGGSG (SEQ ID NO: 275).
  • Linkers that include one or more antibody hinge regions and/or immunoglobulin heavy chain constant regions, such as CH3 alone or a CH2CH3 sequence can also be used. Additional examples of linkers can be found in Chen et al., Adv Drug Deliv Rev.2013 Oct 15; 65(10): 1357– 1369. Linkers can be flexible, rigid, or semi-rigid, depending on the desired functional domain presentation to a target. [0158] In some situations, flexible linkers may be incapable of maintaining a distance or positioning of binding domains needed for a particular use. In these instances, rigid or semi-rigid linkers may be useful. Examples of rigid or semi-rigid linkers include proline-rich linkers.
  • a proline-rich linker is a peptide sequence having more proline residues than would be expected based on chance alone.
  • a proline-rich linker is one having at least 30%, at least 35%, at least 36%, at least 39%, at least 40%, at least 48%, at least 50%, or at least 51% proline residues.
  • proline-rich linkers include fragments of proline-rich salivary proteins (PRPs).
  • binding domains disclosed herein can be used to create bi-, tri, (or more) specific immune cell engaging molecules. Immune cell engaging molecules have at least one binding domain that binds a receptor on an immune cell and alters the activation state of the immune cell.
  • binding domains disclosed herein can be linked to albumin.
  • binding domains disclosed herein can be linked to albumin-binding domains (ABDs).
  • ABDs include, for example, albumin-binding peptides, antibodies, antibody fragments, and designed ankyrin repeat proteins (DARPins).
  • multi-domain binding molecules with extended half-lives include multi-domain binding molecules wherein at least one binding domain binds albumin.
  • the multi-domain binding molecule that binds albumin includes a binding F053-6006PCT / 23-211-WO-PCT domain that binds DENV and/or ZIKV inked to a binding domain that binds albumin.
  • an albumin-binding domain has the sequence: DITGAALLEAKEAAINELKQYGISDYYVTLINKAKTVEGVNALKAEILSALP (SEQ ID NO: 276).
  • an albumin-binding domain includes a variant of the sequence as set forth in SEQ ID NO: 276, wherein the variant sequence is modified by at least one amino acid substitution selected from the group including: E12D, T29H-K35D, and A45D.
  • an albumin-binding domain includes the sequence: LKEAKEKAIEELKKAGITSDYYFDLINKAKTVEGVNALKDEILKA (SEQ ID NO: 277).
  • an albumin-binding domain includes a variant of the sequence as set forth in SEQ ID NO: 277, wherein the variant sequence is modified by at least one amino acid substitution selected from the group including: Y21, Y22, L25, K30, T31, E33, G34, A37, L38, E41, I42 and A45.
  • Additional binding domains that bind albumin include CA645 as described in Adams et al., 2016 MAbs 8(7): 1336-1346 (see, e.g., Protein Data Bank accession codes 5FUZ and 5FUO); anti-HSA Nanobody TM (Ablynx, Ghent, Belgium), AlbudAb TM (GlaxoSmithKline, Brentford, United Kingdom), and other high-affinity albumin nanobody sequences as described in Shen et al., 2020 bioRxiv doi: https://doi.org/10.1101/2020.08.19.257725; Mester, et al., 2021 mAbs.13:1; Tijink et al., 2008 Mol Cancer Ther (7) (8) 2288-2297; and Roovers et al., Cancer Immunol Immunother 2007; 56: 303-317.
  • multi-domain binding molecules are multimers of an antibody disclosed herein.
  • Multimerization strategies include formation of a fusion protein using protein linkers or use of IgA or IgM constant regions as a multimerization scaffold.
  • multimerization is achieved by linking antibodies or binding domains of antibodies in a fusion protein with protein linkers. Fusion proteins include different protein domains linked to each other directly or through intervening linker segments such that the function of each included domain is retained.
  • Certain examples include fusion protein with two or three copies of an antibody or binding domain disclosed herein, each linked with the Gly-Ser linker (Gly 4 Ser) 4 (SEQ ID NO: 266).
  • a “multimerization domain” is a domain that causes two or more proteins (monomers) to interact with each other through covalent and/or non-covalent association(s). Multimerization domains are highly conserved protein sequences that can include different types of sequence motifs such as leucine zipper, helix loop-helix, ankyrin and PAS (Feuerstein et al, Proc. Natl. Acad. Sci. USA, 91:10655-10659, 1994).
  • Multimerization domains present in proteins can bind to form dimers, trimers, tetramers, pentamers, hexamers, heptamers, etc., depending on the number of F053-6006PCT / 23-211-WO-PCT units/monomers incorporated into the multimer, and/or homomultimers or heteromultimers, depending on whether the binding monomers are the same type or a different type (US Patent No.10030065).
  • Dimerization domains can include protein sequence motifs such as coiled coils, acid patches, zinc fingers, calcium hands, a CH1-CL pair, an "interface” with an engineered “knob” and/or “protruberance” (US 5821333), leucine zippers (US 5932448), SH2 and SH3 (Vidal et al., Biochemistry, 43:7336- 44, 2004), PTB (Zhou et al., Nature, 378:584- 592, 1995), WW (Sudol Prog Biochys MoL Bio, 65:113-132, 1996), PDZ (Kim et al., Nature, 378: 85-88, 1995; Komau et al., Science, 269:1737-1740, 1995) and WD40 (Hu et al., J Biol Chem., 273:33489- 33494, 1998).
  • protein sequence motifs such as coiled coils, acid patches, zinc fingers, calcium hands, a
  • IL-8R interleukin-8 receptor
  • integrin heterodimers such as LFA-I and GPIIIb/IIIa
  • dimeric ligand polypeptides such as nerve growth factor (NGF), neurotrophin-3 (NT- 3), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, PDGF members, and brain-derived neurotrophic factor (BDNF)
  • NNF nerve growth factor
  • NT- 3 neurotrophin-3
  • IL-8 interleukin-8
  • VEGF vascular endothelial growth factor
  • VEGF-C vascular endothelial growth factor
  • VEGF-D VEGF-D
  • PDGF members and brain-derived neurotrophic factor (BDNF)
  • BDNF brain-derived neurotrophic factor
  • the sequence corresponding to a dimerization motif/domain includes the leucine zipper domain of Jun (US5932448; RIARLEEKVKTLKAQNSELASTANMLREQVAQLKQKVMN (SEQ ID NO: 278)), the dimerization domain of Fos (US 5932448; LTDTLQAETDQLEDKKSALQTEIANLLKEKEKLEFILAA (SEQ ID NO: 279)), a consensus sequence for a WW motif (PCT Publication No. WO 1997/037223), the dimerization domain of the SH2B adapter protein from GenBank Accession no.
  • AAF73912.1 (Nishi et al., Mol Cell Biol, 25: 2607–2621, 2005; WREFCESHARAAALDFARRFRLYLASHPQYAGPGAEAAFSRRFAELFLQHFEAEVARAS (SEQ ID NO: 280)), the SH3 domain of IB1 from GenBank Accession no. AAD22543.1 (Kristensen el al., EMBO J., 25: 785–797, 2006; THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE (SEQ ID. NO: 281)), the PTB domain of human DOK-7 from GenBank Accession no.
  • NP_005535.1 (Wagner et al., Cold Spring Harb Perspect Biol.5: a008987, 2013; LGEVHRFHVTVAPGTKLESGPATLHLCNDVLVLARDIPPAVTGQWKLSDLRRYGAVPSGFIFEG GTRCGYWAGVFFLSSAEGEQISFLFDCIVRGISPTKG (SEQ ID NO: 282)), the PDZ-like domain of SATB1 from UniProt Accession No. Q01826 (Gaieri et al., Mol Cell Biol.
  • I6L9E7 (Pongratz et al., Mol Cell Biol, 18:4079– 4088, 1998; DQELKHLILEAADGFLFIVSCETGRVVYVSDSVTPVLNQQQSEWFGSTLYDQVHPDDVDKLRE QLSTSENALTGR (SEQ ID NO: 285)) and the EF hand motif of parvalbumin from UniProt Accession No. P20472 (Jamalian et al., Int J Proteomics, 2014: 153712, 2014; LSAKETKMLMAAGDKDGDGKIGVDEFSTLVAES (SEQ ID NO: 286)).
  • the dimerization domain can be a dimerization and docking domain (DDD) on one antibody and an anchoring domain (AD) on another antibody to facilitate a stably tethered structure.
  • DDD dimerization and docking domain
  • AD anchoring domain
  • the DDD (DDD1 and DDD2) are derived from the regulatory subunits of a cAMP-dependent protein kinase (PKA)
  • the AD (AD1 and AD2) are derived from a specific region found in various A-kinase anchoring proteins (AKAPs) that mediates association with the R subunits of PKA.
  • AKAPs A-kinase anchoring proteins
  • DDD1 includes the amino acid sequence: SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO: 287).
  • DDD2 includes the amino acid sequence: CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO: 288).
  • AD1 includes the amino acid sequence: QIEYLAKQIVDNAIQQA (SEQ ID NO: 289).
  • AD2 includes the amino acid sequence: CGQIEYLAKQIVDNAIQQAGC (SEQ ID NO: 290).
  • the 4-helix bundle type DDD domains may be obtained from p53, DCoH (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1)) and HNF-1 (hepatocyte nuclear factor 1).
  • DCoH pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1)
  • HNF-1 hepatocyte nuclear factor 1
  • Other AD sequences of potential use may be found in Patent Publication No. US2003/0232420A1.
  • the X-type four-helix bundle dimerization motif that is a structural characteristic of the DDD (Newlon, et al. EMBO J.2001; 20: 1651-1662; Newlon, et al.
  • S100 proteins for example, S100B and calcyclin
  • HNF hepatocyte nuclear factor family of transcriptional factors
  • Over 300 proteins that are involved in either signal transduction or transcriptional activation also contain a module of 65-70 amino acids termed the sterile a motif (SAM) domain, which has a variation of the X-type four-helix bundle present on its dimerization interface.
  • SAM sterile a motif
  • this X-type four-helix bundle enables the binding of each dimer to two p53 peptides derived from the c-terminal regulatory domain (residues 367-388) with micromolar affinity (Rustandi, et al. Biochemistry.1998; 37: 1951-1960).
  • HNF-1 ⁇ HNF-1 ⁇
  • DCoH dimerization cofactor for HNF-1
  • these naturally occurring systems can also be used to provide stable multimeric structures with multiple functions or binding specificities.
  • Other binding events such as those between an enzyme and its substrate/inhibitor, for example, cutinase and phosphonates (Hodneland, et al. Proc Natl Acd Sci USA.2002; 99: 5048-5052), may also be utilized to generate the two associating components (the “docking” step), which are subsequently stabilized covalently (the “lock” step).
  • dimerization of antibodies can be induced by a chemical inducer.
  • This method of dimerization requires one antibody to contain a chemical inducer of dimerization binding domain 1 (CBD1) and the second antibody to contain the second chemical inducer of dimerization binding domain (CBD2), wherein CBD1 and CBD2 are capable of simultaneously binding to a chemical inducer of dimerization (CID).
  • CBD1 and CBD2 can be the rapamycin binding domain of FK-binding protein 12 (FKBP12) and the FKBP12-Rapamycin Binding (FRB) domain of mTOR.
  • FKBP12 includes the sequence: MGVQVETISPGDGRTFPKRGQTCWHYTGMLEDGKKFDSSRDRNPFKFMLGKQEVIRGWEEG VAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLE (SEQ ID NO: 291).
  • FRB includes the sequence: MASRILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRD LMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKLES (SEQ ID NO: 292).
  • CBD1 and CBD2 can be the FK506 (Tacrolimus) binding domain of FK-binding protein 12 (FKBP12) and the cyclosporin binding domain of cylcophilin A. If the CID is estrone/biotin fusion protein or a derivative thereof, CBD1 and CBD2 can be an oestrogen-binding domain (EBD) and a streptavidin binding domain.
  • FKBP12 FK-binding protein 12
  • CBD1 and CBD2 can be an oestrogen-binding domain (EBD) and a streptavidin binding domain.
  • CBD1 and CBD2 F053-6006PCT / 23-211-WO-PCT can be a glucocorticoid-binding domain (GBD) and a dihydrofolate reductase (DHFR) binding domain.
  • GBD glucocorticoid-binding domain
  • DHFR dihydrofolate reductase
  • CBD1 and CBD2 can be an O 6 -alkylguanine-DNA alkyltransferase (AGT) binding domain and a dihydrofolate reductase (DHFR) binding domain.
  • CBD1 and CBD2 can be a retinoic acid receptor domain and an ecodysone receptor domain. If the CID is AP1903 or a derivative thereof, CBD1 and CBD2 can be the FK506 binding protein (FKBP12) binding domains including a F36V mutation. Use of the CID binding domains can also be used to alter the affinity to the CID. For instance, altering amino acids at positions 2095, 2098, and 2101 of FRB can alter binding to Rapamycin: KTW has high, KHF intermediate and PLW is low (Bayle et al, Chemistry & Biology 13, 99-107, January 2006).
  • antibodies can multimerize using a transmembrane polypeptide derived from a Fc ⁇ RI chain.
  • an antibody can include a part of a Fc ⁇ RI alpha chain and another antibody can include a part of an Fc ⁇ RI beta chain or variant thereof such that said Fc ⁇ RI chains spontaneously dimerize together to form a dimeric antibody.
  • antibodies can include a part of a Fc ⁇ RI alpha chain and a part of a Fc ⁇ RI gamma chain or variant thereof such that said Fc ⁇ RI chains spontaneously trimerize together to form a trimeric antibody
  • the multi-chain antibody can include a part of Fc ⁇ RI alpha chain, a part of Fc ⁇ RI beta chain and a part of Fc ⁇ RI gamma chain or variants thereof such that said Fc ⁇ RI chains spontaneously tetramerize together to form a tetrameric antibody.
  • additional methods of causing dimerization can be utilized.
  • Additional modifications to generate a dimerization domain in antibody could include: replacing the C-terminus domain with murine counterparts; generating a second interchain disulfide bond in the C-terminus domain by introducing a second cysteine residue into both antibodies; swapping interacting residues in each of the antibodies in the C-terminus domains (“knob-in-hole”); and fusing the variable domains of the antibodies directly to CD3 ⁇ (CD3 ⁇ fusion) (Schmitt et al., Hum. Gene Ther.2009.20:1240-1248).
  • Particular embodiments can utilize multimerization domains, such as C4b multimerization domains or ferritin multimerization domains.
  • Full-length native C4b includes seven ⁇ -chains linked together by a multimerization (i.e., heptamerization) domain at the C-terminus of the ⁇ -chains.
  • Ferritin is an iron storage protein found in almost all living organisms, and has been extensively studied and engineered for a number of biochemical/biomedical purposes (US 20090233377; Meldrum, et al. Science 257, 522-523 (1992); U.S.
  • Multimerized antibodies and antibody-like molecules such as IgA and IgM antibodies have emerged as promising drug candidates in the fields of, e.g., immuno-oncology and infectious diseases allowing for improved specificity, improved avidity, and the ability to bind to multiple binding targets. See, e.g., U.S. Patent Nos.9,951,134, 10,400,038, and 9,938,347, U.S. Patent Application Publication Nos. US20190100597A1, US20180118814A1, US20180118816A1, US20190185570A1, and US20180265596A1, and PCT Publication Nos.
  • Particular embodiments include using IgA and IgM constant region domains to allow the binding portion of molecules provided herein to readily multimerize into dimers, pentamers or hexamers.
  • Basic immunoglobulin structures in vertebrate systems are described above and are well understood. (See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd ed.1988).
  • Immunoglobulin A as the major class of antibody present in the mucosal secretions of most mammals, represents a key first line of defense against invasion by inhaled and ingested pathogens. IgA is also found at significant concentrations in the serum of many species, where it functions as a second line of defense mediating elimination of pathogens that have breached the mucosal surface. Receptors specific for the Fc region of IgA, FcaR, are key mediators of IgA effector function. Native IgA is a tetrameric protein including two identical light chains ( ⁇ or ⁇ ) and two identical heavy chains.
  • IgA similarly to IgG, contains three constant domains (CA1-CA3), with a hinge region between the CA1 and CA2 domains.
  • the main difference between IgA1 and IgA2 resides in the hinge region that lies between the two Fab arms and the Fc region.
  • IgA1 has an extended hinge region due to the insertion of a duplicated stretch of amino acids, which is absent in IgA2.
  • Both forms of IgA have the capacity to form dimers, in which two monomer units, are arranged in an end-to-end configuration stabilized by disulfide bridges and incorporation of a J-chain. J-chains are also part of IgM pentamers and are discussed in more detail below.
  • binding domains disclosed herein can be expressed as an IgA antibody. In particular embodiments, binding domains disclosed herein can be expressed as an IgM antibody. In particular embodiments, binding domains disclosed herein can be expressed as an IgG antibody. F053-6006PCT / 23-211-WO-PCT [0182] Both IgA and IgM (discussed further below in relation to pentamers and hexamers) possess an 18-amino acid extension in the C terminus called the "tail-piece" (tp). The IgA and IgM tp is highly conserved among various animal species.
  • the conserved penultimate cysteine residue in the IgA and IgM tp has been demonstrated to be involved in multimerization by forming a disulfide bond between heavy chains to permit formation of a multimer.
  • Both tp contain an N- linked carbohydrate addition site, the presence of which is required for dimer formation in IgA and J-chain incorporation and pentamer formation in IgM.
  • the structure and composition of the N-linked carbohydrates in the tp differ, suggesting differences in the accessibility of the glycans to processing by glycosyltransferases.
  • the IgA (atp) and IgM ( ⁇ t ⁇ ) tp differ at seven amino acid positions.
  • the human IgA1 constant region typically includes the amino acid sequence as set forth in SEQ ID NO: 258. Referring to this SEQ ID NO: 258, the human CA1 domain extends from amino acid 6 to amino acid 98; the human IgA1 hinge region extends from amino acid 102 to amino acid 124, the human CA2 domain extends from amino acid 125 to amino acid 219, the human CA3 domain extends from amino acid 228 to amino acid 330, and the tp extends from amino acid 331 to amino acid 352. [0184]
  • the human IgA2 constant region typically includes the amino acid sequence as set forth in SEQ ID NO: 259.
  • the human CA1 domain extends from amino acid 6 to amino acid 98
  • the human IgA2 hinge region extends from amino acid 102 to amino acid 111
  • the human CA2 domain extends from amino acid 113 to amino acid 206
  • the human CA3 domain extends from amino acid 215 to amino acid 317
  • the tp extends from amino acid 318 to amino acid 340.
  • two IgA binding units can form a complex with two additional polypeptide chains, the J chain (e.g., SEQ ID NO: 305, the mature human J chain) and the secretory component to form a bivalent secretory IgA (sIgA)-derived binding molecule.
  • An exemplary precursor secretory component includes the sequence MLLFVLTCLLAVFPAISTKSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGC ITLISSEGYVSSKYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVS QGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRL DIQGTGQLLFSVVINQLRLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFH CALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKED AGRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIK YWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLS
  • An exemplary mature secretory component includes KSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSSKYAGR ANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVSQGPGLLNDTKVYTVDL GRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQL RLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCR QSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQE GSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLL VDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLT
  • a multimerizing dimeric IgA-derived binding molecule typically includes IgA constant regions that include at least the CA3 and tp domains.
  • An engineered IgA heavy chain constant region can additionally include a CA2 domain or a fragment thereof, an IgA hinge region or fragment thereof, a CA1 domain or a fragment thereof, and/or other IgA (or other immunoglobulin, e.g., IgG) heavy chain domains, including, e.g., an IgG hinge region.
  • a binding molecule as provided herein can include a complete IgA heavy chain constant region (e.g., SEQ ID NO: 258 or SEQ ID NO: 259), or a variant, derivative, or analog thereof.
  • the IgA heavy chain constant regions can include amino acids 125 to 353 of SEQ ID NO: 258 or amino acids 113 to 340 of SEQ ID NO: 259.
  • the IgA heavy chain constant regions can each further include an IgA or IgG hinge region situated N-terminal to the IgA CA2 domains.
  • the IgA heavy chain constant regions can include amino acids 102 to 353 of SEQ ID NO: 258 or amino acids 102 to 340 of SEQ ID NO: 259.
  • the IgA heavy chain constant regions can each further include an IgA CA1 domain situated N-terminal to the IgA hinge region.
  • IgA antibody-based dimers F053-6006PCT / 23-211-WO-PCT
  • Particular embodiments include IgM immunoglobulin constant region domains that allow the binding portion of molecules provided herein to readily multimerize into pentamers or hexamers.
  • Particular embodiments include IgM constant regions (or variants thereof). These embodiments have the ability to form hexamers, or in association with a J-chain, form pentamers.
  • Embodiments with an IgM constant region typically include at least the C ⁇ 4-tp domains of the IgM constant region but can include heavy chain constant region domains from other antibody isotypes, e.g., IgG, from the same species or from a different species.
  • one or more constant region domains can be deleted so long as the IgM antibody is capable of forming hexamers and/or pentamers.
  • an IgM antibody can be, e.g., a hybrid IgM/IgG antibody or can be a “multimerizing fragment” of an IgM-derived binding molecule.
  • a pentameric or hexameric IgM antibody described in this disclosure typically includes at least the C ⁇ 4 and/or tp domains (also referred to herein collectively as C ⁇ 4-tp).
  • a “multimerizing fragment” of an IgM heavy chain constant region thus includes at least the C ⁇ 4-tp domains.
  • An IgM heavy chain constant region can additionally include a C ⁇ 3 domain or a fragment thereof, a C ⁇ 2 domain or a fragment thereof, a C ⁇ 1 domain or a fragment thereof, and/or other IgM heavy chain domains.
  • Five IgM monomers form a complex with a J-chain to form a native IgM molecule.
  • the J- chain is considered to facilitate polymerization of ⁇ chains before IgM is secreted from antibody- producing cells.
  • Sequences for the human IGJ gene are known in the art, for example, (IGMT Accession: J00256, X86355, M25625, AJ879487).
  • the J chain establishes the disulfide bridges between IgM antibodies to form multimeric structures such as pentamers. See, for example, Sorensen et al. International Immunology, (2000), pages 19-27. While crystallization of IgM has proved to be notoriously challenging, Czajkowsky and Shao (PNAS 106(35): 14960-14965, 2009) published a homology-based structural model of IgM, based on the structure of the IgE Fc domain and the known disulfide pairings. The authors report that the human IgM pentamer is a mushroom- shaped molecule with a flexural bias.
  • the IgM heavy ( ⁇ ) chain contains five N-linked glycosylation sites: Asn-171, Asn-332, Asn-395, Asn-402 and Asn-563.
  • the binding molecule itself can have 10 or 12 valencies.
  • the Kabat numbering system for the human IgM constant domain can be found in Kabat, et. al.
  • IgM constant regions can be numbered sequentially (i.e., amino acid #1 starting with the first amino acid of the constant region) or by using the Kabat numbering scheme.
  • a “full length IgM antibody heavy chain” is a polypeptide that includes, in N- terminal to C- terminal direction, an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CM1 or C ⁇ 1), an antibody heavy chain constant domain 2 (CM2 or C ⁇ 2), an antibody heavy chain constant domain 3 (CM3 or C ⁇ 3), and an antibody heavy chain constant domain 4 (CM4 or C ⁇ 4) that can include a tp, as indicated above.
  • each binding unit of a multimeric binding molecule as provided herein includes two IgM heavy chain constant regions or multimerizing fragments or variants thereof, each including at least an IgM C ⁇ 4 domain and an IgM tp domain.
  • the IgM heavy chain constant regions can each further include an IgM C ⁇ 3 domain situated N- terminal to the IgM C ⁇ 4 and IgM tp domains.
  • the IgM heavy chain constant regions can each further include an IgM C ⁇ 2 domain situated N-terminal to the IgM C ⁇ 3 domain.
  • Exemplary multimeric binding molecules provided herein include human IgM constant regions that include the wild-type human C ⁇ 2, C ⁇ 3, and C ⁇ 4-tp domains as follows: VIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAE AKESGPTTYKVTSTLTIKESDWLSQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSF ASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWN SGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADV FVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNR VTERTVDKSTGKPTLYNVSLVMSDTAGTCY (SEQ ID NO: 295).
  • each IgM constant region can include, instead of, or in addition to an IgM C ⁇ 2 domain, an IgG hinge region or functional variant thereof situated N-terminal to the IgM C ⁇ 3 domain.
  • An exemplary variant human IgG1 hinge region amino acid sequence in which the cysteine at position 6 is substituted with serine is VEPKSSDKTHTCPPCPAP (SEQ ID NO: 296).
  • An exemplary IgM constant region of this type includes the variant human IgG1 hinge region fused to a multimerizing fragment of the human IgM constant region including the C ⁇ 3, C ⁇ 4, and tp domains, and includes the amino acid sequence: VEPKSSDKTHTCPPCPAPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNG F053-6006PCT / 23-211-WO-PCT EAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHR PDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPG RYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY (SEQ ID NO: 297).
  • Human IgM constant regions, and also certain non-human primate IgM constant regions, as provided herein typically include five (5) naturally-occurring asparagine (N)-linked glycosylation motifs or sites.
  • N-linked glycosylation motif includes the amino acid sequence N-X1-S/T, wherein N is asparagine, X1 is any amino acid except proline (P), and S/T is serine (S) or threonine (T).
  • S/T serine
  • T threonine
  • the glycan is attached to the nitrogen atom of the asparagine residue. See, e.g., Drickamer K, Taylor ME (2006), Introduction to Glycobiology (2nd ed.). Oxford University Press, USA.
  • N-linked glycosylation motifs occur in the human IgM heavy chain constant regions of SEQ ID NO: 260 or SEQ ID NO: 261 starting at positions 46 (“N1”), 209 (“N2”), 272 (“N3”), 279 (“N4”), and 440 (“N5”). These five motifs are conserved in non-human primate IgM heavy chain constant regions, and four of the five are conserved in the mouse IgM heavy chain constant region. Each of these sites in the human IgM heavy chain constant region, except for N4, can be mutated to prevent glycosylation at that site, while still allowing IgM expression and assembly into a hexamer or pentamer.
  • the human IgM heavy chain constant region typically includes the amino acid sequence as set forth in SEQ ID NO: 260; identical to, e.g., GenBank Accession Nos. pir
  • SEQ ID NO: 260 the human C ⁇ 1 region ranges from amino acid 5 to amino acid 102; the human C ⁇ 2 region ranges from amino acid 114 to amino acid 205, the human C ⁇ 3 region ranges from amino acid 224 to amino acid 319, the C ⁇ 4 region ranges from amino acid 329 to amino acid 430, and the tp ranges from amino acid 431 to amino acid 453.
  • an IgM heavy chain constant region includes the sequence: GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL GQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDS VTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTI SRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSA PMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHE
  • This sequence differs from SEQ ID NO: 260 by one amino acid at position 191.
  • F053-6006PCT / 23-211-WO-PCT [0201]
  • Other forms of the human IgM constant region with minor sequence variations exist, including GenBank Accession Nos. P01871.4, CAB37838.1, and pir
  • the amino acid substitutions, insertions, and/or deletions at positions corresponding to SEQ ID NO: 260 described herein can likewise be incorporated into alternate human IgM sequences, as well as into IgM constant region amino acid sequences of other species, e.g., those shown in FIG.1 of PCT/US2019/020374.
  • a variant human IgM constant region includes an amino acid substitution corresponding to the wild-type human IgM constant region at position P311, P313, R344, E345, S401, E402, and/or E403 of SEQ ID NO: 260.
  • These positions correspond to the Kabat numbering system as follows: S401 of SEQ ID NO: 260 corresponds to S524 of Kabat; E402 of SEQ ID NO: 260 corresponds to E525 of Kabat; E403 of SEQ ID NO: 260 corresponds to E526 of Kabat; R344 of SEQ ID NO: 260 corresponds to R467 of Kabat; and E345 of SEQ ID NO: 260 corresponds to E468 of Kabat.
  • “corresponds to” means the designated position of SEQ ID NO: 260 and the amino acid in the sequence of the IgM constant region of any species which is homologous to the specified position. See FIG.1 of PCT/US2019/020374.
  • P311 of SEQ ID NO: 260 can be substituted, e.g., with alanine (P311A), serine (P311S), or glycine (P311G) and/or P313 of SEQ ID NO: 260 can be substituted, e.g., with alanine (P313A), serine (P313S), or glycine (P313G).
  • P311 and P313 of SEQ ID NO: 260 can be substituted with alanine (P311A) and serine (P313S), respectively as shown in the following sequence: (mutations in bold underline) GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLASSLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVT
  • S401 of SEQ ID NO: 260 can be substituted with any amino acid.
  • S401 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP F053-6006PCT / 23-211-WO-PCT RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTC
  • E402 of SEQ ID NO: 260 can be substituted with any amino acid.
  • E402 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPD
  • E403 of SEQ ID NO: 260 can be substituted with any amino acid.
  • E403 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPD
  • R344 of SEQ ID NO: 260 can be substituted with any amino acid.
  • R344 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL F053-6006PCT / 23-211-WO-PCT SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGER
  • E345 of SEQ ID NO: 260 can be substituted with any amino acid.
  • E345 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPD
  • IgM binding units can form a complex with a J-chain to form a pentameric IgM antibody.
  • the precursor form of the human J-chain includes: MKNHLLFWGVLAVFIKAVHVKAQEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLN NRENISDPTSPLRTRFVYHLSDLCKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKC YTAVVPLVYGGETKMVETALTPDACYPD (SEQ ID NO: 304).
  • the signal peptide extends from amino acid 1 to amino acid 22 of SEQ ID NO: 304 and the mature human J-chain extends from amino acid 23 to amino acid 159 of SEQ ID NO: 304.
  • the mature human J-chain includes the amino acid sequence QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 305).
  • the term “J-chain” as used herein refers to the J-chain of native sequence IgM or IgA antibodies of any animal species.
  • the J-chain of the IgM antibody as provided herein includes an amino F053-6006PCT / 23-211-WO-PCT acid substitution at the amino acid position corresponding to amino acid Y102, T103, N49 or S51 of SEQ ID NO: 305.
  • an amino acid corresponding to” a position of SEQ ID NO: 305 is meant the amino acid in the sequence of the J-chain of any species which is homologous to the referenced residue in the human J-chain.
  • the position corresponding to Y102 in SEQ ID NO: 305 is conserved in the J-chain amino acid sequences of at least 43 other species.
  • the position corresponding to T103 in SEQ ID NO: 305 is conserved in the J-chain amino acid sequences of at least 37 other species.
  • the positions corresponding to N49 and S51 in SEQ ID NO: 305 are conserved in the J-chain amino acid sequences of at least 43 other species. See FIG.4 of U.S.
  • the amino acid corresponding to Y102 of SEQ ID NO: 305 can be substituted with any amino acid.
  • the amino acid corresponding to Y102 of SEQ ID NO: 305 can be substituted with alanine (alanine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCATYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 306), With serine (serine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCSTYDRNKCYTA
  • the amino acid corresponding to T103 of SEQ ID NO: 305 can be substituted with any amino acid.
  • the amino acid corresponding to T103 of SEQ ID NO: 305 can be substituted with alanine as follows (alanine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYAYDRNKCYTAVVPLVYGGETKMVETALTP DACYPD (SEQ ID NO: 309).
  • the variant J-chain or functional fragment thereof of the IgM antibody as provided herein includes an amino acid substitution at the amino acid position corresponding to amino acid N49 or amino acid S51 of SEQ ID NO: 305, provided that S51 is not substituted F053-6006PCT / 23-211-WO-PCT with threonine (T), or wherein the J-chain includes amino acid substitutions at the amino acid positions corresponding to both amino acids N49 and S51 of SEQ ID NO: 305.
  • the amino acids corresponding to N49 and S51 of SEQ ID NO: 305 along with the amino acid corresponding to 150 of SEQ ID NO: 305 include an N-linked glycosylation motif in the J- chain.
  • mutations at N49 and/or S51 can prevent glycosylation at this motif.
  • the asparagine at the position corresponding to N49 of SEQ ID NO: 305 can be substituted with any amino acid.
  • the asparagine at the position corresponding to N49 of SEQ ID NO: 305 can be substituted with alanine (A), glycine (G), threonine (T), serine (S) or aspartic acid (D).
  • the position corresponding to N49 of SEQ ID NO: 305 can be substituted with alanine (A).
  • the J-chain is a variant human J-chain and includes the amino acid sequence: QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNREAISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 310).
  • the serine at the position corresponding to S51 of SEQ ID NO: 305 can be substituted with any amino acid except threonine.
  • the serine at the position corresponding to S51 of SEQ ID NO: 305 can be substituted with alanine (A) or glycine (G).
  • the position corresponding to S51 of SEQ ID NO: 305 can be substituted with alanine (A).
  • the variant J-chain or functional fragment thereof is a variant human J-chain and includes the amino acid sequence: EDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENIADPTSPLRTRFVYHLSDLC KKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPDA CYPD (SEQ ID NO: 311).
  • Particular embodiments include a heterologous polypeptide (e.g., a single-domain antibody binding domain) fused to the J-chain or functional fragment thereof via a peptide linker, e.g., a peptide linker including at least 5 amino acids, but no more than 25 amino acids.
  • the peptide linker includes (GGGGS)n (SEQ ID NO: 262) wherein n is 1-5.
  • a single-domain antibody binding domain can be introduced into the J-chain at any location that allows the binding of the binding domain to its binding target without interfering with J-chain function or the function of an associated IgA, IgM, or hybrid IgG antibody.
  • Insertion locations include at or near the C- terminus, at or near the N-terminus or at an internal location that, based on the three-dimensional structure of the J-chain, is accessible.
  • the antigen-binding domain can be introduced into the mature human J-chain of SEQ ID NO: 305 F053-6006PCT / 23-211-WO-PCT between cysteine residues 92 and 101 of SEQ ID NO: 305.
  • the antigen-binding domain can be introduced into the human J-chain of SEQ ID NO: 305 at or near a glycosylation site.
  • the antigen-binding domain can be introduced into the human J-chain of SEQ ID NO: 305 within 10 amino acid residues from the C- terminus, or within 10 amino acids from the N-terminus.
  • the single-domain antibody is introduced into the native human J-chain sequence of SEQ ID NO: 305 by chemical or chemo-enzymatic derivatization.
  • the single-domain antibody is introduced into the native human J-chain sequence of SEQ ID NO: 305 by a chemical linker.
  • the chemical linker is a cleavable or non-cleavable linker.
  • the cleavable linker is a chemically labile linker or an enzyme-labile linker.
  • the linker is selected from the group including N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-l-carboxylate (SMCC), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), iminothiolane (IT), afunctional derivatives of imidoesters, active esters, aldehydes, bis-azido compounds, bis-diazonium derivatives, diisocyanates, and bis-active fluorine compounds.
  • SPDP N-succinimidyl-3-(2-pyridyldithio) propionate
  • SMCC succinimidyl-4-(N-maleimidomethyl) cyclohexane
  • the modified J-chain is modified by insertion of an enzyme recognition site, and by post-translationally attaching a binding moiety at the enzyme recognition site through a peptide or non-peptide linker.
  • the modified J-chain can include the formula X[Ln]J or J[Ln]X, where J includes a mature native J-chain or functional fragment thereof, X includes a heterologous binding domain, and [Ln] is a linker sequence including n amino acids, where n is a positive integer from 1 to 100, 1 to 50, or 1 to 25. In certain aspects N is 5, 10, 15, or 20.
  • J-chains from the following species can also be used in certain embodiments: Pan troglodytes, Pongo abelii, Callithrix jacchus, Macaca mulatta, Papio Anubis, Saimiri boliviensis, Tupaia chinensis, Tursiops truncatus, Orcinus orca, Loxodonta Africana, Leptonychotes weddellii, Ceratotherium simum, Felis catus, Canis familiaris, Ailuropoda melanoleuca, Mustela furo, Equus caballus, Cavia porcellus, Camelus ferus, Capra hircus, Chinchilla lanigera, Mesocricetus auratus, Ovis aries, Myotis lucifugus, Pantholops hodgsonii, Bos taurus, Mus musculus, Rattus norvegicus, Echinops telfairi, Oryctolagus cuniculate
  • the binding domains disclosed herein are produced from a gene using a protein expression system.
  • Protein expression systems F053-6006PCT / 23-211-WO-PCT can utilize DNA constructs (e.g., chimeric genes, expression cassettes, expression vectors, recombination vectors) including a nucleic acid sequence encoding the protein or proteins of interest operatively linked to appropriate regulatory sequences.
  • DNA constructs are not naturally-occurring DNA molecules and are useful for introducing DNA into host-cells to express selected proteins of interest.
  • a DNA construct that encodes a vaccine protein can be inserted into cells (e.g., bacterial, mammalian, insect, etc.), which can produce the vaccine protein encoded by the DNA construct.
  • Operatively linked refers to the linking of DNA sequences (including the order of the sequences, the orientation of the sequences, and the relative spacing of the various sequences) in such a manner that the encoded protein is expressed. Methods of operatively linking expression control sequences to coding sequences are well known in the art. See, e.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, N.
  • Expression control sequences are DNA sequences involved in any way in the control of transcription or translation. Suitable expression control sequences and methods of making and using them are well known in the art. Expression control sequences generally include a promoter.
  • the promoter may be inducible or constitutive. It may be naturally-occurring, may be composed of portions of various naturally-occurring promoters, or may be partially or totally synthetic. Guidance for the design of promoters is provided by studies of promoter structure, such as that of Harley and Reynolds, Nucleic Acids Res., 15, 2343-2361, 1987.
  • the promoter may include, or be modified to include, one or more enhancer elements.
  • the promoter will include a plurality of enhancer elements. Promoters including enhancer elements can provide for higher levels of transcription as compared to promoters that do not include them.
  • the coding sequences can be operatively linked to a 3' untranslated sequence.
  • the 3' untranslated sequence can include a transcription termination sequence and a polyadenylation sequence.
  • the 3' untranslated region can be obtained, for example, from the flanking regions of genes.
  • a 5' untranslated leader sequence can also be employed.
  • the 5' untranslated leader sequence is the portion of an mRNA that extends from the 5' CAP site to the translation initiation codon.
  • a “hisavi” tag can be added to the N-terminus or C-terminus of F053-6006PCT / 23-211-WO-PCT a gene by the addition of nucleotides coding for the Avitag amino acid sequence, “GLNDIFEAQKIEWHE” (SEQ ID NO: 312), as well as the 6xhistidine tag “HHHHHH” (SEQ ID NO: 313).
  • the Avitag avidity tag can be biotinylated by a biotin ligase to allow for biotin-avidin or biotin-streptavidin based interactions for protein purification, as well as for immunobiology (such as immunoblotting or immunofluorescence) using anti-biotin antibodies.
  • the 6xhistidine tag allows for protein purification using Ni- 2+ affinity chromatography.
  • tags include: Flag tag (DYKDDDDK; SEQ ID NO: 314), Xpress tag (DLYDDDDK; SEQ ID NO: 315), Calmodulin tag (KRRWKKNFIAVSAANRFKKISSSGAL; SEQ ID NO: 316), Polyglutamate tag, HA tag (YPYDVPDYA; SEQ ID NO: 317), Myc tag (EQKLISEEDL; SEQ ID NO: 318), Strep tag (which refers the original STREP ® tag (WRHPQFGG; SEQ ID NO: 319), STREP ® tag II (WSHPQFEK SEQ ID NO: 320 (IBA Institut fur Bioanalytik, Germany); see, e.g., US 7,981,632), Softag 1 (SLAELLNAGLGGS; SEQ ID NO: 321), Softag 3 (TQDPSRVG; SEQ ID NO: 322), and V5 tag (GKPIPNPLLGLDST; SEQ ID NO: 323).
  • the binding domains disclosed herein can be produced using, for example, human suspension cells and/or the Daedalus expression system as described in Pechman et al., Am J Physiol 294: R1234-R1239, 2008.
  • the Daedalus system utilizes inclusion of minimized ubiquitous chromatin opening elements in transduction vectors to reduce or prevent genomic silencing and to help maintain the stability of decigram levels of expression. This system can bypass tedious and time-consuming steps of other protein production methods by employing the secretion pathway of serum-free adapted human suspension cell lines, such as 293 Freestyle.
  • the DNA constructs can be introduced into a cell by transfection, a technique that involves introduction of foreign DNA into the nucleus of eukaryotic cells.
  • the proteins can be synthesized by transient transfection (DNA does not integrate with the genome of the eukaryotic cells, but the genes are expressed for 24- 96 hours).
  • transfection can be achieved by chemical-based means including by the calcium phosphate, by dendrimers, by liposomes, and by the use of cationic polymers.
  • Non-chemical methods of F053-6006PCT / 23-211-WO-PCT transfection include electroporation, sono-poration, optical transfection, protoplast fusion, and hydrodynamic delivery.
  • transfection can be achieved by particle-based methods including gene gun where the DNA construct is coupled to a nanoparticle of an inert solid which is then "shot" directly into the target-cell's nucleus.
  • particle-based transfection methods include magnet assisted transfection and impalefection.
  • Nucleic acid sequences can also include one or more of various sequence polymorphisms, mutations, and/or sequence variants (e.g., splice variants or codon optimized variants). In particular embodiments, the sequence polymorphisms, mutations, and/or sequence variants do not affect the function of the encoded protein.
  • Sequence information provided by public databases can be used to identify additional gene and protein sequences that can be used with the systems and methods disclosed.
  • (V) Antibody Conjugates include binding domains disclosed herein linked to another molecule, other than an additional binding domain. Examples of antibody conjugates include antibody-particle conjugates, antibody-drug conjugates (ADCs), and antibody- detectable label conjugates.
  • Antibody-particle conjugates include an antibody linked to a particle.
  • particles include microparticles, nanoparticles, nanoshells, nanobeads, microbeads, or nanodots.
  • Particles can include, for example, latex beads, polystyrene beads, fluorescent beads, and/or colored beads, and can be made from organic matter and/or inorganic matter. They can be made of any suitable materials that allow for the conjugation of capture proteins, such as antibodies made from the binding domains disclosed herein, to their surface. Examples of suitable materials include: ceramics, glass, polymers, and magnetic materials.
  • Suitable polymers include polystyrene, poly-(methyl methacrylate), poly-(lactic acid), (poly-(lactic- co -glycolic acid)), polyesters, polyethers, polyolef ⁇ ns, polyalkylene oxides, polyamides, polyurethanes, polysaccharides, celluloses, polyisoprenes, methylstyrene, acrylic polymers, thoria sol, latex, nylon, Teflon cross- linked dextrans (e.g., Sepharose), chitosan, agarose, and cross-linked micelles. Additional examples include carbon graphited, titanium dioxide, and paramagnetic materials.
  • microparticles can be made of one or more materials.
  • microparticles are paramagnetic microparticles.
  • Particular embodiments utilize carboxy-modified polystyrene latex (CML) flow cytometry beads and/or magnetic MagPlex® (Luminex, Austin, TX) flow cytometry beads.
  • CML carboxy-modified polystyrene latex
  • MagPlex® Luminex, Austin, TX
  • Antibody-drug conjugates allow for the targeted delivery of a drug moiety to an infected cell or viral particle, in particular embodiments intracellular accumulation therein, where systemic administration of unconjugated drugs may result in unacceptable levels of toxicity to normal cells (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387).
  • antibody-drug conjugates refer to targeted molecules which combine properties of both antibodies and drugs by targeting potent drugs to sites of infection.
  • the drug moiety (D) of an antibody-drug conjugate may include any compound, moiety or group that has a toxic effect.
  • Exemplary drugs include antivirals or anti-infection agents.
  • the drug may be obtained from essentially any source; it may be synthetic or a natural product isolated from a selected source, e.g., a plant, bacterial, insect, mammalian or fungal source.
  • the drug may also be a synthetically modified natural product or an analogue of a natural product.
  • the antibody-drug conjugates include an antibody conjugated, i.e., covalently attached, to the drug moiety.
  • the antibody is covalently attached to the drug moiety through a linker.
  • a linker can include any chemical moiety that is capable of linking an antibody, antibody fragment (e.g., antigen binding fragments) or functional equivalent to another moiety, such as a drug moiety.
  • Linkers can be susceptible to cleavage (cleavable linker), such as, acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage, at conditions under which the compound or the antibody remains active.
  • linkers can be substantially resistant to cleavage (e.g., stable linker or noncleavable linker).
  • the linker is a procharged linker, a hydrophilic linker, or a dicarboxylic acid-based linker.
  • the antibody-drug conjugate selectively delivers an effective dose of a drug to cells whereby greater selectivity, i.e., a lower efficacious dose, may be achieved while increasing the therapeutic index (“therapeutic window”).
  • linker-toxin conjugates can be made by conventional methods analogous to those described by Doronina et al. (Bioconjugate Chem.17: 114-124, 2006).
  • Antibody-drug conjugates with multiple (e.g., four) drugs per antibody can be prepared by partial reduction of the antibody with an excess of a reducing reagent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) at 37°C for 30 min, then the buffer can be exchanged by elution through SEPHADEX G-25 resin with 1 mM DTPA in Dulbecco’s phosphate-buffered saline (DPBS). The eluent can be diluted with further DPBS, and the thiol concentration of the antibody can be measured using 5,5'-dithiobis(2-nitrobenzoic acid) [Ellman's reagent].
  • DTT dithiothreitol
  • TCEP tris(2-carboxyethyl)phosphine
  • the linker-cytotoxin conjugate can be added at 4°C. for 1 hr, and the conjugation reaction can be quenched by addition of a substantial excess, for example 20-fold, of cysteine.
  • the resulting ADC mixture can be purified on SEPHADEX G-25 F053-6006PCT / 23-211-WO-PCT equilibrated in PBS to remove unreacted linker-cytotoxin conjugate, desalted if desired, and purified by size-exclusion chromatography.
  • the resulting ADC can then be sterile filtered, for example, through a 0.2 ⁇ m filter, and can be lyophilized if desired for storage.
  • Antibody-detectable label conjugates include an antibody linked to a detectable label.
  • Detectable labels can include any suitable label or detectable group detectable by, for example, optical, spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means.
  • detectable labels can include fluorescent labels, chemiluminescent labels, spectral colorimetric labels, enzymatic labels, and affinity tags.
  • Fluorescent labels can be particularly useful in cell staining, identification, imaging, and isolation uses. Exemplary fluorescent labels include blue fluorescent proteins (e.g. eBFP, eBFP2, Azurite, mKalama1, GFPuv, Sapphire, T-sapphire); cyan fluorescent proteins (e.g.
  • eCFP Cerulean, CyPet, AmCyanl, Midoriishi-Cyan, mTurquoise
  • green fluorescent proteins e.g. GFP, GFP-2, tagGFP, turboGFP, EGFP, Emerald, Azami Green, Monomeric Azami Green (mAzamigreen)), CopGFP, AceGFP, avGFP, ZsGreenl, Oregon GreenTM(Thermo Fisher Scientific)
  • Luciferase orange fluorescent proteins (mOrange, mKO, Kusabira-Orange, Monomeric Kusabira-Orange, mTangerine, tdTomato); red fluorescent proteins (mKate, mKate2, mPlum, DsRed monomer, mCherry, mRuby, mRFP1, DsRed-Express, DsRed2, DsRed- Monomer, HcRed-Tandem, HcRedl, AsRed2, eqFP611, mR
  • Chemiluminescent labels can include lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt, or oxalate ester.
  • Spectral colorimetric labels can include colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, and latex) beads.
  • Enzymatic labels can produce, for example, a chemiluminescent signal, a color signal, or a fluorescent signal.
  • Enzymes can include malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI- phosphate dehydrogenase, glucoamylase and acetylcholinesterase. [0247] Affinity tags are described elsewhere herein.
  • an antibody as disclosed herein can be linked to a conjugate by any method known in the art.
  • the constant region can be modified F053-6006PCT / 23-211-WO-PCT to allow for site specific conjugation.
  • Such techniques include the use of naturally occurring or engineered cysteine residues, disulfide bridges, poly-histidine sequences, glycoengineering tags, and transglutaminase recognition sequences.
  • Antibody fragments can also be modified for site- specific conjugation, see for example, Kim et al., Mol Cancer Ther 2008;7(8).
  • binding domains described herein e.g., antibodies, multi-domain binding molecules, antibody conjugates, therapeutics
  • nucleic acids encoding the antibodies can also be formulated into compositions for administration (e.g., nucleic acids encapsulated within nanoparticles (e.g., liposomes or polymer-based nanoparticles) and/or as part of a vector delivery system (e.g., a viral vector or plasmid).
  • binding domains e.g., antibodies, multi-domain binding molecules, antibody conjugates
  • nucleic acids encoding antibodies are collectively referred to herein as “active ingredients”.
  • a pharmaceutically acceptable salt includes any salt that retains the activity of the active ingredient and is acceptable for pharmaceutical use.
  • a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
  • Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine, lysine, arginine and procaine.
  • a prodrug includes an active ingredient which is converted to a therapeutically active compound after administration, such as by cleavage of an active ingredient or by hydrolysis of a biologically labile group.
  • exemplary generally used pharmaceutically acceptable carriers include any and all absorption delaying agents, antioxidants, binders, buffering agents, bulking agents or fillers, chelating agents, coatings, disintegration agents, dispersion media, gels, isotonic agents, lubricants, preservatives, salts, solvents or co-solvents, stabilizers, surfactants, and/or delivery F053-6006PCT / 23-211-WO-PCT vehicles.
  • Exemplary antioxidants include ascorbic acid, methionine, and vitamin E.
  • Exemplary buffering agents include citrate buffers, succinate buffers, tartrate buffers, fumarate buffers, gluconate buffers, oxalate buffers, lactate buffers, acetate buffers, phosphate buffers, histidine buffers, and/or trimethylamine salts.
  • An exemplary chelating agent is EDTA.
  • Exemplary isotonic agents include polyhydric sugar alcohols including trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, or mannitol.
  • Exemplary preservatives include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides, hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.
  • Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the active ingredient or helps to prevent denaturation or adherence to the container wall.
  • Typical stabilizers can include polyhydric sugar alcohols; amino acids, such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, and cyclitols, such as inositol; PEG; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, ⁇ - monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (i.e
  • Stabilizers are typically present in the range of from 0.1 to 10,000 parts by weight based on therapeutic weight.
  • the compositions disclosed herein can be formulated for administration by, for example, injection, inhalation, infusion, perfusion, lavage, or ingestion.
  • compositions disclosed herein can further be formulated for intravenous, intradermal, intraarterial, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral and/or subcutaneous administration and more particularly by intravenous, intradermal, intraarterial, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, intrathecal, intratumoral, intramuscular, intravesicular, and/or subcutaneous injection.
  • compositions can be formulated as aqueous solutions, such as in buffers including Hanks' solution, Ringer's solution, or physiological saline.
  • the aqueous solutions can include formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • the formulation can be in lyophilized and/or powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compositions can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like.
  • suitable excipients include binders (gum tragacanth, acacia, cornstarch, gelatin), fillers such as sugars, e.g., lactose, sucrose, mannitol and sorbitol; dicalcium phosphate, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxy-methylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
  • binders such as sugars, e.g., lactose, sucrose, mannitol and sorbitol
  • dicalcium phosphate starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate
  • cellulose preparations such as maize starch, wheat starch, rice starch
  • disintegrating agents can be added, such as corn starch, potato starch, alginic acid, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • solid dosage forms can be sugar-coated or enteric-coated using standard techniques. Flavoring agents, such as peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc. can also be used.
  • Compositions can be formulated as an aerosol. In particular embodiments, the aerosol is provided as part of an anhydrous, liquid or dry powder inhaler.
  • Aerosol sprays from pressurized packs or nebulizers can also be used with a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin for use in an inhaler or insufflator may also be formulated including a powder mix of active ingredient and a suitable powder base such as lactose or starch.
  • Compositions can also be formulated as depot preparations.
  • compositions can be formulated as sustained-release systems utilizing semipermeable matrices of solid polymers including at least one active ingredient.
  • sustained-release materials have been established and are well known by those of ordinary skill in the art. Sustained-release systems may, depending on their chemical nature, release one or F053-6006PCT / 23-211-WO-PCT more active ingredients following administration for a few weeks up to over 100 days.
  • Depot preparations can be administered by injection; parenteral injection; instillation; or implantation into soft tissues, a body cavity, or occasionally into a blood vessel with injection through fine needles.
  • Depot formulations can include a variety of bioerodible polymers including poly(lactide), poly(glycolide), poly(caprolactone) and poly(lactide)-co(glycolide) (PLG) of desirable lactide:glycolide ratios, average molecular weights, polydispersities, and terminal group chemistries. Blending different polymer types in different ratios using various grades can result in characteristics that borrow from each of the contributing polymers.
  • solvents for example, dichloromethane, chloroform, ethyl acetate, triacetin, N-methyl pyrrolidone, tetrahydrofuran, phenol, or combinations thereof
  • Other useful solvents include water, ethanol, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetone, methanol, isopropyl alcohol (IPA), ethyl benzoate, and benzyl benzoate.
  • Exemplary release modifiers can include surfactants, detergents, internal phase viscosity enhancers, complexing agents, surface active molecules, co-solvents, chelators, stabilizers, derivatives of cellulose, (hydroxypropyl)methyl cellulose (HPMC), HPMC acetate, cellulose acetate, pluronics (e.g., F68/F127), polysorbates, Span® (Croda Americas, Wilmington, Delaware), poly(vinyl alcohol) (PVA), Brij® (Croda Americas, Wilmington, Delaware), sucrose acetate isobutyrate (SAIB), salts, and buffers.
  • surfactants e.g., hydroxypropyl)methyl cellulose (HPMC), HPMC acetate, cellulose acetate, pluronics (e.g., F68/F127), polysorbates, Span® (Croda Americas, Wilmington, Delaware), poly(vinyl alcohol) (PVA), Brij® (Croda Americas, Wilmington, Delaware), suc
  • Excipients that partition into the external phase boundary of microparticles such as surfactants including polysorbates, dioctylsulfosuccinates, poloxamers, PVA, can also alter properties including particle stability and erosion rates, hydration and channel structure, interfacial transport, and kinetics in a favorable manner.
  • Additional processing of the disclosed sustained release depot formulations can utilize stabilizing excipients including mannitol, sucrose, trehalose, and glycine with other components such as polysorbates, PVAs, and dioctylsulfosuccinates in buffers such as Tris, citrate, or histidine.
  • compositions include active ingredients of at least 0.1% w/v or w/w of the composition; at least 1% w/v or w/w of composition; at least 10% w/v or w/w of composition; at least 20% w/v or w/w of composition; at least 30% w/v or w/w of composition; at least 40% w/v or w/w of composition; at least 50% w/v or w/w of composition; at least 60% w/v or w/w of composition; at least 70% w/v or w/w of composition; at least 80% w/v or w/w of composition; at least 90% w/v or w/w of composition; at least 95% w/v or w/w of composition; or F053-6006PCT / 23-211-WO-PCT at least 99%
  • cells are genetically modified to express a protein including a disclosed binding domain.
  • cells genetically modified to express the binding domains described herein include genetically modified B cells.
  • the modified B cells are modified according to the teachings of International Publication No. WO2019079772.
  • genetically modified cells can be prepared as formulations for delivery in buffers such as Hanks' solution, Ringer's solution, or physiological saline.
  • Therapeutically effective amounts of cells within formulations can be greater than 10 2 cells, greater than 10 3 cells, greater than 10 4 cells, greater than 10 5 cells, greater than 10 6 cells, greater than 10 7 cells, greater than 10 8 cells, greater than 10 9 cells, greater than 10 10 cells, or greater than 10 11 cells.
  • cells are in a formulation volume of a liter or less, 500 ml or less, 250 ml or less, or 100 ml or less.
  • the density of administered cells is typically greater than 10 4 cells/ml, 10 5 cells/ml, 10 6 cells/ml, 10 7 cells/ml, or 10 8 cells/ml.
  • compositions include an anti-infective agent and/or a secondary treatment.
  • anti-infective agents and secondary treatments are described elsewhere herein.
  • Any composition or formulation disclosed herein can advantageously include any other pharmaceutically acceptable carriers which include those that do not produce significantly adverse, allergic, or other untoward reactions that outweigh the benefit of administration. Exemplary pharmaceutically acceptable carriers and formulations are disclosed in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990.
  • compositions and formulations can be prepared to meet sterility, pyrogenicity, general safety, and purity standards as required by U.S. FDA Office of Biological Standards and/or other relevant foreign regulatory agencies.
  • Methods disclosed herein include treating subjects (e.g., humans, veterinary animals (dogs, cats, reptiles, birds) livestock (e.g., horses, cattle, goats, pigs, chickens) and research animals (e.g., monkeys, rats, mice, fish) with compositions disclosed herein. Treating subjects includes delivering therapeutically effective amounts. Therapeutically effective amounts include those that provide effective amounts, prophylactic treatments and/or therapeutic treatments. [0280] An “effective amount” is the amount of a composition or formulation necessary to result in a desired physiological change in the subject. For example, an effective amount can provide an F053-6006PCT / 23-211-WO-PCT immunogenic effect. Effective amounts are often administered for research purposes.
  • Effective amounts disclosed herein can cause a statistically-significant effect in an in vitro assay, an animal model or clinical study relevant to the assessment of an infection’s development, progression, and/or resolution, as well as the effects of the infection.
  • An immunogenic composition can be provided in an effective amount, wherein the effective amount stimulates an immune response.
  • a prophylactic treatment includes a treatment administered to a subject who does not display signs or symptoms of an infection or displays only early signs or symptoms of an infection such that treatment is administered for the purpose of diminishing or decreasing the risk of developing the infection. Thus, a prophylactic treatment functions as a preventative treatment against an infection and/or the potential effects of an infection.
  • DENV therapeutic can refer to a treatment that reduces the severity of infection and/or induces an immune response in a subject to DENV.
  • D+Z therapeutic can refer to a treatment that reduces the severity of infection and/or induces an immune response in a subject to DENV serotypes 1-4 and ZIKV.
  • a D or D+Z therapeutic may be administered therapeutically to a subject who has been exposed to DENV or ZIKV.
  • a D or D+Z therapeutic can be used to ameliorate a symptom and/or complication associated with DENV or ZIKV, examples of each of which are described elsewhere herein.
  • a DENV therapeutic is a therapeutically effective composition including binding domains disclosed herein that bind the E protein of DENV that neutralizes DENV and/or induces an immune response in a subject against DENV.
  • a D+Z therapeutic is a therapeutically effective composition including binding domains disclosed herein that bind the E protein of DENV and ZIKV and neutralizes DENV and ZIKV and/or induces an immune response in a subject against DENV and ZIKV.
  • the immune system generally is capable of producing an innate immune response and an adaptive immune response.
  • An innate immune response generally can be characterized as not being substantially antigen specific and/or not generating immune memory.
  • An adaptive immune response can be characterized as being substantially antigen specific, maturing over time (e.g., increasing affinity and/or avidity for antigen), and in general can produce immunologic memory. Even though these and other functional distinctions between innate and adaptive immunity can be discerned, the skilled artisan will appreciate that the innate and adaptive immune systems can be integrated and therefore can act in concert. [0284] In particular embodiments, administration of a D or a D+Z therapeutic can further include administration of one or more adjuvants.
  • adjuvant refers to material that enhances an immune response and is used herein in the customary use of the term.
  • Exemplary adjuvants include any kind of Toll-like receptor ligand or combinations thereof (e.g.
  • CpG, Cpg-28 (a TLR9 agonist), polyriboinosinic polyribocytidylic acid (Poly(I:C)), ⁇ - galactoceramide, MPLA, Motolimod (VTX-2337, a novel TLR8 agonist developed by VentiRx), IMO-2055 (EMD1201081), TMX-101 (imiquimod), MGN1703 (a TLR9 agonist), G100 (a stabilized emulsion of the TLR4 agonist glucopyranosyl lipid A), Entolimod (a derivative of Salmonella flagellin also known as CBLB502), Hiltonol (a TLR3 agonist), and Imiquimod), and/or inhibitors of heat-shock protein 90 (Hsp90), such as 17-DMAG (17-dimethylaminoethylamino-17- demethoxygeldanamycin).
  • Hsp90 heat-shock protein 90
  • a squalene-based adjuvant can be used.
  • Squalene is part of the group of molecules known as triterpenes, which are all hydrocarbons with 30 carbon molecules. Squalene can be derived from certain plant sources, such as rice bran, wheat germ, amaranth seeds, and olives, as well as from animal sources, such as shark liver oil.
  • the squalene-based adjuvant is MF59® (Novartis, Basel, Switzerland).
  • An example of a squalene-based adjuvant that is similar to MF59® but is designed for preclinical research use is AddavaxTM (InvivoGen, San Diego, CA).
  • squalene based adjuvants can include 0.1%-20% (v/v) squalene oil.
  • squalene based adjuvants can include 5%(v/v) squalene oil.
  • the adjuvant alum can be used.
  • Alum refers to a family of salts that contain two sulfate groups, a monovalent cation, and a trivalent metal, such as aluminum or chromium.
  • Alum is an FDA approved adjuvant.
  • therapeutics can include alum in the amounts of 1-1000 ⁇ g/dose or 0.1mg-10mg/dose.
  • one or more STING agonists are used as an adjuvant.
  • STING is an abbreviation of "stimulator of interferon genes", which is also known as “endoplasmic reticulum interferon stimulator (ERIS)", “mediator of IRF3 activation (MITA)", “MPYS” or "transmembrane protein 173 (TM173)”.
  • STING agonists include cyclic molecules with one or two phosphodiester linkages, and/or one or two phosphorothioate diester linkages, between two nucleotides. This includes (3',5')-(3',5') nucleotide linkages (abbreviated as (3',3')); (3',5')-(2',5') nucleotide linkages (abbreviated as (3',2')); (2',5')-(3',5') nucleotide linkages (abbreviated as (2',3')); and (2',5')-(2',5') nucleotide linkages (abbreviated as (2',2')).
  • Nucleotide refers to any F053-6006PCT / 23-211-WO-PCT nucleoside linked to a phosphate group at the 5', 3' or 2' position of the sugar moiety.
  • STING agonists include c-AIMP; (3’,2’)c-AIMP; (2’,2’)c-AIMP; (2’,3’)c-AIMP; c-AIMP(S); c-(dAMP-dIMP); c-(dAMP-2’FdIMP); c-(2’FdAMP-2’FdIMP); (2’,3’)c- (AMP-2’FdIMP); c-[2’FdAMP(S)-2’FdIMP(S)]; c-[2’FdAMP(S)-2’FdIMP(S)](POM)2; and DMXAA.
  • STING agonists are described in WO2016/145102.
  • Other immune stimulants can also be used as adjuvants.
  • Additional exemplary small molecule immune stimulants include TGF- ⁇ inhibitors, SHP-inhibitors, STAT-3 inhibitors, and/or STAT-5 inhibitors.
  • Exemplary siRNA capable of down-regulating immune-suppressive signals or oncogenic pathways can be used whereas any plasmid DNA (such as minicircle DNA) encoding immune-stimulatory proteins can also be used.
  • the immune stimulant may be a cytokine and or a combination of cytokines, such as IL-2, IL-12 or IL-15 in combination with IFN- ⁇ , IFN- ⁇ or IFN- ⁇ , or GM-CSF, or any effective combination thereof, or any other effective combination of cytokines.
  • cytokines such as IL-2, IL-12 or IL-15 in combination with IFN- ⁇ , IFN- ⁇ or IFN- ⁇ , or GM-CSF, or any effective combination thereof, or any other effective combination of cytokines.
  • the above- identified cytokines stimulate TH1 responses, but cytokines that stimulate TH2 responses may also be used, such as IL-4, IL-10, IL-11, or any effective combination thereof.
  • combinations of cytokines that stimulate TH1 responses along with cytokines that stimulate TH2 responses may be used.
  • Immuno response refers to a response of the immune system to produce to neutralize and/or destroy DENV or DENV AND ZIKV.
  • an immune response can be an innate and/or adaptive response.
  • the D or D+Z therapeutics described herein are responsible for blocking the entry of a pathogen into a cell so that it is firstly unable to infect healthy cells, and secondly, it is unable to replicate and cause severe infection.
  • D or D+Z therapeutics described herein mark D or D+Z for destruction by immune cells such as macrophages and neutrophils through opsonization.
  • a "therapeutic treatment” includes a treatment administered to a subject who displays symptoms or signs of an infection and is administered to the subject for the purpose of diminishing or eliminating those signs or symptoms of the infection or effects of the infection.
  • the therapeutic treatment can reduce, control, or eliminate the presence or activity of the infection and/or reduce, control or eliminate side effects of the infection.
  • a therapeutic treatment can reduce, control, or eliminate a primary infection with DENV or ZIKV.
  • a therapeutic treatment can reduce or eliminate the symptoms of DENV or ZIKV.
  • a therapeutically effective amount reduces or prevents transmission of DENV or ZIKV.
  • a therapeutically effective amount alleviates or reduces the F053-6006PCT / 23-211-WO-PCT severity or occurrence of symptoms and/or complications associated with DENV or ZIKV infection.
  • Exemplary symptoms of infection with DENV include fever, headache, muscle pain, joint pain, bone pain, nausea, vomiting, pain behind eyes, swollen glands, rash, liver enlargement, mucosal bleeding, lethargy or restlessness, abdominal pain, serious bleeding, and shock.
  • Exemplary symptoms of infection with ZIKV include fever, rash, conjunctivitis, muscle pain, joint pain, malaise, headache, sweating, chills, loss of appetite, fatigue, and vomiting.
  • a therapeutically effective amount reduces the duration of hospitalization for a subject infected with the DENV or ZIKV as compared to a subject that has not received a D or D+Z therapeutic disclosed herein.
  • a therapeutically effective amount reduces the time to sustained non-detectable DENV or ZIKV in the blood or urine in a patient infected with the virus as compared to a subject that has not received D or D+Z therapeutic disclosed herein.
  • a therapeutically effective amount reduces organ damage or death as compared to a subject that has not received a D or D+Z therapeutic disclosed herein.
  • administering may accomplish more than one treatment type.
  • therapeutically effective amounts also referred to herein as doses
  • doses can be initially estimated based on results from in vitro assays and/or animal model studies. Such information can be used to more accurately determine useful doses in subjects of interest.
  • the actual dose amount administered to a particular subject can be determined by a physician, veterinarian or researcher taking into account parameters such as physical and physiological factors including target, body weight, severity of infection, stage of infection, effects of infection (e.g., IM, lymphoproliferative disorders), previous or concurrent therapeutic interventions, idiopathy of the subject and route of administration.
  • Useful doses can range from 0.1 to 5 ⁇ g/kg or from 0.5 to 1 ⁇ g /kg.
  • a dose can include 1 ⁇ g /kg, 15 ⁇ g /kg, 30 ⁇ g /kg, 50 ⁇ g/kg, 55 ⁇ g/kg, 70 ⁇ g/kg, 90 ⁇ g/kg, 150 ⁇ g/kg, 350 ⁇ g/kg, 500 ⁇ g/kg, 750 ⁇ g/kg, 1000 ⁇ g/kg, 0.1 to 5 mg/kg or from 0.5 to 1 mg/kg.
  • a dose can include 1 mg/kg, 10 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 300 mg/kg, 500 mg/kg, 700 mg/kg, 1000 mg/kg or more.
  • Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every F053-6006PCT / 23-211-WO-PCT 8 months, every 9 months, every 10 months, every 11 months or yearly).
  • a treatment regimen e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every F
  • the D or D+Z therapeutic described herein can be administered in combination or alternation with a secondary flavivirus treatment.
  • the secondary treatment can be selected from an mRNA-based vaccine, an adenovirus vaccine, a non-replicating vaccine, a DNA vaccine, a live attenuated vaccine, a plant-based adjuvant vaccine, a multi-epitope peptide-based vaccine, an inactivated virus, and a peptide vaccine, pain medicine or combinations thereof.
  • An exemplary secondary vaccine suitable for use with the vaccines and methods described herein includes Dengvaxia® (Sanofi, France).
  • the D or D+Z therapeutic described herein can be administered on top of the current standard of care for DENV and/or ZIKV patients, or in combination or alternation with any other compound or therapy that the healthcare provider deems beneficial for the patient.
  • the combination and/or alternation therapy can be therapeutic, adjunctive, or palliative.
  • the D or D+Z therapeutic is administered with an anti-infective agent, for example, 1662G07, DN59, NITD448, DV2 419-447 , DN57opt, 10AN1, rolitetracycline, doxycycline, A5, Compound 6, P02, gg-ww, EF, Geraniin, DET2, DET4, MLH40, pr, Pep14-23, VGTI-A3, VGTI-A3-03, bovine lactoferrin, hippeastrum hybrid (HHA), urtica dioica (UDA), galanthus nivalis (GNA), PD1 CD44, PG545, Fucoidan, PI-88, di-galactan hybrid C2S-3, iota carrageenan G3d, CF-238, sulfated galactomannan, sulfated galactan, curdlan sulfate, chondroitin sulfate E
  • compositions and formulations described herein can be administered by, without limitation, injection, inhalation, infusion, perfusion, lavage or ingestion.
  • Routes of administration can include intravenous, intradermal, intraarterial, intraparenteral, intranasal, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral, subcutaneous, and/or sublingual administration and more particularly by intravenous, intradermal, intraarterial, intraparenteral, intranasal, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral, subcutaneous, and/or sublingual injection.
  • compositions and formulations disclosed herein can also be used for research, particularly for research into a vaccine for D or D+Z.
  • the binding domains disclosed herein can be used to study and engineer vaccines that elicit the production of antibodies that F053-6006PCT / 23-211-WO-PCT neutralize D or D+Z.
  • kits including one or more containers including one or more of the binding domains described herein, antibodies described herein, multi-domain binding molecules described herein, antibody conjugates described herein, modified cells (e.g. cells modified to express antibodies disclosed herein), and/or compositions and/or adjuvants, anti- infective agents, or secondary treatments described herein.
  • Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 6 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 6.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 8 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 8.
  • variable light chain includes the sequence as set forth in SEQ ID NO: 7 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 7. 5.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 10 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 10.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 12 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 12.
  • variable light chain includes the sequence as set forth in SEQ ID NO: 11 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 11. 10.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 14 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 14.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 16 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 16.
  • variable light chain includes the sequence as set forth in SEQ ID NO: 15 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 15.
  • variable light chain is encoded by the sequence as set forth in SEQ ID NO: 17 or a sequence having at least 95% sequence identity to F053-6006PCT / 23-211-WO-PCT the sequence as set forth in SEQ ID NO: 17. 16.
  • a binding domain that binds DENV1, DENV2, DENV3, DENV4, and ZIKV wherein the binding domain includes a variable heavy chain including CDRH1, CDRH2, and CDRH3 and a variable light chain including a CDRL1, CDRL2, and CDRL3;
  • the CDRH1 includes the sequence as set forth in SEQ ID NO: 162
  • the CDRH2 includes the sequence as set forth in SEQ ID NO: 163, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 164
  • the CDRL1 includes the sequence as set forth in SEQ ID NO: 165
  • the CDRL2 includes the sequence as set forth in SEQ ID NO: 166
  • the CDRL3 includes the sequence as set forth in SEQ ID NO: 167 according to Kabat
  • the CDRH1 includes the sequence as set forth in SEQ ID NO: 168
  • the CDRH2 includes the sequence as set forth in SEQ ID NO: 169
  • the CDRH3 includes the sequence as set forth in SEQ ID
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 82 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 82; and the variable light chain includes the sequence as set forth in SEQ ID NO: 83 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 83.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 84 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 84; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 85 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 85. 19.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 86 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 86; and the variable light chain includes the sequence as set forth in SEQ ID NO: 87 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 87. 20.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 88 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 88; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 89 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 89. 21.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 90 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 90; and the variable light chain includes the sequence as set forth in SEQ ID NO: 91 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 91. 22.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 92 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 92; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 93 or a sequence having at least 95% sequence identity to F053-6006PCT / 23-211-WO-PCT the sequence as set forth in SEQ ID NO: 93. 23.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 94 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 94; and the variable light chain includes the sequence as set forth in SEQ ID NO: 95 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 95. 24.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 96 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 96; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 97 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 97. 25.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 98 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 98; and the variable light chain includes the sequence as set forth in SEQ ID NO: 99 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 99. 26.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 100 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 100; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 101 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 101. 27.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 102 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 102; and the variable light chain includes the sequence as set forth in SEQ ID NO: 103 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 103. 28.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 104 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 104; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 105 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 105. 29.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 106 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 106; and the variable light chain includes the sequence F053-6006PCT / 23-211-WO-PCT as set forth in SEQ ID NO: 107 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 107. 30.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 108 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 108; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 109 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 109. 31.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 110 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 110; and the variable light chain includes the sequence as set forth in SEQ ID NO: 111 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 111.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 112 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 112; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 113 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 113. 34.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 114 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 114; and the variable light chain includes the sequence as set forth in SEQ ID NO: 115 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 115. 35.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 116 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 116; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 117 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 117. 36.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 118 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 118; and the variable light chain includes the sequence as set forth in SEQ ID NO: 119 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 119. 37.
  • variable heavy chain is encoded by F053-6006PCT / 23-211-WO-PCT the sequence as set forth in SEQ ID NO: 120 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 120; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 121 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 121. 38.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 122 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 122; and the variable light chain includes the sequence as set forth in SEQ ID NO: 123 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 123.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 124 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 124; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 125 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 125. 40.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 126 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 126; and the variable light chain includes the sequence as set forth in SEQ ID NO: 127 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 127. 41.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 128 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 128; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 129 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 129. 42.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 130 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 130; and the variable light chain includes the sequence as set forth in SEQ ID NO: 131 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 131. 43.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 132 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 132; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 133 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 133.
  • variable light chain is encoded by the sequence as set forth in SEQ ID NO: 133 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 133.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 134 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 134; and the variable light chain includes the sequence as set forth in SEQ ID NO: 135 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 135. 45.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 136 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 136; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 137 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 137. 46.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 138 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 138; and the variable light chain includes the sequence as set forth in SEQ ID NO: 139 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 139. 47.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 140 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 140; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 141 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 141. 48.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 142 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 142; and the variable light chain includes the sequence as set forth in SEQ ID NO: 143 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 143. 49.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 144 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 144; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 145 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 145. 50.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 146 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 146; and the variable light chain includes the sequence as set forth in SEQ ID NO: 147 or a sequence having at least 95% sequence identity to the F053-6006PCT / 23-211-WO-PCT sequence as set forth in SEQ ID NO: 147. 51.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 148 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 148; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 149 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 149. 52.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 150 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 150; and the variable light chain includes the sequence as set forth in SEQ ID NO: 151 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 151. 53.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 152 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 152; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 153 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 153. 54.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 154 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 154; and the variable light chain includes the sequence as set forth in SEQ ID NO: 155 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 155. 55.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 156 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 156; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 157 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 157. 56.
  • variable heavy chain includes the sequence as set forth in SEQ ID NO: 158 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 158; and the variable light chain includes the sequence as set forth in SEQ ID NO: 159 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 159. 57.
  • variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 160 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 160; and the variable light chain is encoded by the F053-6006PCT / 23-211-WO-PCT sequence as set forth in SEQ ID NO: 161 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 161.
  • the binding molecule of embodiment 58, wherein the binding molecule is an IgG antibody, an IgA antibody, an IgM antibody, an IgD antibody, or an IgE antibody. 60.
  • the binding molecule of embodiments 58 or 59, wherein the binding molecule is an IgG antibody.
  • 66. The binding molecule of any of embodiments 58-65, wherein the binding molecule is a neutralizing antibody.
  • 68. The binding molecule of any of embodiments 58-67, including a thioMab. 69.
  • the binding molecule of embodiment 69, wherein the one or more modified amino acids include a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, or an amino acid conjugated to an organic derivatizing agent.
  • HSA human serum albumin
  • F053-6006PCT / 23-211-WO-PCT 74 The binding molecule of embodiments 72 or 73, wherein the one or more Fc modifications includes an Fc region with reduced fucose content or lacking fucose. 75. The binding molecule of any of embodiments 58-74, wherein the binding molecule is a part of a multi-domain binding molecule. 76. A multi-domain binding molecule including at least two binding domains wherein at least one binding domain includes the binding domain of any of embodiments 1-57. 77. The multi-domain binding molecule of embodiment 76, wherein the multi-domain binding molecule is a dimer, trimer, tetramer, pentamer, hexamer, or heptamer. 78.
  • the multi-domain binding molecule of embodiments 76 or 77 including an Fc region. 79.
  • the multi-domain binding molecule of embodiment 78, wherein the Fc region is an IgA Fc region or an IgM Fc region.
  • the multi-domain binding molecule of embodiments 78 or 79, wherein the Fc region is an IgA Fc region having the sequence as set forth in SEQ ID NOs: 258 and 259.
  • the multi-domain binding molecule of embodiments 78 or 79, wherein the Fc region is an IgM Fc region having the sequence as set forth in SEQ ID NOs: 260, 261, or 295-304. 82.
  • the multi-domain binding molecule of embodiment 82 wherein the multimerizing fragment of the IgM Fc region includes the IgM tailpiece.
  • 93. The multi-domain binding molecule of any of embodiments 82-92, wherein the multimerizing fragment of the IgM Fc region has the sequence as set forth in any of SEQ ID NOs: 295-304. 94.
  • scFv single-chain variable fragment
  • 96. A composition including the binding molecule of any of embodiments 1-57 and a pharmaceutically acceptable carrier.
  • composition of embodiment 97 wherein the one or more adjuvants are selected from alum, a squalene-based adjuvant, a STING agonist, or a liposome-based adjuvant.
  • 99 The composition of any of embodiments 96-98, further including a second type of binding molecule.
  • 100 The composition of embodiment 99, further including a third type of binding molecule.
  • 101. A nucleic acid sequence encoding the binding domain of any of embodiments 1-57 or the binding molecule of any of embodiments 58- 75.
  • a method of treating a subject in need thereof including administering to the subject a therapeutically effective amount of a composition of any of embodiments 96-100 thereby treating the subject in need thereof.
  • 105. The method of embodiment 104, wherein the subject has DENV. F053-6006PCT / 23-211-WO-PCT 106.
  • the method of any of embodiments 104-106, wherein the subject has previously been infected with DENV or ZIKV. 108.
  • ADE-related safety concerns derailed the widespread use of the first licensed DENV vaccine, which increased the risk of severe dengue disease following subsequent infection in previously DENV-naive recipients (Hadinegoro et al. (2015). N. Engl. J. Med.373, 1195–1206; Villar, et al. (2015). N. Engl. J. Med.372, 113–123).
  • pre-existing IgG antibodies from one prior exposure to ZIKV can also enhance subsequent dengue disease risk (Katzelnick, L.C., et al. (2020).
  • a safe vaccine would ideally induce durable antibodies that can broadly and potently neutralize DENV1-4 and ZIKV to minimize the risk of ADE.
  • secondary exposure to a different DENV serotype typically elicits broadly neutralizing antibody responses associated with protection against subsequent disease (Beltramello; Katzelnick 2; Tsai, et al. (2013). J. Virol. 87, 12562–12575 (“Tsai”); Lai, et al. (2013). PLoS Negl. Trop. Dis.7; Andrade, et al. (2020). J. Infect.
  • EDE bnAbs There are two subclasses of EDE bnAbs, of which EDE1 but not EDE2 antibodies can potently neutralize F053-6006PCT / 23-211-WO-PCT ZIKV in addition to DENV1-4 (Barba-Spaeth, et al. (2016). Nature 536, 48–53 (“Barba-Spaeth”)).
  • a few antibodies that can cross-neutralize ZIKV and some DENV serotypes have also been described (Kotaki, et al. (2021). Sci. Rep.11, 12987; Dussupt, et al. (2020). Nat. Med.26, 228– 235 (“Dussupt”); Robbiani, et al. (2017).
  • SIgN-3C is the only known naturally occurring antibody that can potently neutralize ZIKV and all four DENV serotypes (Xu 1; Kam, et al. (2017). JCI Insight 2 (“Kam”); Zhang, S., et al. (2020). Cell Rep.31 (“Zhang 1”)).
  • one of the identified bnAbs neutralized DENV1-4 and ZIKV and is derived from the IgA1 isotype, thus representing the first non-IgG bnAb described against flaviviruses.
  • monomeric IgA1 versions of newly and previously characterized bnAbs not only retained IgG neutralization breadth and potency, but also inhibited IgG-mediated enhancement of infection in cells expressing both IgG and IgA Fc receptors.
  • Sera was stored F053-6006PCT / 23-211-WO-PCT at -80°C and corresponding PBMCs were cryopreserved and stored in liquid nitrogen. Cohort details have been previously described (Zanini, et al. (2016). Proc. Natl. Acad. Sci. U. S. A.115 (“Zanini”); Robinson, et al. (2019). Cell Rep.26, 1104–1111 (“Robinson”)). [0319] Cell lines.
  • Expi-CHO-S Cells (Cat# A29127; ThermoFisher Scientific, Waltham MA) were cultured in ExpiCHO Expression Medium (Cat# A2910001; ThermoFisher Scientific) and maintained at 37°C in 8% CO 2 on a platform rotating at 125 rotations per minute (rpm) with a rotational diameter of 19 cm. They were subcultured according to the manufacturer’s instructions.
  • HEK-293T/17 cells (Cat# CRL-11268, American Type Culture Collection (ATCC), Manassas, VA) and Vero-C1008 cells (Cat# CRL-1586, ATCC) were maintained in Dulbecco's Modified Eagle Medium (DMEM) (Cat# 11965118; ThermoFisher Scientific) supplemented with 7% fetal bovine serum (FBS) (Cat# 26140079, lot 2358194RP, ThermoFisher) and 100 U/mL penicillin- streptomycin (Cat# 15140–122; ThermoFisher Scientific).
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • Raji cells stably expressing DCSIGNR (Raji-DCSIGNR) (Davis, et al. (2006). J.
  • Virol.80, 1290–1301) (provided by National Institutes of Health), K562 cells (Cat# CCL-243, ATCC), and U937 cells (Cat# CRL-1593.2, ATCC) were maintained in RPMI 1640 supplemented with GlutaMAX (Cat# 72400–047; ThermoFisher Scientific), 7% FBS and 100 U/mL penicillin-streptomycin.
  • C6/36 cells (Cat# CRL-1660, ATCC ) were maintained in EMEM (Cat# 30–2003, ATCC) supplemented with 10% FBS at 30°C in 5% CO2. All cell lines were maintained at 37°C in 5% CO2 unless otherwise stated. [0320] Preparation of cells for single-cell RNA sequencing.
  • PBMCs Cryopreserved PBMCs were thawed quickly in a 37°C water bath and transferred to a 50 mL conical tube. Thirty mL of RPMI 1640 supplemented with 10% FBS (no antibiotics) was added to the cells dropwise while gently swirling. Cells were counted and CD19+ B cells were isolated using the EasySep Human Pan-B cell enrichment kit (Cat# 19554, StemCell Technologies, Vancouver, Canada) according to the manufacturer’s instructions.
  • FBS no antibiotics
  • the resulting cells were incubated in a cocktail containing a live/dead stain (Cat# L34957, Thermo Scientific) and fluorescently labeled antibodies for CD20-eFluor450 (Cat# 48-0209-42, Invitrogen, Waltham, MA), CD38-FITC (Cat# 303504, Biolegend, San Diego, CA), CD27-PE-Cy7 (Cat# 25-0271-82, Invitrogen), CD19-APC (Cat# 555415, BD Biosciences), CD3-APC-Cy7 (Cat# 300318, Biolegend), CD8-APC-Cy7 (Cat# 344714) and CD14-APC-Cy7 (Cat# 301820) for 30 min at 4°C.
  • a live/dead stain Cat# L34957, Thermo Scientific
  • fluorescently labeled antibodies for CD20-eFluor450 Cat# 48-0209-42, Invitrogen, Waltham, MA
  • FACS Fluorescent Activated Cell Sorting
  • wash buffer 10% FBS in PBS
  • strainer caps Cat# 352235, BD
  • the cells were analyzed on a BD FACS Aria flow cytometer to assess the purity of B cells (CD19+) and determine the fraction of cells that were plasmablasts (CD3-, CD8-, CD14-, CD19 mid to hi , CD20-, CD27+, CD38+). If the fraction of plasmablasts in the B cell sample was ⁇ 10% (Donor 012), the plasmablasts were sorted via flow cytometry.
  • the cells were prepared for RNA library generation using the Chromium Next GEM Single Cell 5’ Library and Gel Bead Kit v1.1 (Cat# PN-1000167, 10X Genomics, Pleasanton, CA) according to the manufacturer’s instructions.
  • a library enriched for variable regions of B cell receptors was generated using the Chromium Single Cell V(D)J Enrichment Kit, Human B Cell (Cat# PN-1000016, 10X Genomics) and the global gene expression library (GEX library) was generated using the Chromium Single Cell 5’ Library Construction Kit (Cat# PN- 1000020, 10X Genomics), both according to the manufacturer’s instructions.
  • Both libraries from the sample D014 were sequenced on an Illumina HiSeq (Illumina, San Diego, CA), The libraries for the samples D001 (donor 001), D002 (donor 002), and D012 (donor 012) were sequenced on Illumina NovaSeq 6000.
  • Sequencing data were demultiplexed and aligned to the human transcriptome GRCh38-2020-A using cellranger (10X genomics) version 5.0.1 (D001, D002, D012) or 5.0.0 (D014, donor 014), which also identified the isotype of each antibody.
  • the “filtered” cellranger output was then passed to partis for paired heavy/light chain clustering and annotation with default parameters (Ralph). This included the default partis disambiguation of incomplete and ambiguous heavy/light pairing information, which for instance resolved an atypically large number of droplets in D014 with reads from more than one cell.
  • the largest clonal families from each donor were selected, excluding those in which the mean somatic hypermutation (measured by nucleotide sequence) was below 2%. Within the selected families, 1-2 sequences that had the lowest Hamming distance to consensus (i.e., the sequence consisting the most common amino acid present at each position) were selected, excluding those that were not encoded by plasmablasts.
  • the selected antibodies were screened for their ability to neutralize DENV1-4 and ZIKV (described below) and those that neutralized >50% of infection of 3 or more viruses were considered “hits”.
  • a second round of screening of antibodies was initiated from clonal families that had produced hits in the first round.
  • Variable region sequences for disclosed antibodies were selected from the scRNAseq data; those for control bnAbs were determined based on the protein database (PDB) entries 4UT9 (EDE1-C10), 4UTA (EDE1-C8), 4UT6 (EDE2-B7), 4UT6 (EDE2-A11), and 7BUD (SIgN-3C). All variable regions were cloned into the expression vectors: AbVec-hIgG1 (GenBank accession # FJ475055), AbVec-hIgKappa (GenBank accession# FJ475056) and AbVec-hIgLambda (GenBank accession # FJ517647), respectively .
  • variable regions were synthesized with overlapping sequences to their respective vectors.
  • the sequence that was appended to the 5’ end was the same for all vectors: TAGTAGGAACTGCAACCGGTT (SEQ ID NO: 324).
  • the sequence appended to 3’ ends was specific to each vector: for AbVec heavy: CGGTCGACCAAGGGCCCATCGG (SEQ ID NO: 325), for AbVec kappa: CGTACGGTGGCTGCACCATC (SEQ ID NO: 326), and for AbVec lambda: GGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCACCCTCGAGTGAGGAGCTTCAA GC (SEQ ID NO: 327).
  • Heavy, kappa, and lambda vectors were linearized by digestion with SalI/AgeI, BsiWI/AgeI, and XhoI/AgeI, respectively as described in Guthmiller, et al. (2019). Methods Mol. Biol.1904, 109–145). Synthesized fragments and linearized vectors were ligated using NEBuilder HiFi DNA Assembly Master Mix (Cat# E2612L, New England Biolabs, Ipswich, MA) according to the manufacturer’s instructions. [0324] IgA1 heavy chains were generated by cloning the variable regions of selected antibodies into the expression vector pFUSEss-CHIg-hA1 (Cat# pfusess-hcha1, Invivogen, San Diego, CA).
  • Variable regions of the antibody coding sequences were PCR amplified using the IgG1 heavy chain expression plasmid as a template and custom primers that appended an EcoRI site and an NheI site at the 5’ and 3’ ends respectively.
  • Primer sequences were as follows: for F25.S02 GTACACGAATTCGCAGGTGCAGCTGGTGC (forward) (SEQ ID NO: 328) and GACTCTGCTAGCTGAGGAGACGGTGACC (reverse) (SEQ ID NO: 329); for EDE1-C10 GTACACGAATTCGGAGGTCCAACTTGTTG (forward) (SEQ ID NO: 330) and GACTCTGCTAGCAGAGCTTACGGTTACG (reverse) (SEQ ID NO: 331); and for SIgN-3C GTACACGAATTCGGAAGTACAACTGGTGC (forward) (SEQ ID NO: 332) and GACTCTGCTAGCTGAACTAACAGTTACCAG (reverse) (SEQ ID NO: 333).
  • the PCR amplicons F053-6006PCT / 23-211-WO-PCT and the vector were digested with EcoRI and NheI and the resulting fragments were ligated using T7 DNA ligase (Cat# M0318, New England Biolabs).
  • All AbVec antibody expression plasmids (IgG1-heavy, kappa, and lambda) were confirmed by Sanger sequencing using the primer “AbVec sense”: GCTTCGTTAGAACGCGGCTAC (SEQ ID NO: 334).
  • IgA1 expression plasmids were confirmed by whole plasmid nanopore sequencing (Plasmidsaurus, Eugene, OR).
  • IgG1 and monomeric IgA1 heavy and light chain expression vectors were co-transfected into cultures of ExpiCHO-S cells at 0.8 ng/mL total DNA concentration at 1:1 mass ratio using OptiPro serum free medium (Cat#12309, Gibco) and Expifectamine CHO Transfection Kit (Cat# A29130, Gibco) according to the manufacturer’s instructions.
  • OptiPro serum free medium Cat#12309, Gibco
  • Expifectamine CHO Transfection Kit Cat# A29130, Gibco
  • IgA1 dimers plasmids encoding heavy, light, and joining chain (Cat# pUNO4-hJCHAIN, InvivoGen) were co-transfected at 0.8 ng/mL total DNA concentration at 1:1:1 mass ratio.
  • Recombinant IgG1 produced in transfected ExpiCHO-S cells as described above was purified using MabSelect Sure LX protein A agarose beads (Cat# 17-5474-01, Cytiva Life Sciences, Marlborough, MA) according to the manufacturer’s instructions.
  • Recombinant IgA1 produced in ExpiCHO-S cells as described above was purified using protein M agarose beads (Cat# gel-pdm-2, InvivoGen US, San Diego, CA) according to the manufacturer’s instructions.
  • IgA1 multimers were separated from monomers via size exclusion chromatography on a HiLoad 16/600 Superdex 200 pg column using 70 mL PBS as the eluate.
  • reporter virus particles were produced by co- transfection of HEK-293T/17 cells with (i) a plasmid expressing a WNV subgenomic replicon encoding GFP in place of structural genes (Pierson, et al. (2006).
  • Virology 346, 53–65 (“Pierson 1”)
  • 8 x 10 5 HEK-293T/17 cells were plated in each well of a 6-well plate, The following day each well was co-transfected with 1 ⁇ g of replicon-encoding plasmid and 3 ⁇ g of C-prM-E-encoding plasmid using Lipofectamine 3000 (Cat# L3000-015; ThermoFisher Scientific) according to the manufacturer’s instructions.
  • Virus-containing supernatant was harvested twice per day at days 3 through 8 post-transfection, centrifuged at 700 x g for 5 minutes. The clarified supernatant was passed through a 0.45 ⁇ m Steriflip filter (Cat# SE1M003M00, Millipore-Sigma, St. Louis, MO), pooled, aliquoted, and stored at -80°C.
  • Reporter virus particles with increased efficiency of prM cleavage were produced as above by co-transfecting plasmids encoding the replicon, structural genes, and human furin (provided by NIH) at a 1:3:1 mass ratio.
  • DENV3 strain CH53489 Cat# RVP-301; Integral Molecular, Philadelphia, PA
  • DENV4 strain TVP376 reporter viruses Cat# RVP-401; Integral Molecular
  • Infectious titers of reporter viruses were determined by infection of Raji-DCSIGNR cells. At 2 days post-infection, cells were fixed in 2% paraformaldehyde (Cat# 15714S; Electron Microscopy Sciences, Hatfield, PA), and GFP positive cells quantified by flow cytometry (Intellicyt iQue Screener PLUS, Sartorius AG, Gottingen, Germany).
  • Generation of E protein variants Construction of DENV216681 reporter virus variants in which E protein sites were substituted with corresponding ZIKV H/PF/2013 amino acid residues individually or in combination have been previously described. Similar methods to generate individual alanine mutations were used in this Example.
  • the DENV216681 CprME expression construct (Ansarah-Sobrinho, et al. (2008). Virology 381, 67–74) was used as a template for Q5 site-directed mutagenesis (Cat# E0554S; New England Biolabs, Ipswich, MA) and primers generated by NEBaseChanger (New England Biolabs, Ipswich, MA). The entire plasmid was sequenced (Plasmidsaurus, Eugene, OR) to confirm the presence of the desired mutation(s) only. [0331] ELISA.
  • DENV216681 reporter virus particles were concentrated by ultracentrifugation through 20% sucrose at 166,880 x g for 4 hours at 4°C, resuspended in 1/100 volume of HNE buffer (5 mM HEPES, 150 mM NaCl, 0.1 mM EDTA, pH 7.4), and stored at -80°C.
  • HNE buffer 5 mM HEPES, 150 mM NaCl, 0.1 mM EDTA, pH 7.4
  • Blocking buffer was aspirated from wells that had received 4G2 and replaced with 20uL of 100X concentrated reporter virus particles diluted 1:1 in blocking buffer. Wells that had received E monomers were left in blocking buffer and plates were incubated at 37°C for 45 min. Wells were washed 3 times with 50 uL of wash buffer, received 30 ⁇ L of primary antibody at 100 ⁇ g/mL, and were incubated at 37°C for 45 minutes. Wells were washed 6 times with 50 ⁇ L wash buffer, received 30 ⁇ L of mouse anti-human Ab (Cat# 05-4220, ThermoFisher) at 1 ⁇ g/mL, and were incubated at 37°C for 45 minutes.
  • mouse anti-human Ab Cat# 05-4220, ThermoFisher
  • Binding screen against alanine library Binding of antibodies F25.S02 and F05.S03 to a DENV2 16681 library where each prM/E polyprotein residue was mutated to alanine (or alanine residues to serine) was screened (Davidson and Doranz, (2014).
  • plasmids encoding the DENV protein variants were individually co-transfected with furin expression plasmid into HEK-293T cells and expressed for 22 hours before incubation with purified IgG1 antibodies (0.1-2.0 ⁇ g/mL) diluted in 10% normal goat serum (NGS) (Sigma-Aldrich, St. Louis, MO) in PBS plus calcium and magnesium (PBS++).
  • NGS normal goat serum
  • PBS++ calcium and magnesium
  • Antibody reactivity against each mutant was calculated relative to reactivity with wild-type prM/E, by subtracting the signal from mock-transfected controls and normalizing to the signal from wild-type protein-transfected controls. The entire library data for each antibody was compared to control antibodies. Mutations were identified as critical to the antibody epitope if they did not support reactivity of the test antibody, but supported reactivity of other control antibodies. This counter-screen strategy facilitates the exclusion of DENV prM/E protein mutants that impact folding or expression. [0335] Neutralization and antibody-dependent enhancement assays using reporter virus particles.
  • Viral stocks were expanded by infecting 70% confluent C6/36 cells and virus-containing supernatant was collected and pooled at days 3 to 8 post infection.
  • DENV4 H241 isolated in 1956, Cat# F053-6006PCT / 23-211-WO-PCT TVP17463
  • the seed stock was expanded by infecting 90% confluent Vero cells and virus-containing supernatant was collected 7 days post infection.
  • Fc ⁇ RII anti-CD32-FITC (Cat# 60012.FI, StemCell) and corresponding mouse IgG2b-FITC isotype control were used for staining.
  • anti-CD89/- PE catalog# 555686, BD Biosciences
  • mouse IgG1-PE isotype control catalog# 12- 4714-42, ThermoFisher
  • CD19+ B cells were isolated from PBMCs of these 4 donors (FIG.1B) for single cell RNA sequencing (scRNAseq) of B cell receptor-specific and overall gene expression libraries (FIG. 1C).
  • samples from donors 001 and 012 were dominated by naive B cells that were not members of any clonal family could be discerned. F053-6006PCT / 23-211-WO-PCT By contrast, samples from donors 002 and 014 were composed mostly of plasmablasts in large (4-50 members) or very large (50+ members) clonal families.
  • Antibody isotype distribution also varied by donor: samples from donors 001 and 012 were mostly IgM while those from donors 002 and 014 were primarily IgG1 (FIG.3B). [0343] Functional characterization of antibodies.
  • antibodies were chosen that were 1) encoded by plasmablasts as these are often broadly neutralizing (Zompi; Xu 1; Dejnirattisai; Durham), 2) clonally expanded with >2% somatic hypermutation at the family level, indicating antigen-specific selection (Durham; Cao; Croote, D., et al. (2016). Science 362, 1306– 1309) and 3) most similar to their family’s amino acid consensus sequence, indicating high affinity (Ralph and Matsen, 4th (2020). PLoS Comput. Biol.16).
  • One to three antibodies were selected from up to 28 clonal families per donor to identify families encoding bnAbs. These antibodies were recombinantly expressed as IgG1 by transfection of mammalian cells and the antibody-containing supernatant screened at a single dilution for neutralization of DENV1-4 and ZIKV. As shown in FIG. 4, the number and neutralization profile of clonal family ‘hits’ varied by donor. For example, of 14 total families tested from donor 001, only two (F05, F07) encoded neutralizing antibodies: F05 antibodies displayed weak ZIKV-specific neutralization, while F07 antibodies neutralized DENV1-3 and ZIKV, but not DENV4.
  • donor 012 encoded neutralizing antibodies.
  • donor 002 neutralized DENV1 and DENV3
  • donor 002 neutralized DENV1 and DENV3
  • donor 014 antibodies displayed the broadest neutralization profile: almost all 28 selected clonal families neutralized DENV1-4 and, in some cases, ZIKV with varying potencies.
  • the potency of F25.S02 against ZIKV was comparable to EDE1-C10 (IC50 of 18 and 14 ng/ml, respectively) but was 39 times higher than that of SIgN-3C (IC50 of 694 ng/ml).
  • the geometric mean potency of F25.S02 against DENV1-4 was also 2-fold higher than that of EDE1-C10 (IC50 of 96 ng/ml versus 207 ng/ml, respectively).
  • Family F25 contained 3 other antibodies that broadly neutralized DENV1-4 and ZIKV.
  • FIG.6A shows representative dose-response neutralization assays demonstrating that these disclosed bnAbs are roughly as potent, and in some cases, more potent, than previously published bnAbs (FIGs.6B and 5).
  • DENV4 also potently neutralized the genotype II DENV1 strain 16007 (IC50 range of 4 to 30 ng/ml, FIG.6C).
  • DENV4 also displays antigenic variation across genotypes (I and II) that circulate in humans (Chen and Vasilakis, (2011). Viruses 3, 1562–1608; Gallichotte, et al. (2016). Cell Rep.25, 1214–1224 (Gallichotte)).
  • flavivirus antigenic variation can also arise from heterogeneous virion maturation states resulting from inefficient cleavage of prM, a chaperone for the E protein.
  • Many but not all flavivirus-specific antibodies preferentially neutralize incompletely mature virions that retain prM on the surface (Cherrier, et al. (2009). EMBO J.28, 3269–3276; Nelson, et al. (2008). PLoS Pathog.4 (“Nelson”); Goo, et al. (2019). Nat Microbiol 4, 71–77).
  • the ability to neutralize the structurally mature form of flaviviruses is important for in vivo protection (Raut, et al.
  • ELISA was performed to assess binding to soluble monomeric E protein or to virus particles of the prototype DENV216681 strain. Unlike antibody B10, which was previously shown to efficiently bind E proteins displayed in both contexts (Durham), F25.S02, F09.S05, and F05.S03 bound efficiently to E proteins displayed on virus particles only, similar to the known bnAb EDE1-C10 (Dejnirattisai) (FIGs. 8A, 8B). These results indicate that the disclosed bnAbs preferentially recognize quaternary epitopes.
  • EDE1-C10 which retained 50- 85% of wild type binding reactivity (FIG.7D).
  • EDE1-C10 and F25.S02 are further distinguished by their dependence on K310A, which abolished binding by EDE1-C10, but not by F25.S02 (FIG. 7D).
  • F25.S02 and EDE1-C10 display a similar neutralization profile against DENV1-4 and ZIKV, their binding determinants on DENV2 are distinct.
  • FIG.17 provides antibody binding reactivity to a DENV216681 E protein alanine scanning mutagenesis library. Mean percentage and range of binding reactivity to alanine mutant relative to wild type DENV2 from at least two independent experiments are shown. [0361] Mapping neutralization determinants.
  • F25.S02 was derived from the IgA1 isotype.
  • F25.S02, EDE1-C10, and SIgN-3C were expressed as monomeric or dimeric IgA1 and their neutralization profile was compared to IgG1 versions.
  • F25.S02 monomeric IgA1 and IgG1 displayed comparable potency against DENV1-4 and ZIKV (maximum of 2-fold IC50 change)
  • monomeric IgA1 versions of EDE1-C10 and SIgN-3C were more potent against some viruses (FIG. 12B).
  • IgA1 antibodies inhibit enhancement of infection by IgG1.
  • Virtually all IgG antibodies can enhance flavivirus infection in vitro at sub-neutralizing concentrations, presumably by facilitating uptake of IgG-virus complexes into Fc ⁇ R-expressing cells (Pierson, et al. (2007). Cell Host Microbe 1, 135–145).
  • IgG1 versions of newly and previously identified bnAbs enhanced infection to various extents in K562 cells (FIG.13) commonly used to study ADE as they express Fc ⁇ RIIa (FIG.14) and are poorly permissive to flavivirus infection in the absence of IgG (Littaua, et al. (1990). J.
  • FIGs.12A and 12B demonstrate that regardless of native isotype, F25.S02, EDE1-C10, and SIgN-3C bnAbs expressed as IgA1 retained IgG1 neutralization breadth and potency.
  • IgA1 versions of F25.S02, EDE1-C10, and SIgN-3C were chosen as the infectivity curves obtained across the concentration range of IgG1 versions of bnAbs of interest fully captured both enhancement and neutralization in K562 cells (FIG.13).
  • F053-6006PCT / 23-211-WO-PCT [0371]
  • IgG1 but not IgA1 versions of F25.S02, EDE1-C10, and SIgN-3C enhanced DENV infection in K562 cells (FIG.15A), which do not express Fc alpha receptor (Fc ⁇ R1) (FIG. 14).
  • IgA1 antibodies can broadly interfere with IgG1-mediated ADE.
  • an isotype control IgA1 antibody had virtually no effect on ADE mediated by IgG, indicating that inhibition was due neither to a reduction in IgG1 concentration in IgG1/IgA1 mixtures nor the presence of non-specific IgA1. Rather, this indicates that IgA1 inhibits ADE mediated by IgG1 via direct competition of binding to virions.
  • DH1017.IgM naturally occurring ZIKV-specific pentameric IgM antibody
  • DH1017.IgM which did not neutralize DENV
  • F25.S02 an IgA1 antibody that potently cross- neutralized ZIKV and DENV1-4 and retained its potency as IgG1.
  • IgA bnAbs have been described for other antigenically distinct viruses such as HIV (Scheepers 1) and SARS-CoV-2 (Wang 2)
  • F25.S02 is the first known IgA bnAb against flaviviruses.
  • F25.S02 has unique binding and neutralization determinants compared to EDE1-C10 (Dejnirattisai; Rouvinski; Barba-Spaeth) and SIgN-3C (Xu 1; Kam; Zhang 1) IgG1 antibodies, which represent the only 2 known classes of bnAbs that potently neutralize ZIKV and DENV1-4.
  • EDE1-C10 Dejnirattisai; Rouvinski; Barba-Spaeth
  • SIgN-3C Xu 1; Kam; Zhang 1
  • IgG1 antibodies which represent the only 2 known classes of bnAbs that potently neutralize ZIKV and DENV1-4.
  • Human IgA antibodies in serum and mucosal sites exist primarily as monomeric or dimeric/polymeric forms, respectively (Woof and Russell, (2011). Mucosal Immunol.4, 590–597).
  • IgA1 antibodies not only displayed neutralization breadth and potency comparable or superior to IgG1, but also inhibited IgG1-mediated ADE in a dose-dependent manner, likely via competition for binding to virions.
  • Previous results demonstrating the ability of monomeric IgA1 to antagonize IgG-mediated ADE of DENV in cells that express Fc ⁇ R but not Fc ⁇ R1 are extended in this Example (Wegman, et al. (2021). Front. Immunol.12, 777672).
  • Existing studies of flavivirus immunity have heavily focused on the role of IgG antibodies and their interactions with Fc ⁇ Rs (Katzelnick 1; Chau; Wang 1; Katzelnick 2; Thulin; Halstead, (2014).
  • IgA-Fc ⁇ R1 interactions can modulate activating or inhibitory responses mediated by other Fc receptors (Pasquier, et al. (2005). Immunity 22, 31–42; Breedveld and van Egmond, (2019). Front. Immunol. 10, 553).
  • a conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains.
  • suitable conservative substitutions of amino acids are known to those of skill in this art and generally can be made without altering a biological activity of a resulting molecule.
  • Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin/Cummings Pub. Co., p.224).
  • Naturally occurring amino acids are generally divided into conservative substitution families as follows: Group 1: Alanine (Ala), Glycine (Gly), Serine (Ser), and Threonine (Thr); Group 2: (acidic): Aspartic acid (Asp), and Glutamic acid (Glu); Group 3: (acidic; also classified as polar, negatively charged residues and their amides): Asparagine (Asn), Glutamine (Gln), Asp, and Glu; Group 4: Gln and Asn; Group 5: (basic; also classified as polar, positively charged residues): Arginine (Arg), Lysine (Lys), and Histidine (His); Group 6 (large aliphatic, nonpolar residues): Isoleucine (Ile), Leucine (Leu), Methionine (Met), Valine (Val) and Cysteine (Cys); Group 7 (uncharged polar): Tyrosine (Tyr), Gly, Asn, Gln, Cys, Ser,
  • substitution of amino acids whose hydropathic indices are within ⁇ 2 is preferred, those within ⁇ 1 are particularly preferred, and those within ⁇ 0.5 are even more particularly preferred. It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity.
  • amino acid substitutions may be based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like.
  • variants of gene sequences can include codon optimized variants, sequence polymorphisms, splice variants, and/or mutations that do not affect the function of an encoded product to a statistically-significant degree.
  • Variants of the protein, nucleic acid, and gene sequences disclosed herein also include sequences with at least 70% sequence identity, 80% sequence identity, 85% sequence, 90% sequence identity, 95% sequence identity, 96% sequence identity, 97% sequence identity, 98% sequence identity, or 99% sequence identity to the protein, nucleic acid, or gene sequences F053-6006PCT / 23-211-WO-PCT disclosed herein.
  • “% sequence identity” refers to a relationship between two or more sequences, as determined by comparing the sequences. In the art, "identity” also means the degree of sequence relatedness between protein, nucleic acid, or gene sequences as determined by the match between strings of such sequences.
  • GCG Genetics Computer Group
  • BLASTP BLASTN
  • BLASTX Altschul, et al., J. Mol. Biol.215:403-410 (1990); DNASTAR (DNASTAR, Inc., Madison, Wisconsin)
  • FASTA program incorporating the Smith-Waterman algorithm (Pearson, Comput. Methods Genome Res., [Proc. Int. Symp.] (1994), Meeting Date 1992, 111- 20. Editor(s): Suhai, Sandor. Publisher: Plenum, New York, N.Y..
  • variants also include nucleic acid molecules that hybridize under stringent hybridization conditions to a sequence disclosed herein and provide the same function as the reference sequence.
  • Exemplary stringent hybridization conditions include an overnight incubation at 42 °C in a solution including 50% formamide, 5XSSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5XDenhardt's solution, 10% dextran sulfate, and 20 ⁇ g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1XSSC at 50 °C. Changes in the stringency of hybridization and signal detection are primarily accomplished through the F053-6006PCT / 23-211-WO-PCT manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature.
  • washes performed following stringent hybridization can be done at higher salt concentrations (e.g.5XSSC). Variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments.
  • Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.
  • "Specifically binds" refers to an association of a binding domain (of, for example, an antibody (e.g., broadly neutralizing antibody) to a virus) to its cognate binding molecule with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M) equal to or greater than 10 5 M -1 , while not significantly associating with any other molecules or components in a relevant environment sample.
  • a binding domain of, for example, an antibody (e.g., broadly neutralizing antibody) to a virus
  • Ka i.e., an equilibrium association constant of a particular binding interaction with units of 1/M
  • Binding domains may be classified as “high affinity” or “low affinity”.
  • “high affinity” binding domains refer to those binding domains with a Ka of at least 10 7 M -1 , at least 10 8 M -1 , at least 10 9 M -1 , at least 10 10 M -1 , at least 10 11 M -1 , at least 10 12 M -1 , or at least 10 13 M -1 .
  • "low affinity" binding domains refer to those binding domains with a Ka of up to 10 7 M -1 , up to 10 6 M -1 , up to 10 5 M -1 .
  • affinity may be defined as an equilibrium dissociation constant (Kd) of a particular binding interaction with units of M (e.g., 10 -5 M to 10 -13 M).
  • Kd equilibrium dissociation constant
  • a binding domain may have "enhanced affinity,” which refers to a selected or engineered binding domains with stronger binding to a cognate binding molecule than a wild type (or parent) binding domain.
  • enhanced affinity may be due to a Ka (equilibrium association constant) for the cognate binding molecule that is higher than the reference binding domain or due to a Kd (dissociation constant) for the cognate binding molecule that is less than that of the reference binding domain, or due to an off-rate (K off ) for the cognate binding molecule that is less than that of the reference binding domain.
  • Ka Equilibrium association constant
  • Kd dissociation constant
  • K off off-rate
  • the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.”
  • the transition term “comprise” or “comprises” means has, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts.
  • the transitional phrase “consisting of” excludes any element, step, ingredient or component not specified.
  • the transition phrase “consisting essentially of” limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment. A material effect would cause a statistically significant increase in dengue virus and/or zika virus infection, as described herein.
  • the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ⁇ 20% of the stated value; ⁇ 19% of the stated value; ⁇ 18% of the stated value; ⁇ 17% of the stated value; ⁇ 16% of the stated value; ⁇ 15% of the stated value; ⁇ 14% of the stated value; ⁇ 13% of the stated value; ⁇ 12% of the stated value; ⁇ 11% of the stated value; ⁇ 10% of the stated value; ⁇ 9% of the stated value; ⁇ 8% of the stated value; ⁇ 7% of the stated value; ⁇ 6% of the stated value; ⁇ 5% of the stated value; ⁇ 4% of the stated value; ⁇ 3% of the stated value; ⁇ 2% of F053-6006PCT / 23-211-WO-PCT the stated value; or ⁇ 1% of the stated value.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Binding domains that bind the four dengue virus (DENV) serotypes are described herein. In some cases, the binding domains also bind Zika virus (ZIKV). The binding domains can be used to neutralize DENV or DENV and ZIKV.

Description

F053-6006PCT / 23-211-WO-PCT CROSS-FLAVIVIRUS BINDING DOMAINS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No.63/495,063 filed April 7, 2023, which is incorporated herein by reference in its entirety as if fully set forth herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with government support under AI146028 awarded by the National Institutes of Health. The government has certain rights in the invention. REFERENCE TO SEQUENCE LISTING [0003] The Sequence Listing associated with this application is provided in XML format in lieu of a paper copy and is hereby incorporated by reference into the specification. The name of the file containing the Sequence Listing is 31F8523.xml. The file is 360,448 bytes, was created on April 5, 2024, and is being submitted electronically via Patent Center. FIELD OF THE DISCLOSURE [0004] The current disclosure describes binding domains that bind the four dengue virus (DENV) serotypes. In some cases, the binding domains also bind Zika virus (ZIKV). The binding domains can be used to neutralize DENV and/or ZIKV. BACKGROUND OF THE DISCLOSURE [0005] Zika virus (ZIKV) and the four circulating serotypes of dengue virus (DENV1, DENV2, DENV3, and DENV4) are mosquito-borne flaviviruses with overlapping geographic distributions. Climate change is predicted to further expand the geographic range of mosquito vectors, highlighting the need for effective clinical interventions to curb epidemics. The complex antibody response to DENV1-4 has hampered the development of safe and effective vaccines. A first exposure to a given DENV serotype generates potently neutralizing antibodies that typically provide long-term, though sometimes incomplete protection against reinfection by that serotype. However, antibodies that are cross-reactive in binding but not neutralizing activity against other DENV serotypes are also elicited and pre-existing non-neutralizing antibodies predict the risk of severe disease following secondary exposure to a different DENV serotypes. This phenomenon is attributed to a process called antibody-dependent enhancement (ADE), in which non- neutralizing IgG antibodies facilitate the uptake of bound DENV particles into relevant myeloid target cells via Fc-Fc gamma receptor (FcɣR)-dependent pathways. Because of ADE-related F053-6006PCT / 23-211-WO-PCT safety concerns, a vaccine that can broadly and potently neutralize DENV1-4 and in some cases, ZIKV, is needed. SUMMARY OF THE DISCLOSURE [0006] The present disclosure describes binding domains that bind the four dengue virus (DENV) serotypes (DENV1-4). In some cases, the binding domains also bind Zika virus (ZIKV). [0007] In particular embodiments, a Category 1 binding domain binds DENV1, DENV2, DENV3, DENV4, and ZIKV. In particular embodiments, a Category 1 binding domain includes binding domains from F25.S02, F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, or F02.S05. In particular embodiments, a Category 2 binding domain binds DENV1, DENV2, DENV3, and DENV4. In particular embodiments, the Category 2 binding domain includes binding domains from F09.S05, F05.S03, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, or F22.S01. [0008] In particular embodiments, a binding domain from F25.S02 includes a variable heavy chain including a complementarity determining region (CDR) heavy (H)1 including the sequence as set forth in SEQ ID NO: 18, a CDRH2 including the sequence as set forth in SEQ ID NO: 19, and a CDRH3 including the sequence as set forth in SEQ ID NO: 20; and a variable light chain including a CDR light (L)1 including the sequence as set forth in SEQ ID NO: 21, a CDRL2 including the sequence as set forth in SEQ ID NO: 22, and a CDRL3 including the sequence as set forth in SEQ ID NO: 23. [0009] In particular embodiments, a binding domain from F25.S02 includes a variable heavy chain including the sequence as set forth in SEQ ID NO: 6 and a variable light chain including the sequence as set forth in SEQ ID NO: 7. [0010] In particular embodiments, a binding domain from F09.S05 includes a variable heavy chain including a CDRH1 including the sequence as set forth in SEQ ID NO: 39, a CDRH2 including the sequence as set forth in SEQ ID NO: 40, and a CDRH3 including the sequence as set forth in SEQ ID NO: 41; and a variable light chain including a CDRL1 including the sequence as set forth in SEQ ID NO: 42, a CDRL2 including the sequence as set forth in SEQ ID NO: 43, and a CDRL3 including the sequence as set forth in SEQ ID NO: 44. [0011] In particular embodiments, a binding domain from F09.S05 includes a variable heavy chain including the sequence as set forth in SEQ ID NO: 10 and a variable light chain including the sequence as set forth in SEQ ID NO: 11. [0012] In particular embodiments, a binding domain from F053.S03 includes a variable heavy chain including a CDRH1 including the sequence as set forth in SEQ ID NO: 61, a CDRH2 F053-6006PCT / 23-211-WO-PCT including the sequence as set forth in SEQ ID NO: 62, and a CDRH3 including the sequence as set forth in SEQ ID NO: 63; and a variable light chain including a CDRL1 including the sequence as set forth in SEQ ID NO: 64, a CDRL2 including the sequence as set forth in SEQ ID NO: 65, and a CDRL3 including the sequence as set forth in SEQ ID NO: 66. [0013] In particular embodiments, a binding domain from F05.S03 includes a variable heavy chain including the sequence as set forth in SEQ ID NO: 14 and a variable light chain including the sequence as set forth in SEQ ID NO: 15. [0014] Additional binding domains are described in the Detailed Description. [0015] In particular embodiments, the binding domains described herein can be used to neutralize DENV in a subject in need thereof. In particular embodiments, the binding domains described herein can be used to neutralize DENV and ZIKV in a subject in need thereof. BRIEF DESCRIPTION OF THE FIGURES [0016] Some of the drawings submitted herewith may be better understood in color. Applicant considers the color versions of the drawings as part of the original submission and reserves the right to present color images of the drawings in later proceedings. [0017] FIGs. 1A-1F. Workflow to identify broadly neutralizing antibodies (bnAbs) from donor samples. (1A) Serum neutralization profile of 4 cohort participants chosen for downstream analysis based on potent neutralizing activity against dengue virus (DENV)1-4 and zika virus (ZIKV). The mean reciprocal serum dilution that neutralized 50% of virus infection (NT50) in 3 independent experiments is depicted as a heatmap with a darker color indicating greater potency according to the key. (1B) B cells were isolated from the peripheral blood mononuclear cells (PBMCs) of donors selected in (FIG.1A) and processed for (1C) single-cell RNA sequencing of both global gene expression (GEX) and B cell receptor (BCR)-specific libraries. (1D) BCR libraries are analyzed by the software package partis (Ralph and Matsen, 4th (2022). PLoS Comput. Biol. 18 (“Ralph”)), which groups antibodies into clonal families and infers their shared ancestry. (1E) Antibody sequences most likely to encode flavivirus-specific, high-affinity antibodies are bioinformatically down-selected for functional characterization. (1F) Selected antibodies were recombinantly expressed as IgG1 and screened for the ability to neutralize DENV1-4 and ZIKV. [0018] FIG. 2. Serum neutralizing activity against flaviviruses. Serum samples from 38 cohort participants with the indicated age and DENV and/or ZIKV exposure histories collected at the time point(s) shown were diluted either 1:240 (expt1) or 1:300 (expt2) and tested for their ability to neutralize the indicated flaviviruses in two independent experiments. Bottom rows indicate control antibodies, which include human convalescent sera to DENV (BEI Resources NR-50232) or ZIKV F053-6006PCT / 23-211-WO-PCT (BEI Resources NR-50752) and monoclonal antibodies (mAb) E60134, ZV-67135, CR4354136, and EDE1 C1028. The percent neutralizing activity shown under each virus column is normalized to infection in the absence of antibody. Heatmap colors represent neutralizing activity of at least 50% as indicated in the key under the table. Corresponding PBMC samples from the donors were selected and time points highlighted under the ‘Days post-fever’ column for single-cell RNA sequencing to isolate monoclonal antibodies. [0019] FIGs.3A, 3B. Distribution of B cell subsets and antibody isotypes within clonal families. Graphs depict the number of antibodies encoded (3A) by distinct B cell subsets and (3B) as various isotypes in clonal families of different sizes in each of the four donor samples analyzed. B cell subset and antibody isotype were determined by analysis of the cell’s transcriptome as captured by the gene expression library. Only B cells for which a corresponding antibody sequence was observed in the B cell receptor library were included. Sections without a symbol include multiple B cell subsets (3A) or multiple Ab isotypes (3B). [0020] FIG.4. Neutralization profiles of IgG1 transfection supernatants. Heatmaps displaying the results of neutralization assays against DENV1-4 and ZIKV using 1/10 diluted ExpiCHO-S culture supernatant containing the antibodies indicated. Antibodies were named based on the source of the antibody in the format DXX.FYY.SZZ, where XX is the donor number, YY is the clonal family within the donor ranked by decreasing size, and ZZ is assigned by the chronological order in which antibodies from the family were produced. The percent neutralization is calculated relative to infection in the absence of antibody. The final column displays the number of viruses that were neutralized by >50% by that antibody. The antibodies whose names were left were screened in round 1, which was intended to screen many different families. Antibodies that were considered hits due to the breadth and/or potency of their neutralization in round 1 are shown in bold font. For round 2 additional antibodies were selected, shown indented and italicized, from the clonal families of hits identified in round 1. EDE1-C10, which served as a positive control, was expressed and assayed in parallel in every trial of both rounds. [0021] FIG.5. Heatmaps of IC50 values obtained from dose-response neutralization assays using previously published bnAbs, novel category 1 bnAbs, which neutralize DENV1-4 and ZIKV, and novel category 2 novel bnAbs, which neutralize DENV1-4 but not ZIKV. *Geometric mean IC50 for all neutralized reporter virus particles obtained from at least three independent experiments performed in duplicate. All antibodies were isolated from donor 014 except for F15.S02, which was isolated from donor 012. [0022] FIGs.6A-6D. Neutralization profile of top bnAbs expressed as IgG1. (6A) Representative dose-response neutralization curves of each antibody against the indicated reporter virus particles F053-6006PCT / 23-211-WO-PCT performed in at least 3 biological replicates in duplicate wells. The data points represent the mean and the error bars represent the range of the duplicates. (6B) Mean IC50 values for antibody-virus pairs shown in (6A) and compiled from FIG. 5. The final column displays the geometric mean IC50 values against neutralized viruses. (6C) IC50 values against additional DENV variants selected due to known antigenic divergence from the panel in (6A). Values shown are means from at least two biological replicates. (6D) Mean IC50 values against fully infectious DENV clinical isolates from 2004-2006. The values are means of at least two biological replicates. The final column displays the geometric mean IC50 of each antibody against the four viruses. In (6B- 6D), IC50 values are displayed as heatmaps according to the key. [0023] FIGs. 7A, 7B. Effect of virion maturation state on bnAb activity. (7A) The indicated antibodies were tested against DENV216681 (star) or ZIKV H/PF/2013 (diamond) reporter virus particles prepared either under standard conditions (solid circles and lines) or in the presence of excess furin (open circles and dashed lines). Data were obtained from two independent experiments, each performed in duplicate wells. Data points and error bars represent the mean infection and standard deviation of the four total replicates, respectively. (7B) The table displays the mean IC50 values at which the indicated antibodies neutralized the indicated forms of DENV and ZIKV in dose response neutralization curves as shown in (7A). [0024] FIGs. 8A-8F. Determinants of E protein binding by bnAbs. Relative binding efficiency (measured by ELISA) by the indicated antibodies to (8A) E protein monomers (8B) or virus particles of DENV216681. The results are from two independent experiments, each performed in duplicate wells. The absorbance of each duplicate, reported in arbitrary units (AU), was normalized to the wells that received positive control antibody B1039. HIV-specific antibody, PGT121133 was used as a negative control. Data points represent the normalized means of each experiment and the bars represent the means of the two experiments. (8C-8F) DENV2 16681 E protein sites important for binding by antibody (8C) F25.S02 or (8E) F05.S03 are shown on the ribbon structure of the DENV2 E dimer (PDB: 1OAN) and labeled on one monomer. Sites in E domains I, II, and III are shown by triangles, stars, and diamonds, respectively. Bar graphs show the mean binding reactivity to individual alanine mutants that selectively impact (8D) F25.S02 or (8F) F05.S03 as a percentage of wildtype (WT) DENV2 E protein reactivity. Binding of control antibodies EDE1-C10 and J9 to these mutants was tested in parallel. Error bars show the range of binding reactivity from two independent experiments. The dotted line indicates 70% reduction in antibody binding activity to mutant compared to WT. [0025] FIGs.9A-9F. E protein residues critical for neutralization by bnAbs. Bar graphs show the mean IC50 fold change for antibodies (9A) F09.S05, (9B) F25.S02, (9C) F05.S03, (9D) EDE1- F053-6006PCT / 23-211-WO-PCT C10, and (9E) J9 against DENV216681 reporter virus particles encoding E protein variants relative to wild type (WT) DENV2. Values of 1, >1, and <1 indicate no change, decreased sensitivity, and increased sensitivity of mutant relative to WT DENV2, respectively. Mean values were obtained from at least 2 independent experiments shown as individual data points in which WT and mutant DENV2 were tested in parallel. WT ZIKV H/PF/2013 (first sample) was included as a control. Error bars indicate the standard deviation (n>2) or range (n=2). In each graph, the dotted horizontal line represents a 4-fold IC50 change. Sites in E domains I, II, and III are shown by stars, triangles, and diamonds, respectively. (9F) The location of individual mutations that strongly impacted neutralization by two or more antibodies in (9A-9E) are shown on the ribbon structure of the DENV2 E dimer (PDB: 1OAN) and labeled on one monomer. [0026] FIGs.10A-10E. Effect of antibody valency on neutralizing activity. Monovalent Fab (open circles and dashed lines) or bivalent IgG (solid circles and lines) versions of antibodies (10A) F25.S02, (10B) F09.S05, (10C) F05.S03, (10D) EDE1-C10, and (10E) SIgN-3C were tested against DENV216681 (star) or ZIKV H/PF/2013 (triangle) reporter virus particles. Dose-response neutralization curves shown are from two independent experiments, each performed in duplicate wells. Data points and error bars represent the mean infection and standard deviation of the four total replicates, respectively. [0027] FIGs. 11A-11C. Purity of IgA1 antibody preparations. Graphs on the top display absorbance profiles (at 280 nm) of eluates from size-exclusion chromatography (SEC), which was used to separate monomeric and polymeric IgA1. Images on the bottom display SDS-PAGE gels to assess purity of preparations. Eluates from SEC were collected in 2 mL fractions and the fractions indicated were collected, pooled, and concentrated to obtain purified monomers and polymers. SDS-PAGE was run on non-reduced (top, 11A-11C) and reduced (bottom, 11A-11C) samples of each type of antibody. Each half of a gel has one well containing a commercially purchased IgA1 isotype control (IgA Std). Each half also has a well containing IgA1 monomers of the indicated antibody that was produced as monomers, i.e., in the absence of a J chain expression plasmid (Mono) in addition to a well containing monomers that were purified via SEC (S-Mono). The two sources of monomers appear identical on the gel, but for simplicity only the ones produced in the absence of a J chain expression plasmid were used for experiments. [0028] FIGs.12A, 12B. Neutralization profiles of antibodies expressed as IgA1. (12A) IgG (open circles), monomeric IgA1 (triangle), and polymeric IgA1 (star) versions of F25.S02 (top row), EDE1-C10 (middle row), and SIgN-3C (bottom row) were tested for their ability to neutralize reporter virus particles indicated in each column. Dose-response curves are representative of 3 independent experiments, each tested in duplicate wells. Data points and error bars represent F053-6006PCT / 23-211-WO-PCT the mean and range of the duplicates, respectively. (12B) Comparison of IC50 values of F25.S02 (top), EDE1-C10 (middle), SIgN-3C (bottom) expressed as IgG, monomeric IgA1, and polymeric IgA1 against the viruses indicated on the x-axes. Legend notation scheme is similar to (12A). Each data point represents an independent experiment in which antibody isotypes were tested in parallel. Horizontal bars indicate the mean. Error bars represent the standard error of the mean. [0029] FIG. 13. Antibody dependent enhancement (ADE) profile of IgG1 bnAbs in K562 cells. Serial dilutions of antibodies indicated in the key were complexed with reporter virus particles shown above graphs prior to infection of K562 cells. Dose-response ADE profiles of antibodies that do or do not neutralize ZIKV in addition to DENV1-4 are shown in top and bottom panels, respectively. Data points and error bars indicate the mean and range of infection in duplicate wells, respectively. Graphs shown are representative of 4-5 independent experiments. [0030] FIG.14. Fc receptor expression profile of K562 and U937 cells. Histograms display the fluorescence intensity of K562 (top row) or U937 (bottom row) cells stained for the indicated Fc receptors. Histograms are normalized to the modal cell count. The isotype control was conjugated to the same fluorophore and used at the same concentration as anti-FcγRIIa or anti-FcαR1 antibody on the same population of cells. [0031] FIGs.15A-15C. Effect of antibody isotype on ADE. In (15A, 15B), DENV1 (left panel) and DENV4 (right panel) reporter virus particles were pre-incubated with serial dilutions of IgG1 and/or IgA1 forms of the indicated antibodies prior to infection of target cells expressing Fc receptor for IgG and/or IgA. (15A) Dose-response ADE assays in K562 cells, which express FcγRII but not FcαRI. IgG1 and IgA1 antibodies were tested individually. The data points and error bars represent the means and range of duplicate infection, respectively. (15B) Dose-response ADE assays in U937 monocytes, which express both FcγRII and FcαR. F25.S02 (first row), EDE1-C10 (second row) or SIgN-3C (third row) IgG1 was mixed with autologous IgA1 or an IgA1 isotype control at the indicated ratios by mass before serial dilution and pre-incubation with virus. The experiment was performed twice in duplicate wells and a representative experiment is shown. The data points represent the means of the duplicates and the error bars the range. (15C) Area under the curve analysis for experiments represented in (15B). For both experimental replicates the area of the curve for each infection condition was calculated and normalized to infection in the 100% IgG1 condition. [0032] FIG.16. Genetic characteristics of broadly neutralizing antibodies whose IC50 values are displayed in FIG.7. Bold = chosen for detailed characterization; triangle = non-IgG isotype; ? = insufficient sequence coverage of constant gene to determine isotype information; pb = plasmablast. F053-6006PCT / 23-211-WO-PCT [0033] FIG. 17. Antibody binding reactivity to DENV2 16681 E protein alanine scanning mutagenesis library. Mean percentage and range of binding reactivity. [0034] FIG. 18. Sequences supporting the disclosure including F25.S03 variable heavy chain (SEQ ID NO: 335) and encoding sequence (SEQ ID NO: 336); F25.S03 variable light chain (SEQ ID NO: 337) and encoding sequence (SEQ ID NO: 338); F25.S04 variable heavy chain (SEQ ID NO: 339) and encoding sequence (SEQ ID NO: 340); F25.S04 variable light chain (SEQ ID NO: 341) and encoding sequence (SEQ ID NO: 342); F25.S06 variable heavy chain (SEQ ID NO: 343) and encoding sequence (SEQ ID NO: 344); F25.S06 variable light chain (SEQ ID NO: 345) and encoding sequence (SEQ ID NO: 346); 4UT9_1 (SEQ ID NO: 347); 4UT9_2 (SEQ ID NO: 348); 4UT9_3 (SEQ ID NO: 349); 4UTA_1 (SEQ ID NO: 350); 4UTA_2 (SEQ ID NO: 351); 4UTA_3 (SEQ ID NO: 352); 4UT6_1 (SEQ ID NO: 353); 4UT6_2 (SEQ ID NO: 354); 4UT6_3 (SEQ ID NO: 355); 4UTB_1 (SEQ ID NO: 356); 4UTB_2 (SEQ ID NO: 357); 4UTB_3 (SEQ ID NO: 358); 7BUD_1 (SEQ ID NO: 359); 7BUD_2 (SEQ ID NO: 360); 7BUD_3 (SEQ ID NO: 361); 7BUD_4 (SEQ ID NO: 362); 3N9G_1 (SEQ ID NO: 363); and 3N9G_2 (SEQ ID NO: 364). DETAILED DESCRIPTION [0035] Dengue virus (DENV) is a positive-sense RNA virus of the Flavivirus genus of the Flaviviridae family, which also includes West Nile virus, Yellow Fever Virus, and Japanese Encephalitis virus. It is transmitted to humans through Stegomyia aegypti (formerly Aedes) mosquito vectors and is mainly found in the tropical and semitropical areas of the world, where it is endemic. There are four serotypes of DENV including DENV1, DENV2, DENV3, and DENV4. The four serotypes show immunological cross-reactivity, but are distinguishable in plaque reduction neutralization tests and by their respective monoclonal antibodies. The DENV envelope (E) protein is composed of three domains: E protein domain I (ED1) is the central domain, ED2 is the dimerization domain and contains the conserved fusion loop, and ED3 is the putative receptor- binding domain (Modis et al., Proc Natl Acad Sci U S A 100, 2003, p6986-6991). The E protein occupies the majority of the viral surface and is the primary antigen targeted by the humoral immune response (Kuhn et al., Cell 108, 2002, p717–725; and Pierson et al., Expert Rev Mol Med 10, 2008, e12). [0036] Zika virus (ZIKV) is a member of the Flaviviridae virus family and the flavivirus genus. In humans, it causes a disease known as Zika fever. It is related to dengue, and like dengue, ZIKV is spread to people through mosquito bites. The most common symptoms of Zika fever are fever, rash, joint pain, and red eye. The illness is usually mild with symptoms lasting from several days to a week. There is no vaccine to prevent, or medicine to treat, Zika virus. F053-6006PCT / 23-211-WO-PCT [0037] The complex antibody response to DENV1-4 has hampered the development of safe and effective vaccines. A first exposure to a given DENV serotype generates potently neutralizing antibodies that typically provide long-term, though sometimes incomplete protection against reinfection by that serotype. However, antibodies that are cross-reactive in binding but not neutralizing activity against other DENV serotypes are also elicited and pre-existing non- neutralizing antibodies predict the risk of severe disease following secondary exposure to a different DENV serotypes. This phenomenon is attributed to a process called antibody-dependent enhancement (ADE), in which non-neutralizing IgG antibodies facilitate the uptake of bound DENV particles into relevant myeloid target cells via Fc-Fc gamma receptor (FcɣR)-dependent pathways. Because of ADE-related safety concerns, a vaccine that can broadly and potently neutralize DENV1-4 is needed. [0038] In particular embodiments, the binding domains disclosed herein bind the E protein of DENV. In particular embodiments, binding domains also bind the E protein of ZIKV. In particular embodiments, the binding domains disclosed herein bind quaternary epitopes of the E protein. [0039] In particular embodiments, the E protein of DENV1 includes the sequence MRCVGIGNRDFVEGLSGATWVDVVLEHGSCVTTMAKNKPTLDIELLKTEVTNPAVLRKLCIEAKI SNTTTDSRCPTQGEATLVEEQDANFVCRRTFVDRGWGNGCGLFGKGSLLTCAKFKCVTKLEG KIVQYENLKYSVIVTVHTGDQHQVGNETTEHGTIATITPQAPTSEIQLTDYGALTLDCSPRTGLD FNEMVLLTMKEKSWLVHKQWFLDLPLPWTSGASTSHETWNRQDLLVTFKTAHAKKQEVVVLG SQEGAMHTALTGATEIQMSGTTTIFAGHLKCRLKMDKLTLKGVSYVMCTGSFKLEKEVAETQH GTVLVQVKYEGTDAPCKIPFSIQDEKGVTQNGRLITANPIATDKEKPVNIETEPPFGESYIVIGAG EKALKLSWFKKGSSIGKMFEATARGARRMAILGDTAWDFGSIGGVFTSVGKLVHQVFGTAYGV LFSGVSWTMKIGIGILLTWLGLNSRSTSLSMTCIAVGMVTLYLGVMVQA (SEQ ID NO: 1). [0040] In particular embodiments, the E protein of DENV2 includes the sequence: MDKLQLKGMSYSMCTGKFKVVKEIAETQHGTIVIRVQYEGDGSPCKIPFEIMDLEKRHVLGRLIT VNPIVTEKDSPVNIEAEPPFGDSYIIIGVEP (SEQ ID NO: 2). [0041] In particular embodiments, the E protein of DENV3 includes the sequence: LEHGGCVTTMAKNKPTLDIELQKTEATQLATLRKLCIEGKITNVTTDSRCPTQGEAILPEEQDQN (SEQ ID NO: 3). [0042] In particular embodiments, the E protein of DENV4 includes the sequence: MRCVGVGNRDFVEGVSGGAWVDLVLEHGGCVTTMAQGKPTLDFELIKTTAKEVALLRTYCIEA SISNITTATRCPTQGEPYLKEEQDQQYICRRDMVDRGWGNGCGLFGKGGVVTCAKFSCSGKIT GNLVQIENLEYTVVVTVHNGDTHAVGNDTSNHGETATITPRSPSVEVKLPDYGELTLDCEPRSG IDFNEMILMKMKTKTWLVHKQWFLDLPLPWTAGADTSEVHWNHKERMVTFKVPHAKRQDVTV F053-6006PCT / 23-211-WO-PCT LGSQEGAMHSALAGATEVDSGDGNHMFAGHLKCKVRMEKLRIKGMSYTMCSGKFSIDKEMAE TQHGTTVVKVKYEGTGAPCKVPIEIRDVNKEKVVGRIISSTPFAENTNSVTNIELEPPFGDSYIVI GVGDSALTLHWFRKGSSIGKMFESTYRGAKRMAILGETAWDFGSVGGLLTSLGKAVHQVFGS VYTTMFGGVSWMVRILIGLLVLWIGTNSRNTSMAMSCIAVGGITLFLGFTVHA (SEQ ID NO: 4). [0043] In particular embodiments, the E protein of ZIKV includes the sequence IRCIGVSNRDFVEGMSGGTWVDVVLEHGGCVTVMAQDKPTVDIELVTTTVSNMAEVRSYCYEA SISDMASDSRCPTQGEAYLDKQSDTQYVCKRTLVDRGWGNGCGLFGKGSLVTCAKFACSKK MTGKSIQPENLEYRIMLSVHGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL DCEPRTGLDFSDLYYLTMNNKHWLVHKEWFHDIPLPWHAGADTGTPHWNNKEALVEFKDAHA KRQTVVVLGSQEGAVHTALAGALEAEMDGAKGRLSSGHLKCRLKMDKLRLKGVSYSLCTAAF TFTKIPAETLHGTVTVEVQYAGTDGPCKVPAQMAVDMQTLTPVGRLITANPVITESTENSKMML ELDPPFGDSYIVIGVGEKKITHHWHRSGSTIGKAFEATVRGAKRMAVLGDTAWDFGSVGGALN SLGKGIHQIFGAAFKSLFGGMSWFSQILIGTLLMWLGLNTKNGSISLMCLALGGVLIFLSTAVSA (SEQ ID NO: 5). [0044] In particular embodiments, a Category 1 binding domain binds DENV1, DENV2, DENV3, DENV4, and ZIKV. In particular embodiments, a Category 1 binding domain includes binding domains from F25.S02, F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, or F02.S05. In particular embodiments, a Category 2 binding domain binds DENV1, DENV2, DENV3, and DENV4. In particular embodiments, the Category 2 binding domain includes binding domains from F09.S05, F05.S03, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, or F22.S01. [0045] In particular embodiments, a binding domain from F25.S02 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSAKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIMPIFGTVNYAQ KFQGRVTITADESTSTAYMELSRLRSEDTAVYFCARGWGGNYRSADLWIYFDLWGQGTLVTV SS (SEQ ID NO: 6) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKAPKLMIYDVTKRPSGVPD RFSGSKSGNTASLTISGLQADDEADYYCCSYAGSYTHVVFGGGTKLTVL (SEQ ID NO: 7). [0046] In particular embodiments, a binding domain from F25.S02 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGCGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAAGTATCATGCCTATCTTTGGTACAGTAAACTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTAC F053-6006PCT / 23-211-WO-PCT ATGGAGTTGAGCAGACTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGAGGATGG GGTGGGAACTACAGGTCTGCGGATTTGTGGATCTACTTTGACTTATGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAG (SEQ ID NO: 8) and a variable light chain encoded by the sequence: CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATC TCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAAGTATGTCTCCTGGTACCAACAGC ACCCAGGCAAAGCCCCCAAACTCATGATTTATGATGTCACTAAGCGGCCCTCAGGGGTCC CTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCC AGGCTGACGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCAGCTACACCCATGTGGT ATTCGGCGGAGGGACCAAGCTGACCGTCCTAG (SEQ ID NO: 9). [0047] F25.S02 is derived from an IgA1 isotype as opposed to an IgG1 isotype (other binding domains are derived from IgG1 isotype). F25.S02 is beneficial because it has limited potential for antibody-dependent enhancement of infection in vitro. Furthermore, F25.S02 potently and broadly neutralizes DENV1-4 and ZIKV; it has greater geometric mean potency against DENV1-4 compared to previously described EDE1 antibody of similar breadth (FIG.6B). [0048] In particular embodiments, a binding domain from F09.S05 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVRVSCKASGYTFTSYGISWVRQAPGQGLEWMGWIGTYNGNTNYA PKFHGRVTMTTDTPTSTAYMDLRGLRSDDTAVYYCARDTRHFYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 10) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLVWYQQKPGQAPRLLIHDASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 11). [0049] In particular embodiments, a binding domain from F09.S05 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGT CTCCTGCAAGGCTTCTGGTTACACCTTTACCAGTTATGGTATCAGTTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGATCGGCACTTACAATGGAAACACAAACTAT GCACCGAAATTCCACGGCAGAGTCACCATGACCACAGACACACCCACGAGTACAGCCTAC ATGGACCTGAGGGGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATACC CGCCATTTTTATGATACAAGTGGTTATTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 12) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTACTTAGTCTGGTACCAACAGAAAC F053-6006PCT / 23-211-WO-PCT CTGGCCAGGCTCCCAGGCTCCTCATCCATGATGCATCCAGCAGGGCCACTGGCATCCCAG ACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGC CTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCATTGATCACCTTCGGCCAA GGGACACGACTGGAGATTAAAC (SEQ ID NO: 13). [0050] In particular embodiments, a binding domain from F05.S03 includes a variable heavy chain including the sequence: VQQLVESGGGLVKPGGSLRLSCAASGITFSTYTMNWVRQAPGKGLEWISSINGGSSNIYYADS VEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRGHYYDSSGYFQMGEIDYWGQGTLVS VSS (SEQ ID NO: 14) and a variable light chain including the sequence: DIQMTQSPSTLSASVGDRVTITCRASQSITNWLAWYQQKPGKAPRLLIYKASSLEGGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQQYKTYSRTFGQGTKVEIK (SEQ ID NO: 15). [0051] In particular embodiments, a binding domain from F05.S03 includes a variable heavy chain encoded by the sequence: GTGCAGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGAATCACCTTCAGTACCTATACCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGATCTCATCCATTAATGGTGGTAGTAGTAACATATATTACG CAGACTCAGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTACC TGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAGATAGGG GCCATTACTATGATAGTAGTGGTTATTTCCAAATGGGGGAAATTGACTACTGGGGCCAGGG AACCCTGGTCTCCGTCTCCTCAG (SEQ ID NO: 16) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTTGGAGACAGAGTCACCA TCACTTGCCGGGCCAGTCAGAGTATTACTAACTGGTTGGCCTGGTATCAGCAGAAACCTG GGAAAGCCCCTAGACTCCTGATCTATAAGGCGTCTAGTTTAGAAGGTGGGGTCCCATCAA GGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTG ATGATTTTGCAACTTATTACTGCCAACAATATAAGACTTATTCCCGGACGTTCGGCCAAGGG ACCAAGGTGGAAATCAAAC (SEQ ID NO: 17). [0052] In particular embodiments, CDRs for binding domains of F25.S02, F09.S05, and F05.S03 are in Table 1. [0053] Table 1. CDR sequences for F25.S02, F09.S05, and F05.S03. Antibody CDR CDR Sequence SEQ ID NO
Figure imgf000014_0001
F053-6006PCT / 23-211-WO-PCT CDRL1 TGTSSDVGGYKYVS 21 CDRL2 DVTKRPS 22 CDRL3 CSYAGSYTHVV 23
Figure imgf000015_0001
F053-6006PCT / 23-211-WO-PCT CDRL2 HDASSRAT 54 CDRL3 QQYGSSLIT 51 C CDRH1 TSYGIS 55
Figure imgf000016_0001
ain including the sequence: QGQLVQSGAEVRKPGSSVKVSCKAAGGTFSTYGVSWVRLAPGQGLEWMGGIIPYFGTTNYA QKFHGRVTITADESTSTVYMELRSLRSEDTAVYYCARGWGGNYRNMDLWIYFDYWGQGTLVT VSS (SEQ ID NO: 82) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGSSSDVGGYKYVSWYKQHPGKAPKLIIYDVNKRPSGVPDR FSGSKSGNTASLTISGLQDEDEADYYCCSYAGSYTHVLFGGGTKLTVL (SEQ ID NO: 83). F053-6006PCT / 23-211-WO-PCT [0055] In particular embodiments, a binding domain from F25.S06 includes a variable heavy chain encoded by the sequence: CAGGGGCAGCTGGTGCAGTCTGGGGCTGAGGTGAGGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTGCTGGAGGCACCTTCAGCACCTATGGTGTCAGCTGGGTGCGACTGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTTACTTCGGTACCACGAACTA CGCACAGAAGTTTCACGGTAGAGTCACGATAACCGCCGACGAATCCACGAGCACAGTCTA CATGGAACTGCGCAGCCTGAGATCTGAGGACACGGCCGTCTATTACTGTGCGAGAGGATG GGGTGGGAACTACAGGAATATGGATTTGTGGATCTACTTTGACTATTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCAG (SEQ ID NO: 84) and a variable light chain encoded by the sequence: CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATC TCCTGCACTGGAAGCAGCAGTGATGTTGGTGGTTATAAGTATGTCTCCTGGTATAAACAAC ACCCAGGCAAAGCCCCCAAACTCATTATTTATGATGTCAATAAGCGGCCCTCAGGGGTCCC TGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCA GGATGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCAGCTACACCCATGTGCTG TTCGGCGGAGGGACCAAGCTGACCGTCCTAG (SEQ ID NO: 85). [0056] In particular embodiments, a binding domain from F25.S03 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYAVSWVRQAPGQGLEWMGGIIPFFGTTNYA QRFQGRITITADESTGTAYMELRSLRSEDTAVYYCARGWGGNYRNADLWIYFDSWGQGTLVT VSS (SEQ ID NO: 86) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKAPKLMIYDVSKRPSGVPD RYSGSKSGNTASLTISGLQAEDEADYYCCSYADSFTHVIFGGGTKLTVL (SEQ ID NO: 87). [0057] In particular embodiments, a binding domain from F25.S03 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGGTATGCTGTCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTTTTTTTGGTACAACGAATTAC GCACAGAGGTTCCAGGGCAGAATCACAATTACCGCGGACGAATCCACGGGCACAGCCTAC ATGGAGTTGAGGAGTCTCAGATCTGAAGACACGGCCGTGTATTACTGTGCGAGAGGATGG GGTGGGAATTATAGGAATGCGGATTTGTGGATCTACTTTGACTCCTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAG (SEQ ID NO: 88) and a variable light chain encoded by the sequence: CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATC F053-6006PCT / 23-211-WO-PCT TCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAAGTATGTCTCCTGGTACCAACAGC ACCCAGGCAAAGCCCCCAAACTCATGATTTATGATGTCTCTAAGCGGCCCTCAGGGGTCC CTGATCGGTACTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCC AGGCAGAGGATGAGGCTGATTATTACTGCTGCTCATATGCTGACAGCTTCACCCATGTGAT ATTCGGCGGAGGGACCAAGCTGACCGTCCTAG (SEQ ID NO: 89). [0058] In particular embodiments, a binding domain from F25.S05 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTVSSYAISWVRQAPGQGLEWMGGILPLFDTRNFAQ KFQGRVTITADESTSTAYMELNSLRYEDTAVYYCARGWGGNYRTADLWIYFDSWGQGTLVTV SS (SEQ ID NO: 90) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKVPKLMIYDVNRRPSGVPD RFSGSKSGNTASLTISGLQAEDEANYYCCSYAGTYTHVLFGGGTKLTVL (SEQ ID NO: 91). [0059] In particular embodiments, a binding domain from F25.S05 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCGTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCCTCCCTCTGTTTGACACAAGAAACTT CGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTA CATGGAGCTGAACAGCCTGAGATATGAGGACACGGCCGTGTATTACTGTGCGCGAGGATG GGGTGGGAACTACAGGACTGCGGATTTGTGGATCTACTTTGACTCCTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCAG (SEQ ID NO: 92) and a variable light chain encoded by the sequence: CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATC TCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAAGTATGTCTCCTGGTACCAACAGC ACCCAGGCAAAGTCCCCAAACTCATGATTTATGATGTCAATAGGCGGCCCTCAGGGGTCC CTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCC AGGCTGAGGATGAGGCTAATTATTACTGCTGCTCATATGCAGGCACCTACACCCATGTGCT ATTCGGCGGGGGGACCAAGCTGACCGTCCTAG (SEQ ID NO: 93). [0060] In particular embodiments, a binding domain from F02.S30 includes a variable heavy chain including the sequence: EVQLVESGGGLVKPGGSLRLSCAGSGFTFSGYSMNWVRQAPGKGLEWVSSLSSSRTYMYYA DSVRGRFTISRDNAENSLFLQMNSLRAEDTAVYYCTRGAPLDDNSGYFVPWYFDLWGRGALV TVSS (SEQ ID NO: 94) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIHGASTRATGIPARFS F053-6006PCT / 23-211-WO-PCT GSGSGTEFTLTISSLQSEDLAVYYCQQYNDWPPETFGQGTKVEIK (SEQ ID NO: 95). [0061] In particular embodiments, a binding domain from F02.S30 includes a variable heavy chain encoded by the sequence: GAGGTGCAGCTGGTGGAATCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGGCTCTGGATTCACCTTCAGTGGCTACAGCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCATCCCTTAGTAGTAGTCGTACTTACATGTACTAC GCAGACTCAGTGAGGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACTCACTGTTT CTCCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTACGAGAGGCGCC CCCCTCGATGACAATAGTGGTTATTTCGTCCCCTGGTACTTCGATCTCTGGGGCCGTGGC GCCCTAGTCACTGTCTCCTCAG (SEQ ID NO: 96) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCCATGGTGCGTCCACCAGGGCCACTGGTATCCCAGC CAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTC TGAAGATTTGGCAGTTTATTACTGTCAGCAGTATAATGACTGGCCTCCGGAGACGTTCGGC CAAGGGACCAAGGTGGAAATCAAAC (SEQ ID NO: 97). [0062] In particular embodiments, a binding domain from F25.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGGIIPIFGTTNYAQ KFQGRVTITADESTNTAYMELSSLRSEDTAVYYCAKGWGGNYRTADLWIYFDLWGQGTLVTV SS (SEQ ID NO: 98) and a variable light chain including the sequence: QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYKYVSWYQQHPGKAPKLMIYDVTKRPSGVPA RFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHVVFGGGTKLTVL (SEQ ID NO: 99). [0063] In particular embodiments, a binding domain from F25.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTTTCAGCTGGGTGCGACAGGC CCCTGGACAAGGACTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAACAAACTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAACACAGCCTAC ATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTATATTACTGTGCGAAAGGATGG GGTGGGAACTACAGGACTGCGGATTTGTGGATCTACTTTGACCTCTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAG (SEQ ID NO: 100) and a variable light chain encoded by the sequence: F053-6006PCT / 23-211-WO-PCT CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATC TCCTGCACTGGAACCAGCAGTGATGTCGGTGGTTATAAGTATGTCTCCTGGTACCAACAGC ACCCAGGCAAAGCCCCCAAACTCATGATTTATGATGTCACTAAGCGGCCCTCAGGGGTCC CTGCTCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCC AGGCTGAAGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCAGTTACACCCATGTGGT GTTCGGCGGAGGGACCAAGCTGACCGTCCTAG (SEQ ID NO: 101). [0064] In particular embodiments, a binding domain from F02.S27 includes a variable heavy chain including the sequence: EVQLVESGGGLVKPGGSLRLSCAGSGFTFSSYTMNWVRQAPGKGLEWVSSLSSSRSYMFYA DSVKGRFTISRDNAENSLSLRMNSLRGEDTAVYYCARGAPLDENSGYFVPWYFDLWGRGTLV TVSS (SEQ ID NO: 102) and a variable light chain including the sequence: EIVMTQSPATLSASPGERVTLSCRASQSVSSKLAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYFCQQYNKWPPETFGQGTKVEIK (SEQ ID NO: 103). [0065] In particular embodiments, a binding domain from F02.S27 includes a variable heavy chain encoded by the sequence: GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGGGTCCCTGAGAC TCTCCTGTGCAGGCTCTGGATTCACCTTCAGTTCCTATACCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGTTGGAGTGGGTCTCATCCCTTAGTAGTAGTCGCAGTTACATGTTCTAC GCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAAAATTCATTGTCTT TGCGAATGAACTCCCTGAGAGGCGAGGACACGGCTGTGTATTACTGTGCGAGGGGCGCC CCCCTCGATGAAAACAGTGGTTATTTCGTCCCCTGGTACTTCGATCTCTGGGGCCGTGGCA CCCTGGTCACTGTCTCGTCAG (SEQ ID NO: 104) and a variable light chain encoded by the sequence: GAAATAGTAATGACGCAGTCTCCAGCCACCCTGTCTGCGTCTCCAGGGGAAAGAGTCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGTAGCAAGTTAGCCTGGTATCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGAGCATCCACCAGGGCCACTGGTATCCCAGCC AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCT GAAGATTTTGCAGTTTATTTCTGTCAGCAGTATAATAAGTGGCCTCCGGAGACGTTTGGCC AAGGGACCAAGGTGGAAATCAAAC (SEQ ID NO: 105). [0066] In particular embodiments, a binding domain from F02.S05 includes a variable heavy chain including the sequence: EVQMVESGGGLVKPGGSLRLSCAASGFTFSGYTMNWVRQAPGKGLEWVSSLSSSRSYMYYA DSVKGRFTISRDNAENSLYLQMNSLTAEDTAVYYCARGAPLDENSGFFVPWYFDLWGRGTLV TVSS (SEQ ID NO: 106) and a variable light chain including the sequence: F053-6006PCT / 23-211-WO-PCT EIVMTQSPATLSVSPGERATLSCRASQSISSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPETFGQGTKVEIK (SEQ ID NO: 107). [0067] In particular embodiments, a binding domain from F02.S05 includes a variable heavy chain encoded by the sequence: GAGGTGCAGATGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGGTTATACCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTCTCATCCCTTAGTAGTAGTAGGAGTTACATGTACTAC GCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACTCACTGTAT CTGCAAATGAACAGCCTGACAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGCGCC CCCCTCGATGAAAATAGTGGATTTTTCGTCCCCTGGTACTTCGATCTCTGGGGCCGTGGCA CCCTGGTCACTGTCTCCTCAG (SEQ ID NO: 108) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCC AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCT GAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCTCCGGAGACGTTCGGCC AGGGGACCAAGGTAGAAATCAAAC (SEQ ID NO: 109). [0068] In particular embodiments, a binding domain from F09.S07 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYGISWVRQAPGQGLEWMGWIGTYNYNTNYA PKFQDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDTRHYYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 110) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSITNNYLTWYQQKPGQPPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGTSLITFGQGTRLAIK (SEQ ID NO: 111). [0069] In particular embodiments, a binding domain from F09.S07 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAAGT CTCCTGTAAGGCTTCTGGTTACACCTTTACCACCTATGGTATCAGTTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGATCGGCACTTACAATTATAATACAAACTATG CACCGAAGTTCCAGGACAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACA TGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTTTACTACTGTGCGAGAGATACGC GGCATTACTATGATACTAGTGGTTATTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAGG GAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 112) and a variable light chain encoded by F053-6006PCT / 23-211-WO-PCT the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTATTACCAACAACTACTTAACCTGGTACCAGCAGAAAC CTGGCCAACCTCCCAGGCTCCTCATTTATGGTGCATCCAGCAGGGCCACTGGCATCCCAG ACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGC CTGAAGATTTTGCAGTCTATTACTGTCAGCAGTATGGTACCTCATTGATCACCTTCGGCCAA GGGACACGACTGGCGATTAAAC (SEQ ID NO: 113). [0070] In particular embodiments, a binding domain from F27.S01 includes a variable heavy chain including the sequence: QVQLIQSGAEVKKPGSSVKVSCKASGGTFNSYTINWVRQAPGQGLEWMGNIIPVLGTTNYAEK YQGRVTITADESTSTVYLDLSSLRSGDTAVYYCARGINFYDSSNYFSANWFDPWGQGTLVTVT S (SEQ ID NO: 114) and a variable light chain including the sequence: EIVMTQSPATLSVSPGETATLSCRTSQSVNNNLVWYQQKPGQAPRLLIYAASSRVTGVPARFS GSGSGTEFTLTISSLQSEDSAVYYCQQYKNWPATFGPGTKVDLK (SEQ ID NO: 115). [0071] In particular embodiments, a binding domain from F27.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGTTGATTCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTC TCCTGTAAGGCGTCTGGAGGCACATTCAACAGTTATACTATCAACTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGAAACATCATCCCTGTCCTTGGTACAACAAATTACG CAGAGAAGTACCAGGGCAGAGTCACGATTACCGCGGACGAATCCACCAGTACAGTCTACT TGGACCTGAGCAGTCTGAGATCTGGGGACACGGCCGTCTATTATTGTGCGAGAGGGATCA ACTTCTATGACAGCTCCAACTATTTTTCGGCCAACTGGTTCGACCCCTGGGGCCAGGGAAC CCTGGTCACCGTCACCTCAG (SEQ ID NO: 116) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCGGTGTCTCCAGGGGAAACAGCCACC CTCTCCTGCAGGACAAGTCAGAGTGTCAACAATAACTTAGTCTGGTACCAGCAAAAACCTG GCCAGGCTCCCAGGCTCCTCATTTATGCTGCATCCAGTAGGGTCACTGGTGTCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACCCTCACCATCAGCAGCCTGCAGTCTG AAGATTCTGCAGTTTATTACTGTCAGCAGTATAAGAACTGGCCTGCGACTTTCGGCCCTGG GACCAAAGTGGATCTCAAAC (SEQ ID NO: 117). [0072] In particular embodiments, a binding domain from F09.S08 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYGISWVRQAPGQGPEWMAWISTYNGNTNFA PKFQGRVTMTTDTSTSTAYLELRSLRSDDTAVYYCARDTRHFYDTSGYYLGGWFAPWGPGTQ F053-6006PCT / 23-211-WO-PCT VTVSS (SEQ ID NO: 118) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQAPRLVIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 119). [0073] In particular embodiments, a binding domain from F09.S08 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGTTACTCCTTTACCAGTTATGGTATCAGCTGGGTGCGACAGGCC CCTGGACAAGGGCCTGAGTGGATGGCATGGATCAGCACTTACAATGGTAACACAAACTTT GCACCGAAGTTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC TTGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTACTGTGCGCGAGATACC CGTCATTTCTATGATACTAGTGGTTACTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCCG GGAACCCAGGTCACCGTCTCCTCAG (SEQ ID NO: 120) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCACCTACTTAGCCTGGTACCAGCAGAAA CCTGGCCAGGCTCCCAGGCTCGTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCA GACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCATTGATCACCTTCGGCC AAGGGACTCGACTGGAGATTAAAC (SEQ ID NO: 121). [0074] In particular embodiments, a binding domain from F09.S02 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVKVSCKTSGYTFTSYGISWLRQAPGQGLEWIGWIGTYNGNTNYAP KFQGTVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDTRHYYDTSGYYLGGWFAPWGQGTL VTVSS (SEQ ID NO: 122) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GWGSGTDFTLTISRLEPEDFALYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 123). [0075] In particular embodiments, a binding domain from F09.S02 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGACCTCTGGTTACACCTTTACCAGTTATGGTATCAGCTGGTTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATTGGATGGATCGGCACTTACAATGGTAACACAAACTATG CACCGAAGTTCCAGGGCACAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACA TGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGGGATACCC GGCATTACTATGATACTAGTGGTTACTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAGG F053-6006PCT / 23-211-WO-PCT GAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 124) and a variable light chain encoded by the sequence: GAGATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGTTACTTAGCCTGGTACCAGCAGAAA CCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCA GACAGGTTCAGTGGCTGGGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCACTTTATTACTGTCAGCAGTATGGTAGCTCATTGATCACCTTCGGCCA AGGGACACGACTGGAGATTAAA (SEQ ID NO: 125). [0076] In particular embodiments, a binding domain from F09.S06 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASLKVSCKASGYTFTSYGISWLRQAPGQGLEWMGWSSPYNGNTHYA PKFQGRVTMTTDTSTSTAYMDLRSLRSDDTAVYYCARDTRHFYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 126) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFITFGQGTRLEIK (SEQ ID NO: 127). [0077] In particular embodiments, a binding domain from F09.S06 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCCGAGGTGAAGAAGCCTGGGGCCTCACTGAAGGT CTCCTGCAAGGCTTCTGGTTACACTTTTACCAGTTATGGTATCAGCTGGCTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGAGCAGCCCTTACAATGGTAACACACATTAC GCACCGAAGTTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC ATGGACCTGAGGAGCCTGAGATCTGACGACACGGCCGTCTATTATTGTGCGAGAGATACC CGGCATTTCTATGATACTAGTGGTTATTACTTGGGGGGGTGGTTCGCCCCCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 128) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAATCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAA CCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCA GACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCATTCATCACCTTCGGCCA AGGGACACGACTGGAGATTAAAC (SEQ ID NO: 129). [0078] In particular embodiments, a binding domain from F05.S01 includes a variable heavy chain including the sequence: VQQLVESGGGLVKPGGSLRLSCAASGITFSTYTMNWVRQAPGKGLEWISSINGGSTNIYYADS F053-6006PCT / 23-211-WO-PCT VEGRFTISRDNAKNSLYLQMNSLRAEETAVYYCARDRGHYYDSSGYFHMGEIDYWGQGTLVS VSS (SEQ ID NO: 130) and a variable light chain including the sequence: DIQMTQSPSTLSASVGDRVTITCRASQSISNWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQQYKTYSRTFGQGTKVEIK (SEQ ID NO: 131). [0079] In particular embodiments, a binding domain from F05.S01 includes a variable heavy chain encoded by the sequence: GTGCAGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGAATCACCTTCAGTACCTATACCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGATCTCATCCATTAATGGTGGTAGTACTAACATATACTACG CAGACTCAGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGAGACGGCTGTATATTACTGTGCGAGAGATAGGG GCCATTATTATGATAGTAGTGGTTATTTCCATATGGGGGAAATTGACTACTGGGGCCAGGG AACCCTGGTCTCCGTCTCCTCAG (SEQ ID NO: 132) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTTGGAGACAGAGTCACCA TCACTTGCCGGGCCAGTCAGAGTATTAGTAACTGGTTGGCCTGGTATCAGCAGAAACCTG GGAAAGCCCCTAAGCTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAG GTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGA TGATTTTGCAACTTATTACTGCCAACAATATAAGACTTATTCCCGGACGTTCGGCCAAGGGA CCAAGGTGGAAATCAAAC (SEQ ID NO: 133). [0080] In particular embodiments, a binding domain from F10.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGSYSSYRISWVRQAPGQGLEWMGRIVPFFGTVDYA EKFQGRVTITADESTSTVYMELTSLRSEDTAVYYCARDINYFDSSYYHSGWWFDPWGQGTLV TVSS (SEQ ID NO: 134) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSSNLVWYQQKPGQAPRLLIYGASTRVTGIPARFTG SGSGTEFTLTISSLQSEDFAVYYCQQYYSWRPITFGQGTRLEIK (SEQ ID NO: 135). [0081] In particular embodiments, a binding domain from F10.S01 includes a variable heavy chain encoded by the sequence: CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT GTCCTGTAAGGCTTCTGGAGGCTCCTACAGCAGCTATAGGATCAGTTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCGTCCCTTTCTTTGGTACAGTAGACTA CGCAGAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGTACAGTGTA TATGGAGCTGACCAGCCTGAGATCTGAGGACACGGCCGTGTATTATTGTGCGAGAGACAT F053-6006PCT / 23-211-WO-PCT AAACTACTTTGATAGTAGTTATTATCATTCTGGTTGGTGGTTCGACCCCTGGGGCCAGGGA ACCCTGGTCACCGTCTCTTCAG (SEQ ID NO: 136) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCCCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTCAGCAGCAACTTAGTCTGGTACCAGCAAAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACGAGGGTCACTGGTATCCCAGCC AGGTTCACTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCT GAAGATTTTGCAGTTTATTACTGTCAGCAATATTATAGCTGGCGGCCGATCACCTTCGGCC AAGGGACACGACTGGAGATTAAAC (SEQ ID NO: 137). [0082] In particular embodiments, a binding domain from F09.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGASVRVSCKASGYTFTTYGISWVRQAPGQGLEWMGWIGTYNGNTIYA QKFQGRVTMTTDTSTSTAYMELRSLRFDDTAVYYCARDTRHYYDTSGYYLGGWFAPWGQGT LVTVSS (SEQ ID NO: 138) and a variable light chain including the sequence: EIVLTQSPGTLSLSPGERASLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLITFGQGTRLEIK (SEQ ID NO: 139). [0083] In particular embodiments, a binding domain from F09.S01 includes a variable heavy chain encoded by the sequence: CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGT CTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTATGGTATTAGCTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGATGGATCGGCACTTACAATGGTAACACAATCTAT GCACAGAAATTTCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTAC ATGGAGCTGAGGAGCCTGAGATTTGACGACACGGCCGTGTATTACTGTGCGAGAGATACC CGGCATTACTATGATACTAGTGGTTATTACTTAGGGGGGTGGTTCGCCCCCTGGGGCCAG GGAACCCTGGTCACCGTCTCCTCAG (SEQ ID NO: 140) and a variable light chain encoded by the sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAGC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAA CCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCA GACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCATTGATCACCTTCGGCC AAGGGACACGACTGGAGATTAAAC (SEQ ID NO: 141). [0084] In particular embodiments, a binding domain from F02.S13 includes a variable heavy chain including the sequence: F053-6006PCT / 23-211-WO-PCT EVQLEESGGGLVKPGGSLRLSCAGSGFTFRSYTMNWVRQAPGKGLEWVSSLSSSRSYMFYA DSVRGRFTISRDNAQNSLYLQMRSLRAEDTAVYYCARGAPLDDNSDYFVPWYFDLWGRGTLV TVSS (SEQ ID NO: 142) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSSKLAWYQQKPGQAPRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPETFGQGTKVEIK (SEQ ID NO: 143). [0085] In particular embodiments, a binding domain from F02.S13 includes a variable heavy chain encoded by the sequence: GAGGTGCAGCTGGAGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGGGGTCCCTGAGAC TCTCTTGTGCAGGCTCTGGGTTCACCTTCAGGAGTTACACCATGAACTGGGTCCGTCAGG CTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCCTTAGTAGTAGCCGCTCTTACATGTTCT ACGCAGACTCAGTGAGGGGCCGATTCACCATCTCCAGAGACAACGCCCAGAACTCACTGT ATCTGCAAATGCGCAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGCG CCCCCCTCGATGATAACAGCGATTATTTCGTCCCCTGGTATTTCGATCTCTGGGGCCGTGG CACCCTGGTCACTGTCTCCTCAG (SEQ ID NO: 144) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAAGTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCC AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCT GAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCTCCGGAGACGTTCGGCC AAGGGACCAAGGTGGAAATCAAAC (SEQ ID NO: 145). [0086] In particular embodiments, a binding domain from F28.S01 includes a variable heavy chain including the sequence: QVQLQESGPGLVRPSETLSLTCTVSGGSIDGHYWSWIRQPPGKGLEWIGFMFYRGGTNFNPS LKSRVTISVETSKSQFSLKLTSVTAADTAMYYCARGVIRDYGLRFDYWGQGSLVTVSS (SEQ ID NO: 146) and a variable light chain including the sequence: DIQMTQSPSSVSASVGDRVTITCRASQDINSWLAWYQQKPGKAPKLLIYAASNLQNGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQGNSFGVTFGQGTRLEIK (SEQ ID NO: 147). [0087] In particular embodiments, a binding domain from F28.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAGGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCGATGGTCACTACTGGAGCTGGATCCGGCAGCC CCCAGGTAAGGGACTGGAGTGGATTGGCTTTATGTTTTACAGGGGGGGCACCAACTTCAA CCCCTCCCTCAAGAGTCGAGTCACCATATCAGTCGAGACGTCCAAGAGTCAGTTCTCCCTG F053-6006PCT / 23-211-WO-PCT AAACTGACATCTGTGACCGCTGCGGACACGGCCATGTATTACTGTGCGAGAGGAGTCATT CGTGACTACGGTCTTCGATTTGACTACTGGGGCCAGGGATCCCTGGTCACCGTCTCCTCA G (SEQ ID NO: 148) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCCGTCTTCCGTGTCTGCATCTGTGGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCAAGATATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCAG GGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAATTTGCAAAATGGGGTCCCATCAAG GTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCAACTTACTATTGTCAACAGGGTAACAGTTTCGGGGTCACCTTCGGCCAAGGG ACACGACTGGAGATTAAGC (SEQ ID NO: 149). [0088] In particular embodiments, a binding domain from F15.S01 includes a variable heavy chain including the sequence: QLHLQESGPGLAKPSETLSLTCTVSRGSIDTATYYWAWIRQTPGKGLEWIGSIYLSADTYYNPS LKSRVSISMDTSTNQFSLKLSSVTAADTAVYYCARQLGNYFDSWGQGTLVTVSS (SEQ ID NO: 150) and a variable light chain including the sequence: AIQLTQSPSSLSASVGDRVTITCRASQGIASYLAWYQQKPGQAPKLLIHTASTLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQLSAYLFTFGQGTRLEIK (SEQ ID NO: 151). [0089] In particular embodiments, a binding domain from F15.S01 includes a variable heavy chain encoded by the sequence: CAACTGCATCTTCAGGAGTCGGGCCCAGGGCTGGCGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTGTCTCGTGGCTCCATCGACACTGCAACTTACTACTGGGCCTGGATACG CCAGACCCCCGGGAAGGGACTGGAGTGGATTGGGAGTATCTATCTCAGTGCGGATACCTA CTACAACCCGTCCCTCAAGAGTCGAGTCTCCATATCCATGGACACGTCTACGAACCAGTTC TCCCTGAAGCTGAGCTCAGTCACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGACAG CTGGGTAACTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCCG (SEQ ID NO: 152) and a variable light chain encoded by the sequence: GCCATCCAGTTGACCCAGTCTCCATCGTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCA TCACTTGCCGGGCCAGTCAGGGCATTGCCAGTTATTTAGCCTGGTATCAGCAGAAACCAG GGCAAGCCCCTAAGCTCCTGATCCATACTGCATCCACTTTGCAAAGTGGGGTCCCATCAAG GTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCAACTTATTACTGTCAACAACTTAGTGCTTACCTTTTCACCTTCGGCCAAGGGA CACGGCTGGAGATTAAAC (SEQ ID NO: 153). [0090] In particular embodiments, a binding domain from F13.S01 includes a variable heavy chain including the sequence: QVQLVQSGAEVKKPGSSVKVSCKASGDTFSSYFFTWVRQAPGQGLEWMGGIIPMYGTRNYA F053-6006PCT / 23-211-WO-PCT QKFQGRVTITADESTSTAYMELSSLRSDDTAVYYCARVKFGDFGAYYYYYGMDVWGQGTTVT VSS (SEQ ID NO: 154) and a variable light chain including the sequence: EIVMTQSPATLSVSPGERVTLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFS GSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPAFTFGPGTKVDIK (SEQ ID NO: 155). [0091] In particular embodiments, a binding domain from F13.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGACACCTTCAGCAGTTATTTTTTCACGTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATGTATGGTACAAGAAATTAC GCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTAC ATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTATATTACTGTGCGAGAGTGAAG TTCGGTGACTTCGGGGCCTACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACC ACGGTCACCGTCTCCTCAN (SEQ ID NO: 156) and a variable light chain encoded by the sequence: GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGTCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCC AGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCT GAAGATTTTGCAGTTTATTACTGTCAACAATATAATAACTGGCCTCCGGCTTTCACTTTCGG CCCTGGGACCAAAGTGGATATCAAAC (SEQ ID NO: 157). [0092] In particular embodiments, a binding domain from F22.S01 includes a variable heavy chain including the sequence: QVHLVQSGAEVKKPGSSVKVSCKASGGTLSNYAISWVRQAPGQGLEWMGGIIPVFTTGVYAQ SFQGRVTITADESTGTAYMELSSLRSEDTAIYYCATEPQSGVSGRYFDSWGQGTLVTVSS (SEQ ID NO: 158) and a variable light chain including the sequence: DIQMTQSPSTLSPSVGDRVTITCRASQSISSWLAWYQQKPGKAPNLLIYKASTLQSGVPSRFSG SGSGTEFTLTISSLQPDDVATYYCQQYESHPTFGQGTKVEIK (SEQ ID NO: 159). [0093] In particular embodiments, a binding domain from F22.S01 includes a variable heavy chain encoded by the sequence: CAGGTGCACCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGCGGCACCCTCAGCAACTATGCTATCAGCTGGGTGCGACAGGC CCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCAGTCTTTACTACAGGAGTCTA CGCACAGAGCTTCCAGGGCAGAGTCACCATTACCGCGGACGAGTCCACGGGGACAGCCT ACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCATTTATTACTGTGCGACGGAGC F053-6006PCT / 23-211-WO-PCT CCCAGTCGGGTGTCTCGGGGCGCTACTTTGACTCCTGGGGCCAGGGAACCCTGGTCACC GTCTCCTCAG (SEQ ID NO: 160) and a variable light chain encoded by the sequence: GACATCCAGATGACCCAGTCTCCTTCTACCCTGTCTCCATCTGTAGGAGACAGAGTCACCA TCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTGGTATCAACAGAAACCAG GGAAAGCCCCTAATCTCCTAATCTATAAGGCGTCTACTTTACAAAGTGGGGTCCCATCAAG GTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGA TGATGTTGCGACTTATTACTGCCAACAGTATGAAAGTCATCCGACCTTCGGCCAAGGGACC AAGGTGGAAATCAAAC (SEQ ID NO: 161). [0094] CDRs for binding domains of F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, F02.S05, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, and F22.S01 are provided in Table 2. [0095] Table 2. CDR sequences for F25.S06, F25.S03, F25.S05, F02.S30, F25.S01, F02.S27, F02.S05, F09.S07, F27.S01, F09.S08, F09.S02, F09.S06, F05.S01, F10.S01, F09.S01, F02.S13, F28.S01, F15.S01, F13.S01, and F22.S01 according to Kabat. Antibody CDR Sequence SEQ ID NO F25.S06 CDRH1 TYGVS 162
Figure imgf000030_0001
F053-6006PCT / 23-211-WO-PCT CDRL2 DVTKRPS 22 CDRL3 CSYAGSYTHVV 23 F02S27 CDRH1 SYTMN 186
Figure imgf000031_0001
F053-6006PCT / 23-211-WO-PCT CDRL3 QQYKTYSRT 66 F10.S01 CDRH1 SYRIS 218 CDRH2 RIVPFFGTVDYAEKFQG 219
Figure imgf000032_0001
Contact can be determined by one of ordinary skill in the art for the binding domains listed in Table 2. [0097] In particular embodiments, the binding domains described herein can be used to neutralize DENV1-4. In particular embodiments, the binding domains described herein can be used to F053-6006PCT / 23-211-WO-PCT neutralize DENV1-4 and ZIKV. [0098] Aspects of the current disclosure are now described in more supporting detail as follows: (I) Antibodies; (II) Antibody Variants; (III) Multi-Domain Binding Molecules; (IV) Recombinant Production; (V) Antibody Conjugates; (VI) Compositions or Formulations for Administration; (VII) Methods of Use; (VIII) Kits; (IX) Exemplary Embodiments; (X) Experimental Example; and (XI) Closing Paragraphs. These headings are provided for organizational purposes only and do not limit the scope or interpretation of the disclosure. [0099] (I) Antibodies. Naturally occurring antibody structural units include a tetramer. Each tetramer includes two pairs of polypeptide chains, each pair having one light chain and one heavy chain. The amino-terminal portion of each chain includes a variable region that is responsible for antigen recognition and epitope binding. The variable regions exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called complementarity determining regions (CDRs). The CDRs from the two chains of each pair are aligned by the framework regions, which enables binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chain variable regions include the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. [0100] The assignment of amino acids to each domain can be in accordance with Kabat numbering (Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme)); Chothia (Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme)), Martin (Abinandan et al., Mol Immunol.45:3832-3839 (2008), “Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains”), Gelfand, Contact (MacCallum et al., J. Mol. Biol.262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol.262, 732-745.” (Contact numbering scheme)), IMGT (Lefranc M P et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 January; 27(1):55-77 (“IMGT” numbering scheme)), AHo (Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun. 8; 309(3):657-70, (AHo numbering scheme)), North (North et al., J Mol Biol. 406(2):228-256 (2011), “A new clustering of antibody CDR loop conformations”), or other numbering schemes. [0101] Definitive delineation of a CDR and identification of residues including the binding site of an antibody can be accomplished by solving the structure of the antibody and/or solving the structure of the antibody-epitope complex. In particular embodiments, this can be accomplished by methods such as X-ray crystallography and cryoelectron microscopy. Alternatively, CDRs are F053-6006PCT / 23-211-WO-PCT determined by comparison to known antibodies (linear sequence) and without resorting to solving a crystal structure. To determine residues involved in binding, a co-crystal structure of the Fab (antibody fragment) bound to the target can optionally be determined. Software programs and bioinformatical tools, such as ABodyBuilder and Paratome can also be used to determine CDR sequences. [0102] The carboxy-terminal portion of each chain defines a constant region, which can be responsible for effector function particularly in the heavy chain (the Fc). Examples of effector functions include: C1q binding and complement dependent cytotoxicity (CDC); antibody- dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B-cell receptors); and B-cell activation. [0103] Within full-length light and heavy chains, the variable and constant regions are joined by a “J” region of amino acids, with the heavy chain also including a “D” region of amino acids. See, e.g., Fundamental Immunology, Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)). [0104] Human light chains are classified as kappa and lambda light chains. In particular embodiments, a human kappa light chain (Igκ) constant region includes the sequence: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 250). In particular embodiments, a human lambda light chain (Igλ) constant region includes the sequence: GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 251). [0105] Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses including IgM1 and IgM2. IgA is similarly subdivided into subclasses including IgA1 and IgA2. IgG causes opsonization and cellular cytotoxicity and crosses the placenta, IgA functions on the mucosal surface, IgM is most effective in complement fixation, and IgE mediates degranulation of mast cells and basophils. The function of IgD is still not well understood. Resting B cells, which are immunocompetent but not yet activated, express IgM and IgD. Once activated and committed to secrete antibodies these B cells can express any of the five isotypes. The heavy chain isotypes of IgG, IgA, IgM, IgD and IgE are respectively designated the γ, α, μ, δ, and ε chains. [0106] The constant region of the antibody with multiple binding domains may be of any suitable immunoglobulin subtype. In particular embodiments the subtype of the antibody may be of the class IgG, IgD, IgE, IgA, or IgM. Such an antibody may further belong to any subclass, e.g., IgG1, IgG2a, IgG2b, IgG3 and IgG4. In particular embodiments, a constant region includes a light chain F053-6006PCT / 23-211-WO-PCT constant region and a heavy chain constant region. A “functional constant heavy chain” or “functional CH” activates an aspect of the immune response. [0107] In particular embodiments, a human IgG1 Fc region includes the sequence: THTCPPCPAPEFFGGPSVFFFPPKPKDTFMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVETVFHQDWENGKEYKCKVSNKAFPVPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 252). [0108] In particular embodiments, a human IgG2 Fc region includes the amino acid sequence: PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 253) [0109] In particular embodiments, a human IgG3 Fc region includes the amino acid sequence: PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPR EEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNIFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 254). [0110] In particular embodiments, a human IgG4 Fc region includes the amino acid sequence: PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 255). [0111] The human IgD constant region typically includes the amino acid sequence: APTKAPDVFPIISGCRHPKDNSPVVLACLITGYHPTSVTVTWYMGTQSQPQRTFPEIQRRDSYY MTSSQLSTPLQQWRQGEYKCVVQHTASKSKKEIFRWPESPKAQASSVPTAQPQAEGSLAKAT TAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFT CFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTL NHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQRE VNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSY VTDHGPMK (SEQ ID NO: 256). [0112] The human IgE constant region typically includes the amino acid sequence: ASTQSPSVFPLTRCCKNIPSNATSVTLGCLATGYFPEPVMVTWDTGSLNGTTMTLPATTLTLSG HYATISLLTVSGAWAKQMFTCRVAHTPSSTDWVDNKTFSVCSRDFTPPTVKILQSSCDGGGHF PPTIQLLCLVSGYTPGTINITWLEDGQVMDVDLSTASTTQEGELASTQSELTLSQKHWLSDRTY F053-6006PCT / 23-211-WO-PCT TCQVTYQGHTFEDSTKKCADSNPRGVSAYLSRPSPFDLFIRKSPTITCLVVDLAPSKGTVNLTW SRASGKPVNHSTRKEEKQRNGTLTVTSTLPVGTRDWIEGETYQCRVTHPHLPRALMRSTTKTS GPRAAPEVYAFATPEWPGSRDKRTLACLIQNFMPEDISVQWLHNEVQLPDARHSTTQPRKTK GSGFFVFSRLEVTRAEWEQKDEFICRAVHEAASPSQTVQRAVSVNPGK (SEQ ID NO: 257). [0113] The human IgA1 constant region typically includes the amino acid sequence: ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDL YTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPR LSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVL PGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLAR GFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMV GHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY (SEQ ID NO: 258). [0114] The human IgA2 constant region typically includes the amino acid sequence ASPTSPKVFPLSLDSTPQDGNVVVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDASGD LYTTSSQLTLPATQCPDGKSVTCHVKHYTNPSQDVTVPCPVPPPPPCCHPRLSLHRPALEDLL LGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHG ETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRW LQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQK TIDRLAGKPTHVNVSVVMAEVDGTCY (SEQ ID NO: 259). [0115] The human IgM constant region typically includes the amino acid sequence GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 260; identical to, e.g., GenBank Accession Nos. pir||S37768, CAA47708.1, and CAA47714.1). Referring to this SEQ ID NO: 260, the human Cµ1 region ranges from amino acid 5 to amino acid 102; the human Cµ2 region ranges from amino acid 114 to amino acid 205, the human Cµ3 region ranges from amino acid 224 to amino acid 319, the Cµ4 region ranges from amino acid 329 to amino acid 430, and the tailpiece ranges from amino acid 431 to amino acid 453. [0116] In particular embodiments, an IgM heavy chain constant region includes the sequence: GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK F053-6006PCT / 23-211-WO-PCT YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL GQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDS VTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTI SRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSA PMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLV MSDTAGTCY (SEQ ID NO: 261; (UniProt ID P01871)—allele IGHM*04). This sequence differs from SEQ ID NO: 260 by one amino acid at position 191. [0117] The Kabat numbering system for the human IgM constant domain can be found in Kabat, et. al. “Tabulation and Analysis of Amino acid and nucleic acid Sequences of Precursors, V- Regions, C-Regions, J-Chain, T-Cell Receptors for Antigen, T-Cell Surface Antigens, b-2 Microglobulins, Major Histocompatibility Antigens, Thy-l, Complement, C-Reactive Protein, Thymopoietin, Integrins, Post-gamma Globulin, a-2 Macroglobulins, and Other Related Proteins,” U.S. Dept of Health and Human Services (1991). IgM constant regions can be numbered sequentially (i.e., amino acid #1 starting with the first amino acid of the constant region) or by using the Kabat numbering scheme. [0118] In particular embodiments, human IgM constant regions, and also certain non-human primate IgM constant regions, as provided herein typically include five (5) naturally-occurring asparagine (N)-linked glycosylation motifs or sites. As used herein “an N-linked glycosylation motif” includes the amino acid sequence N-X1-S/T, wherein N is asparagine, X1 is any amino acid except proline (P), and S/T is serine (S) or threonine (T). The glycan is attached to the nitrogen atom of the asparagine residue. See, e.g., Drickamer K, Taylor ME (2006), Introduction to Glycobiology (2nd ed.). Oxford University Press, USA. N- linked glycosylation motifs occur in the human IgM heavy chain constant regions of SEQ ID NO: 260 or SEQ ID NO: 258 starting at positions 46 (“Nl”), 209 (“N2”), 272 (“N3”), 279 (“N4”), and 440 (“N5”). These five motifs are conserved in non-human primate IgM heavy chain constant regions, and four of the five are conserved in the mouse IgM heavy chain constant region. Each of these sites in the human IgM heavy chain constant region, except for N4, can be mutated to prevent glycosylation at that site, while still allowing IgM expression and assembly into a hexamer or pentamer. [0119] In certain aspects, a variant human IgM constant region includes an amino acid substitution corresponding to the wild-type human IgM constant region at position P311, P313, R344, E345, S401, E402, and/or E403 the corresponding IgM sequence in SEQ ID NO: 260. These positions correspond to the Kabat numbering system as follows: S401 of the corresponding IgM sequence above corresponds to S524 of Kabat; E402 of the corresponding IgM sequence F053-6006PCT / 23-211-WO-PCT above corresponds to E525 of Kabat; E403 of the corresponding IgM sequence above corresponds to E526 of Kabat; R344 of the corresponding IgM sequence above corresponds to R467 of Kabat; and E345 of the corresponding IgM sequence above corresponds to E468 of Kabat. [0120] As indicated, antibodies bind epitopes on antigens. The term antigen refers to a molecule or a portion of a molecule that is bound by an antibody when in the non-blocked presence of the antibody. An epitope is a region of an antigen that is bound by the variable region of an antibody. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three- dimensional structural characteristics, and/or specific charge characteristics. When the antigen is a protein or peptide, the epitope includes specific amino acids within that protein or peptide that contact the variable region of an antibody. [0121] In particular embodiments, an epitope denotes the binding site on a viral peptide, bacterial peptide, cancer protein, or other antigen bound by a corresponding variable region of an antibody. The variable region either binds to a linear epitope, (e.g., an epitope including a stretch of 5 to 12 consecutive amino acids), or the variable region binds to a three-dimensional structure formed by the spatial arrangement of several short stretches of the protein target. Three-dimensional epitopes recognized by a variable region, e.g., by the epitope recognition site or paratope of an antibody or antibody fragment, can be thought of as three-dimensional surface features of an epitope molecule. These features fit precisely (in)to the corresponding binding site of the variable region and thereby binding between the variable region and its target protein (more generally, antigen) is facilitated. In particular embodiments, an epitope can be considered to have two levels: (i) the “covered patch” which can be thought of as the shadow an antibody variable region would cast on the antigen to which it binds; and (ii) the individual participating side chains and backbone residues that facilitate binding. Binding is then due to the aggregate of ionic interactions, hydrogen bonds, and hydrophobic interactions. [0122] Epitopes of the currently disclosed antibodies (that is, epitopes to which the antibodies bind) can be found on a virus (e.g., dengue virus (DENV) or zika virus (ZIKV)). [0123] In particular embodiments, “bind” means that the variable regions that form a binding domain associate with their target epitope with a dissociation constant (Kd or KD) of 10-8 M or less, in particular embodiments of from 10-5 M to 10-13 M, in particular embodiments of from 10-5 M to 10-10 M, in particular embodiments of from 10-5 M to 10-7 M, in particular embodiments of from 10-8 M to 10-13 M, or in particular embodiments of from 10-9 M to 10-13 M. The term can be further used to indicate that the variable regions do not bind to other biomolecules present (e.g., it binds F053-6006PCT / 23-211-WO-PCT to other biomolecules with a dissociation constant (Kd) of 10-4 M or more, in particular embodiments of from 10-4 M to 1 M). A “functional antigen binding domain” is a binding domain that binds its intended antigen. [0124] In particular embodiments, Kd can be characterized using BIAcore. For example, in particular embodiments, Kd can be measured using surface plasmon resonance assays using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25°C with immobilized antigen CM5 chips at 10 response units (RU). [0125] Unless otherwise indicated, the term “antibody” refers to naturally occurring antibodies (having two full-length heavy chains and two full-length light chains as described above), and variants, derivatives, and fragments thereof, examples of which are described below. Furthermore, unless explicitly excluded, antibodies can include monoclonal antibodies (mAbs), human or humanized antibodies, multi-specific antibodies, bi-specific antibodies, tri-specific antibodies, tetra-specific antibodies, penta-specific antibodies, polyclonal antibodies, linear antibodies, minibodies, domain antibodies, synthetic antibodies, chimeric antibodies, antibody fusions, single chain variable fragments (scFvs), polyclonal antibodies, and fragments thereof, respectively. In particular embodiments, antibodies can include oligomers or multiplexed versions of the antibodies disclosed herein. [0126] A monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies including the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies can be made by a variety of techniques, including the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci. [0127] A “human antibody” is one which includes an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. [0128] A “human consensus framework” is a framework that represents the most commonly F053-6006PCT / 23-211-WO-PCT occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. The subgroup of sequences can be a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91- 3242, Bethesda Md. (1991), vols. 1-3. In particular embodiments, for the VL, the subgroup is subgroup kappa I as in Kabat et al. (supra). In particular embodiments, for the VH, the subgroup is subgroup III as in Kabat et al. (supra). [0129] A neutralizing antibody is an antibody that is responsible for blocking the entry of a pathogen into a cell so that it is firstly unable to infect healthy cells, and secondly, it is unable to replicate and cause severe infection. [0130] In particular embodiments, the binding domains disclosed herein are part of a full antibody. In particular embodiments, the antibody is an IgG antibody, an IgA antibody, an IgM antibody, an IgE antibody, or an IgD antibody. In particular embodiments, the IgG antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In particular embodiments, the IgG antibody is an IgG1 antibody. In particular embodiments, the IgA antibody is an IgA1 antibody or an IgA2 antibody. In particular embodiments, the IgA antibody is an IgA1 antibody. In particular embodiments, the IgA antibody is monomeric, dimeric, or polymeric. [0131] (II) Antibody Variants. Binding domains disclosed herein can be utilized to prepare various forms of relevant binding domain molecules. For example, particular embodiments can include binding fragments of an antibody, e.g., Fv, Fab, Fab', F(ab')2, and single chain Fv fragments (scFvs) or any biologically effective fragments of an immunoglobulin that bind specifically to an epitope described herein. [0132] In particular embodiments, an antibody fragment is used. An “antibody fragment” denotes a portion of a full-length antibody that retains the ability to bind to an epitope. Antibody fragments can be made by various techniques, including proteolytic digestion of an intact antibody as well as production by recombinant host-cells (e.g., mammalian suspension cell lines, E. coli or phage), as described herein. Antibody fragments can be screened for their binding properties in the same manner as intact antibodies. Examples of antibody fragments include Fv, scFv, Fab, Fab', Fab'- SH, F(ab')2; diabodies; and linear antibodies. [0133] A single chain variable fragment (scFv) is a fusion protein of the variable regions of the heavy and light chains of immunoglobulins connected with a short linker peptide. Fv fragments include the VL and VH domains of a single arm of an antibody but lack the constant regions. Although the two domains of the Fv fragment, VL and VH, are coded by separate genes, they can be joined, using, for example, recombinant methods, by a synthetic linker that enables them to be F053-6006PCT / 23-211-WO-PCT made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (single chain Fv (scFv)). For additional information regarding Fv and scFv, see e.g., Bird, et al., Science 242:423-426, 1988; Huston, et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988; Plueckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore (eds.), Springer-Verlag, New York), (1994) 269-315; WO 1993/16185; U.S. Pat. No.5,571,894; and No.5,587,458. [0134] Linker sequences that are used to connect the VL and VH of an scFv are generally five to 35 amino acids in length. In particular embodiments, a VL-VH linker includes from five to 35, ten to 30 amino acids or from 15 to 25 amino acids. Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies. Linker sequences of scFv are commonly Gly-Ser linkers, described in more detail elsewhere herein. [0135] Additional examples of antibody-based binding domain formats include scFv-based grababodies and soluble VH domain antibodies. These antibodies form binding regions using only heavy chain variable regions. See, for example, Jespers et al., Nat. Biotechnol.22:1161, 2004; Cortez-Retamozo et al., Cancer Res.64:2853, 2004; Baral et al., Nature Med.12:580, 2006; and Barthelemy et al., J. Biol. Chem.283:3639, 2008. [0136] A Fab fragment is a monovalent antibody fragment including VL, VH, CL and CH1 domains. A F(ab')2 fragment is a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region. For discussion of Fab and F(ab')2 fragments having increased in vivo half-life, see U.S. Patent 5,869,046. Diabodies include two epitope-binding sites that may be bivalent. See, for example, EP 0404097; WO1993/01161; and Holliger, et al., Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993. Dual affinity retargeting antibodies (DART™; based on the diabody format but featuring a C-terminal disulfide bridge for additional stabilization (Moore et al., Blood 117:4542-51, 2011)) can also be used. Antibody fragments can also include isolated CDRs. For a review of antibody fragments, see Hudson, et al., Nat. Med. 9:129-134, 2003. In particular embodiments, the binding domains disclosed herein are expressed as a Fab. [0137] In particular embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody, thereby generating an Fc region variant. The Fc region variant may include a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) including an amino acid modification (e.g., a substitution) at one or more amino acid positions. Numerous Fc modifications are known in the art, and a representative sampling of such possible modifications are described herein. [0138] In particular embodiments, variants (including Fc variants) have been modified from a reference sequence to produce an administration benefit. Exemplary administration benefits can F053-6006PCT / 23-211-WO-PCT include (1) reduced susceptibility to proteolysis, (2) reduced susceptibility to oxidation, (3) altered binding affinity for forming protein complexes, (4) altered binding affinities, (5) reduced immunogenicity; and/or (6) extended half-live. While the disclosure below describes these modifications in terms of their application to antibodies, when applicable to another particular anti- CD45 binding domain format (e.g., bispecific antibodies), the modifications can also be applied to these other formats. [0139] In particular embodiments, the Fc moiety of an antibody includes a substitution at positions CH2 4, CH25, or both. In general, the amino acid at positions 4 and 5 of CH2 of the wild-type IgG1 and IgG3 is a leucine ("L"). In particular embodiments, the antibody includes an amino acid at position CH24, CH25, or both, that is not an L. In particular embodiments, an antibody includes an alanine ("A") at position CH24, or CH25, or both. In particular embodiments, the antibody includes both, a CH2 L4A and a CH2 L5A substitution. Such antibodies are referred to herein as a "LALA" variant. Interestingly, a "LALA" mutation in the Fc moiety does not only result in a lack of contribution of the respective antibody in antibody-dependent enhancement (ADE), but also blocks ADE. [0140] In particular embodiments, an IgG4 Fc region is mutated to form the IgG4_S228P Fc region. IgG4 antibodies can undergo a process called Fab arm exchange which results in functionally monovalent, bispecific antibodies with unknown specificity and thus potentially reduced therapeutic efficacy. Mutating the wildtype IgG4 serine at position 228 within the core- hinge region to a proline creates the IgG4_S228P mutant. In particular embodiments, the IgG4_S228P mutant prevents Fab arm exchange. [0141] In particular embodiments the antibodies can be mutated to increase their affinity for Fc receptors. Exemplary mutations that increase the affinity for Fc receptors include: G236A/S239D/A330L/I332E (GASDALIE). Smith et al., Proceedings of the National Academy of Sciences of the United States of America, 109(16), 6181-6186, 2012. In particular embodiments, an antibody variant includes an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues). In particular embodiments, alterations are made in the Fc region that result in altered C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No.6,194,551, WO 99/51642, and Idusogie et al., J. Immunol.164: 4178-4184, 2000. [0142] In particular embodiments, it may be desirable to create cysteine engineered antibodies, e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned F053-6006PCT / 23-211-WO-PCT at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further below. In particular embodiments, residue 5400 (EU numbering) of the heavy chain Fc region is selected. Cysteine engineered antibodies may be generated as described, e.g., in U.S. Pat. No. 7,521,541. [0143] Antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., WO2000/61739; WO 2001/29246; WO2002/031140; US2002/0164328; WO2003/085119; WO2003/084570; US2003/0115614; US2003/0157108; US2004/0093621; US2004/0110704; US2004/0132140; US2004/0110282; US2004/0109865; WO2005/035586; WO2005/035778; WO2005/053742; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); and Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys.249:533-545, 1986, and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614, 2004; Kanda et al., Biotechnol. Bioeng., 94(4):680-688, 2006; and WO2003/085107). [0144] In particular embodiments, modified antibodies include those wherein one or more amino acids have been replaced with a non-amino acid component, or where the amino acid has been conjugated to a functional group or a functional group has been otherwise associated with an amino acid. The modified amino acid may be, e.g., a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, or an amino acid conjugated to an organic derivatizing agent. Amino acid(s) can be modified, for example, co-translationally or post-translationally during recombinant production (e.g., N-linked glycosylation at N-X-S/T motifs during expression in mammalian cells) or modified by synthetic means. The modified amino acid can be within the F053-6006PCT / 23-211-WO-PCT sequence or at the terminal end of a sequence. Modifications also include nitrited constructs. [0145] In particular embodiments, variants include glycosylation variants wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a reference sequence. In particular embodiments, glycosylation variants include a greater or a lesser number of N-linked glycosylation sites than the reference sequence. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X can be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (e.g., those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the reference sequence. These cysteine variants can be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. These cysteine variants generally have fewer cysteine residues than the reference sequence, and typically have an even number to minimize interactions resulting from unpaired cysteines. [0146] PEGylation particularly is a process by which polyethylene glycol (PEG) polymer chains are covalently conjugated to other molecules such as proteins. Several methods of PEGylating proteins have been reported in the literature. For example, N-hydroxy succinimide (NHS)-PEG was used to PEGylate the free amine groups of lysine residues and N-terminus of proteins; PEGs bearing aldehyde groups have been used to PEGylate the amino-termini of proteins in the presence of a reducing reagent; PEGs with maleimide functional groups have been used for selectively PEGylating the free thiol groups of cysteine residues in proteins; and site-specific PEGylation of acetyl-phenylalanine residues can be performed. [0147] Covalent attachment of proteins to PEG has proven to be a useful method to increase the half-lives of proteins in the body (Abuchowski, A. et al., Cancer Biochem. Biophys.,1984, 7:175- 186; Hershfield, M. S. et al., N. Engl. J. Medicine, 1987, 316:589-596; and Meyers, F. J. et al., Clin. Pharmacol. Ther., 49:307-313, 1991). The attachment of PEG to proteins not only protects the molecules against enzymatic degradation, but also reduces their clearance rate from the body. The size of PEG attached to a protein has significant impact on the half-life of the protein. The ability of PEGylation to decrease clearance is generally not a function of how many PEG groups are attached to the protein, but the overall molecular weight of the altered protein. F053-6006PCT / 23-211-WO-PCT Usually the larger the PEG is, the longer the in vivo half-life of the attached protein. In addition, PEGylation can also decrease protein aggregation (Suzuki et al., Biochem. Bioph. Acta 788:248, 1984), alter protein immunogenicity (Abuchowski et al., J. Biol. Chem.252: 3582, 1977), and increase protein solubility as described, for example, in PCT Publication No. WO 92/16221). [0148] Several sizes of PEGs are commercially available (Nektar Advanced PEGylation Catalog 2005-2006; and NOF DDS Catalogue Ver 7.1), which are suitable for producing proteins with targeted circulating half-lives. A variety of active PEGs have been used including mPEG succinimidyl succinate, mPEG succinimidyl carbonate, and PEG aldehydes, such as mPEG- propionaldehyde. [0149] In particular embodiments, the antibody can be fused or coupled to an Fc polypeptide that includes amino acid alterations that extend the in vivo half-life of an antibody that contains the altered Fc polypeptide as compared to the half-life of a similar antibody containing the same Fc polypeptide without the amino acid alterations. In particular embodiments, Fc polypeptide amino acid alterations can include M252Y, S254T, T256E, M428L, and/or N434S and can be used together, separately or in any combination. For example, M428L/N434S is a pair of mutations that increase the half-life of antibodies in serum, as described in Zalevsky et al., Nature Biotechnology 28, 157-159, 2010. Other alterations that can be helpful are described in US Patent No.7,083,784, US Patent No.7,670,600, US Publication No.2010/0234575, PCT/US2012/070146, and Zwolak, Scientific Reports 7: 15521, 2017. In particular embodiments, any substitution at one of the following amino acid positions in an Fc polypeptide can be considered an Fc alteration that extends half-life: 250, 251, 252, 259, 307, 308, 332, 378, 380, 428, 430, 434, 436. Each of these alterations or combinations of these alterations can be used to extend the half-life of a bispecific antibody as described herein. [0150] In particular embodiments, Fc modifications include huIgG4 ProAlaAla, huIgG2m4, and/or huIgG2sigma mutations. In particular embodiments, one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules. Substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No.5,624,821; Tso et al., US Patent No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004). For additional information regarding Fc mutations that create administration benefits, see Saunders, Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life, Frontiers in Immunology (2019) Vol.10, Article 1296. F053-6006PCT / 23-211-WO-PCT [0151] (III) Multi-Domain Binding Molecules. Multi-domain binding molecules include at least two binding domains, wherein at least one binding domain includes a binding domain disclosed herein. In particular embodiments, a multi-domain binding molecule includes at least one, at least two, at least, three, at least four binding domains that bind an epitope on DENV and/or ZIKV. In particular embodiments, all of the binding domains of a multi-domain binding molecule bind DENV and/or ZIKV. [0152] Multi-domain binding molecules include bispecific antibodies which bind at least two epitopes wherein at least one of the epitopes is located on DENV and/or ZIKV. Multi-domain binding molecules include trispecific antibodies which binds at least 3 epitopes, wherein at least one of the epitopes is located on DENV and/or ZIKV, and so on. [0153] Bispecific antibodies can be prepared utilizing antibody fragments (for example, F(ab')2 bispecific antibodies). For example, WO 1996/016673 describes a bispecific anti-ErbB2/anti-Fc gamma RIII antibody; US Pat. No.5,837,234 describes a bispecific anti-ErbB2/anti-Fc gamma RI antibody; WO 1998/002463 describes a bispecific anti-ErbB2/Fc alpha antibody; and US 5,821,337 describes a bispecific anti-ErbB2/anti-CD3 antibody. [0154] Some additional exemplary bispecific antibodies have two heavy chains (each having three heavy chain CDRs, followed by (N-terminal to C-terminal) a CH1 domain, a hinge, a CH2 domain, and a CH3 domain), and two immunoglobulin light chains that confer antigen-binding specificity through association with each heavy chain. However, as indicated, additional architectures are envisioned, including bi-specific antibodies in which the light chain(s) associate with each heavy chain but do not (or minimally) contribute to antigen-binding specificity, or that can bind one or more of the epitopes bound by the heavy chain antigen-binding regions, or that can associate with each heavy chain and enable binding of one or both of the heavy chains to one or both epitopes. [0155] Two antibodies or fragments thereof can be linked through a linker to form a bispecific antibody. In particular embodiments, the two antibodies or fragments thereof can bind the same epitope or different epitopes. Examples of linkers can be found in Chen et al., Adv Drug Deliv Rev. 2013 Oct 15; 65(10): 1357–1369. Linkers can be flexible, rigid, or semi-rigid, depending on the desired functional domain presentation to a target. [0156] Commonly used flexible linkers include a linker sequence with the amino acids glycine and serine (Gly-Ser linkers). In particular embodiments, the linker sequence includes sets of glycine and serine repeats such as from one to ten repeats of (GlyxSery)n, wherein x and y are independently an integer from 0 to 10 provided that x and y are not both 0 and wherein n is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10). Particular examples include (Gly4Ser)n (SEQ ID NO: 262), F053-6006PCT / 23-211-WO-PCT (Gly3Ser)n(Gly4Ser)n (SEQ ID NO: 263), (Gly3Ser)n(Gly2Ser)n (SEQ ID NO: 264), and (Gly3Ser)n(Gly4Ser)1 (SEQ ID NO: 265). In particular embodiments, the linker is (Gly4Ser)4 (SEQ ID NO: 266), (Gly4Ser)3 (SEQ ID NO: 267), (Gly4Ser)2 (SEQ ID NO: 268), (Gly4Ser)1 (SEQ ID NO: 269), (Gly3Ser)2 (SEQ ID NO: 270), (Gly3Ser)1 (SEQ ID NO: 271), (Gly2Ser)2 (SEQ ID NO: 272) or (Gly2Ser)1, GGSGGGSGGSG (SEQ ID NO: 273), GGSGGGSGSG (SEQ ID NO: 274), or GGSGGGSG (SEQ ID NO: 275). [0157] Linkers that include one or more antibody hinge regions and/or immunoglobulin heavy chain constant regions, such as CH3 alone or a CH2CH3 sequence can also be used. Additional examples of linkers can be found in Chen et al., Adv Drug Deliv Rev.2013 Oct 15; 65(10): 1357– 1369. Linkers can be flexible, rigid, or semi-rigid, depending on the desired functional domain presentation to a target. [0158] In some situations, flexible linkers may be incapable of maintaining a distance or positioning of binding domains needed for a particular use. In these instances, rigid or semi-rigid linkers may be useful. Examples of rigid or semi-rigid linkers include proline-rich linkers. In particular embodiments, a proline-rich linker is a peptide sequence having more proline residues than would be expected based on chance alone. In particular embodiments, a proline-rich linker is one having at least 30%, at least 35%, at least 36%, at least 39%, at least 40%, at least 48%, at least 50%, or at least 51% proline residues. Particular examples of proline-rich linkers include fragments of proline-rich salivary proteins (PRPs). [0159] In particular embodiments, binding domains disclosed herein can be used to create bi-, tri, (or more) specific immune cell engaging molecules. Immune cell engaging molecules have at least one binding domain that binds a receptor on an immune cell and alters the activation state of the immune cell. [0160] Bispecific binding molecules with extended half-lives are described in, for example, US Patent No.8,921,528 and US Patent Publication No.2014/0308285. [0161] Because albumin has an extended serum half-life, it can be of use in improving the pharmacokinetics of administered binding domains. In particular embodiments, binding domains disclosed herein can be linked to albumin. In other particular embodiments, binding domains disclosed herein can be linked to albumin-binding domains (ABDs). ABDs include, for example, albumin-binding peptides, antibodies, antibody fragments, and designed ankyrin repeat proteins (DARPins). [0162] In particular embodiments, multi-domain binding molecules with extended half-lives include multi-domain binding molecules wherein at least one binding domain binds albumin. In particular embodiments, the multi-domain binding molecule that binds albumin includes a binding F053-6006PCT / 23-211-WO-PCT domain that binds DENV and/or ZIKV inked to a binding domain that binds albumin. [0163] In particular embodiments, an albumin-binding domain has the sequence: DITGAALLEAKEAAINELKQYGISDYYVTLINKAKTVEGVNALKAEILSALP (SEQ ID NO: 276). In particular embodiments, an albumin-binding domain includes a variant of the sequence as set forth in SEQ ID NO: 276, wherein the variant sequence is modified by at least one amino acid substitution selected from the group including: E12D, T29H-K35D, and A45D. [0164] In particular embodiments, an albumin-binding domain includes the sequence: LKEAKEKAIEELKKAGITSDYYFDLINKAKTVEGVNALKDEILKA (SEQ ID NO: 277). In particular embodiments, an albumin-binding domain includes a variant of the sequence as set forth in SEQ ID NO: 277, wherein the variant sequence is modified by at least one amino acid substitution selected from the group including: Y21, Y22, L25, K30, T31, E33, G34, A37, L38, E41, I42 and A45. [0165] Additional binding domains that bind albumin include CA645 as described in Adams et al., 2016 MAbs 8(7): 1336-1346 (see, e.g., Protein Data Bank accession codes 5FUZ and 5FUO); anti-HSA NanobodyTM (Ablynx, Ghent, Belgium), AlbudAbTM (GlaxoSmithKline, Brentford, United Kingdom), and other high-affinity albumin nanobody sequences as described in Shen et al., 2020 bioRxiv doi: https://doi.org/10.1101/2020.08.19.257725; Mester, et al., 2021 mAbs.13:1; Tijink et al., 2008 Mol Cancer Ther (7) (8) 2288-2297; and Roovers et al., Cancer Immunol Immunother 2007; 56: 303-317. [0166] In particular embodiments, multi-domain binding molecules are multimers of an antibody disclosed herein. Multimerization strategies include formation of a fusion protein using protein linkers or use of IgA or IgM constant regions as a multimerization scaffold. In certain aspects, multimerization is achieved by linking antibodies or binding domains of antibodies in a fusion protein with protein linkers. Fusion proteins include different protein domains linked to each other directly or through intervening linker segments such that the function of each included domain is retained. [0167] Certain examples include fusion protein with two or three copies of an antibody or binding domain disclosed herein, each linked with the Gly-Ser linker (Gly4Ser)4 (SEQ ID NO: 266). [0168] A “multimerization domain” is a domain that causes two or more proteins (monomers) to interact with each other through covalent and/or non-covalent association(s). Multimerization domains are highly conserved protein sequences that can include different types of sequence motifs such as leucine zipper, helix loop-helix, ankyrin and PAS (Feuerstein et al, Proc. Natl. Acad. Sci. USA, 91:10655-10659, 1994). Multimerization domains present in proteins can bind to form dimers, trimers, tetramers, pentamers, hexamers, heptamers, etc., depending on the number of F053-6006PCT / 23-211-WO-PCT units/monomers incorporated into the multimer, and/or homomultimers or heteromultimers, depending on whether the binding monomers are the same type or a different type (US Patent No.10030065). [0169] Dimerization domains can include protein sequence motifs such as coiled coils, acid patches, zinc fingers, calcium hands, a CH1-CL pair, an "interface" with an engineered "knob" and/or "protruberance" (US 5821333), leucine zippers (US 5932448), SH2 and SH3 (Vidal et al., Biochemistry, 43:7336- 44, 2004), PTB (Zhou et al., Nature, 378:584- 592, 1995), WW (Sudol Prog Biochys MoL Bio, 65:113-132, 1996), PDZ (Kim et al., Nature, 378: 85-88, 1995; Komau et al., Science, 269:1737-1740, 1995) and WD40 (Hu et al., J Biol Chem., 273:33489- 33494, 1998). Additional examples of molecules that contain dimerization domains/motifs are receptor dimer pairs such as the interleukin-8 receptor (IL-8R), integrin heterodimers such as LFA-I and GPIIIb/IIIa, dimeric ligand polypeptides such as nerve growth factor (NGF), neurotrophin-3 (NT- 3), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, PDGF members, and brain-derived neurotrophic factor (BDNF) (Arakawa et al., J Biol. Chem., 269:27833-27839, 1994; Radziejewski et al., Biochem, 32: 1350, 1993) and variants of some of these domains with modified affinities (PCT Publication No. WO 2012/001647). [0170] In particular embodiments, the sequence corresponding to a dimerization motif/domain includes the leucine zipper domain of Jun (US5932448; RIARLEEKVKTLKAQNSELASTANMLREQVAQLKQKVMN (SEQ ID NO: 278)), the dimerization domain of Fos (US 5932448; LTDTLQAETDQLEDKKSALQTEIANLLKEKEKLEFILAA (SEQ ID NO: 279)), a consensus sequence for a WW motif (PCT Publication No. WO 1997/037223), the dimerization domain of the SH2B adapter protein from GenBank Accession no. AAF73912.1 (Nishi et al., Mol Cell Biol, 25: 2607–2621, 2005; WREFCESHARAAALDFARRFRLYLASHPQYAGPGAEAAFSRRFAELFLQHFEAEVARAS (SEQ ID NO: 280)), the SH3 domain of IB1 from GenBank Accession no. AAD22543.1 (Kristensen el al., EMBO J., 25: 785–797, 2006; THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE (SEQ ID. NO: 281)), the PTB domain of human DOK-7 from GenBank Accession no. NP_005535.1 (Wagner et al., Cold Spring Harb Perspect Biol.5: a008987, 2013; LGEVHRFHVTVAPGTKLESGPATLHLCNDVLVLARDIPPAVTGQWKLSDLRRYGAVPSGFIFEG GTRCGYWAGVFFLSSAEGEQISFLFDCIVRGISPTKG (SEQ ID NO: 282)), the PDZ-like domain of SATB1 from UniProt Accession No. Q01826 (Galande et al., Mol Cell Biol. Aug; 21: 5591–5604, 2001; DCKEEHAEFVLVRKDMLFNQLIEMALLSLGYSHSSAAQAKGLIQVGKWNPVPLSYVTDAPDAT F053-6006PCT / 23-211-WO-PCT VADMLQDVYHVVTLKIQLHSCPKLEDLPPEQWSHTTVRNALKDLLKDMNQSS (SEQ ID NO: 283)), the WD40 repeats of APAF from UniProt Accession No. O14727 (Jorgensen et al., 2009. PLOS One.4(12):e8463; CAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHHNSRN ASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINT EDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIG NVSTPLMCLSESTNSTERNVMWGGCGSQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWD KKTEKLCGLIDCVHFLREVMVKETKIFSFSNDFTIQKLIETRTNKESKHKMSYSGRVKTLCLQKN TALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQ KEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE (SEQ ID NO: 284)), the PAS motif of the dioxin receptor from UniProt Accession No. I6L9E7 (Pongratz et al., Mol Cell Biol, 18:4079– 4088, 1998; DQELKHLILEAADGFLFIVSCETGRVVYVSDSVTPVLNQQQSEWFGSTLYDQVHPDDVDKLRE QLSTSENALTGR (SEQ ID NO: 285)) and the EF hand motif of parvalbumin from UniProt Accession No. P20472 (Jamalian et al., Int J Proteomics, 2014: 153712, 2014; LSAKETKMLMAAGDKDGDGKIGVDEFSTLVAES (SEQ ID NO: 286)). [0171] In particular embodiments, the dimerization domain can be a dimerization and docking domain (DDD) on one antibody and an anchoring domain (AD) on another antibody to facilitate a stably tethered structure. In particular embodiments, the DDD (DDD1 and DDD2) are derived from the regulatory subunits of a cAMP-dependent protein kinase (PKA), and the AD (AD1 and AD2) are derived from a specific region found in various A-kinase anchoring proteins (AKAPs) that mediates association with the R subunits of PKA. In particular embodiments, DDD1 includes the amino acid sequence: SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO: 287). In particular embodiments, DDD2 includes the amino acid sequence: CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO: 288). In particular embodiments, AD1 includes the amino acid sequence: QIEYLAKQIVDNAIQQA (SEQ ID NO: 289). In particular embodiments, AD2 includes the amino acid sequence: CGQIEYLAKQIVDNAIQQAGC (SEQ ID NO: 290). However, one skilled in the art will realize that other DDDs and ADs are known and can be used such as: the 4-helix bundle type DDD domains may be obtained from p53, DCoH (pterin 4 alpha carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1)) and HNF-1 (hepatocyte nuclear factor 1). Other AD sequences of potential use may be found in Patent Publication No. US2003/0232420A1. [0172] The X-type four-helix bundle dimerization motif that is a structural characteristic of the DDD (Newlon, et al. EMBO J.2001; 20: 1651-1662; Newlon, et al. Nature Struct Biol.1999; 3: F053-6006PCT / 23-211-WO-PCT 222-227) is found in other classes of proteins, such as the S100 proteins (for example, S100B and calcyclin), and the hepatocyte nuclear factor (HNF) family of transcriptional factors (for example, HNF-1a and HNF-1β). Over 300 proteins that are involved in either signal transduction or transcriptional activation also contain a module of 65-70 amino acids termed the sterile a motif (SAM) domain, which has a variation of the X-type four-helix bundle present on its dimerization interface. For S100B, this X-type four-helix bundle enables the binding of each dimer to two p53 peptides derived from the c-terminal regulatory domain (residues 367-388) with micromolar affinity (Rustandi, et al. Biochemistry.1998; 37: 1951-1960). Similarly, the N-terminal dimerization domain of HNF-1α (HNF-p1) was shown to associate with a dimer of DCoH (dimerization cofactor for HNF-1) via a dimer of HNF-p1 (Rose, et al. Nature Struct Biol.2000; 7: 744-748). In alternative embodiments, these naturally occurring systems can also be used to provide stable multimeric structures with multiple functions or binding specificities. Other binding events such as those between an enzyme and its substrate/inhibitor, for example, cutinase and phosphonates (Hodneland, et al. Proc Natl Acd Sci USA.2002; 99: 5048-5052), may also be utilized to generate the two associating components (the “docking” step), which are subsequently stabilized covalently (the “lock” step). [0173] In particular embodiments, dimerization of antibodies can be induced by a chemical inducer. This method of dimerization requires one antibody to contain a chemical inducer of dimerization binding domain 1 (CBD1) and the second antibody to contain the second chemical inducer of dimerization binding domain (CBD2), wherein CBD1 and CBD2 are capable of simultaneously binding to a chemical inducer of dimerization (CID). If the CID is rapamycin, CBD1 and CBD2 can be the rapamycin binding domain of FK-binding protein 12 (FKBP12) and the FKBP12-Rapamycin Binding (FRB) domain of mTOR. In particular embodiments, FKBP12 includes the sequence: MGVQVETISPGDGRTFPKRGQTCWHYTGMLEDGKKFDSSRDRNPFKFMLGKQEVIRGWEEG VAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLE (SEQ ID NO: 291). [0174] In particular embodiments, FRB includes the sequence: MASRILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRD LMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKLES (SEQ ID NO: 292). If the CID is FK506/cyclosporin fusion protein or a derivative thereof, CBD1 and CBD2 can be the FK506 (Tacrolimus) binding domain of FK-binding protein 12 (FKBP12) and the cyclosporin binding domain of cylcophilin A. If the CID is estrone/biotin fusion protein or a derivative thereof, CBD1 and CBD2 can be an oestrogen-binding domain (EBD) and a streptavidin binding domain. If the CID is dexamethasone/methotrexate fusion molecule or a derivative thereof, CBD1 and CBD2 F053-6006PCT / 23-211-WO-PCT can be a glucocorticoid-binding domain (GBD) and a dihydrofolate reductase (DHFR) binding domain. If the CID is O6-benzylguanine derivative/methotrexate fusion molecule or a derivative thereof, CBD1 and CBD2 can be an O6-alkylguanine-DNA alkyltransferase (AGT) binding domain and a dihydrofolate reductase (DHFR) binding domain. If the CID is RSL1 or a derivative thereof, CBD1 and CBD2 can be a retinoic acid receptor domain and an ecodysone receptor domain. If the CID is AP1903 or a derivative thereof, CBD1 and CBD2 can be the FK506 binding protein (FKBP12) binding domains including a F36V mutation. Use of the CID binding domains can also be used to alter the affinity to the CID. For instance, altering amino acids at positions 2095, 2098, and 2101 of FRB can alter binding to Rapamycin: KTW has high, KHF intermediate and PLW is low (Bayle et al, Chemistry & Biology 13, 99-107, January 2006). [0175] In particular embodiments, antibodies can multimerize using a transmembrane polypeptide derived from a FcεRI chain. In particular embodiments, an antibody can include a part of a FcεRI alpha chain and another antibody can include a part of an FcεRI beta chain or variant thereof such that said FcεRI chains spontaneously dimerize together to form a dimeric antibody. In particular embodiments, antibodies can include a part of a FcεRI alpha chain and a part of a FcεRI gamma chain or variant thereof such that said FcεRI chains spontaneously trimerize together to form a trimeric antibody, and in another embodiment the multi-chain antibody can include a part of FcεRI alpha chain, a part of FcεRI beta chain and a part of FcεRI gamma chain or variants thereof such that said FcεRI chains spontaneously tetramerize together to form a tetrameric antibody. [0176] In particular embodiments, additional methods of causing dimerization can be utilized. Additional modifications to generate a dimerization domain in antibody could include: replacing the C-terminus domain with murine counterparts; generating a second interchain disulfide bond in the C-terminus domain by introducing a second cysteine residue into both antibodies; swapping interacting residues in each of the antibodies in the C-terminus domains (“knob-in-hole”); and fusing the variable domains of the antibodies directly to CD3ζ (CD3ζ fusion) (Schmitt et al., Hum. Gene Ther.2009.20:1240-1248). [0177] Particular embodiments can utilize multimerization domains, such as C4b multimerization domains or ferritin multimerization domains. Full-length native C4b includes seven α-chains linked together by a multimerization (i.e., heptamerization) domain at the C-terminus of the α-chains. Blom et al., (2004) Mol Immunol 40: 1333–1346. Ferritin is an iron storage protein found in almost all living organisms, and has been extensively studied and engineered for a number of biochemical/biomedical purposes (US 20090233377; Meldrum, et al. Science 257, 522-523 (1992); U.S. 20110038025; Yamashita, Biochim Biophys Acta 1800, 846-857 (2010), including F053-6006PCT / 23-211-WO-PCT as a multimerizing vaccine platform for displaying peptide epitopes (US 20060251679 (2006); Li, et al. Industrial Biotechnol 2, 143-147 (2006)). [0178] Mutlimerization with encapsulin and lumazine synthase can also be performed. Both can be linked to antibodies to create self-assembling 60mer particles (Jardine et al., 2013, Science 340, 711-716 and Kanekiyo et al., 2015, Cell 162, 1090-1100). [0179] Multimerized antibodies and antibody-like molecules such as IgA and IgM antibodies have emerged as promising drug candidates in the fields of, e.g., immuno-oncology and infectious diseases allowing for improved specificity, improved avidity, and the ability to bind to multiple binding targets. See, e.g., U.S. Patent Nos.9,951,134, 10,400,038, and 9,938,347, U.S. Patent Application Publication Nos. US20190100597A1, US20180118814A1, US20180118816A1, US20190185570A1, and US20180265596A1, and PCT Publication Nos. WO 2018/017888, WO 2018/017763, WO 2018/017889, WO 2018/017761, and WO 2019/165340. [0180] Particular embodiments include using IgA and IgM constant region domains to allow the binding portion of molecules provided herein to readily multimerize into dimers, pentamers or hexamers. Basic immunoglobulin structures in vertebrate systems are described above and are well understood. (See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd ed.1988). [0181] Immunoglobulin A (IgA), as the major class of antibody present in the mucosal secretions of most mammals, represents a key first line of defense against invasion by inhaled and ingested pathogens. IgA is also found at significant concentrations in the serum of many species, where it functions as a second line of defense mediating elimination of pathogens that have breached the mucosal surface. Receptors specific for the Fc region of IgA, FcaR, are key mediators of IgA effector function. Native IgA is a tetrameric protein including two identical light chains (κ or λ) and two identical heavy chains. IgA, similarly to IgG, contains three constant domains (CA1-CA3), with a hinge region between the CA1 and CA2 domains. The main difference between IgA1 and IgA2 resides in the hinge region that lies between the two Fab arms and the Fc region. IgA1 has an extended hinge region due to the insertion of a duplicated stretch of amino acids, which is absent in IgA2. Both forms of IgA have the capacity to form dimers, in which two monomer units, are arranged in an end-to-end configuration stabilized by disulfide bridges and incorporation of a J-chain. J-chains are also part of IgM pentamers and are discussed in more detail below. In particular embodiments, binding domains disclosed herein can be expressed as an IgA antibody. In particular embodiments, binding domains disclosed herein can be expressed as an IgM antibody. In particular embodiments, binding domains disclosed herein can be expressed as an IgG antibody. F053-6006PCT / 23-211-WO-PCT [0182] Both IgA and IgM (discussed further below in relation to pentamers and hexamers) possess an 18-amino acid extension in the C terminus called the "tail-piece" (tp). The IgA and IgM tp is highly conserved among various animal species. The conserved penultimate cysteine residue in the IgA and IgM tp has been demonstrated to be involved in multimerization by forming a disulfide bond between heavy chains to permit formation of a multimer. Both tp contain an N- linked carbohydrate addition site, the presence of which is required for dimer formation in IgA and J-chain incorporation and pentamer formation in IgM. However, the structure and composition of the N-linked carbohydrates in the tp differ, suggesting differences in the accessibility of the glycans to processing by glycosyltransferases. Particularly, the IgA (atp) and IgM (μtρ) tp differ at seven amino acid positions. [0183] The human IgA1 constant region typically includes the amino acid sequence as set forth in SEQ ID NO: 258. Referring to this SEQ ID NO: 258, the human CA1 domain extends from amino acid 6 to amino acid 98; the human IgA1 hinge region extends from amino acid 102 to amino acid 124, the human CA2 domain extends from amino acid 125 to amino acid 219, the human CA3 domain extends from amino acid 228 to amino acid 330, and the tp extends from amino acid 331 to amino acid 352. [0184] The human IgA2 constant region typically includes the amino acid sequence as set forth in SEQ ID NO: 259. Referring to this SEQ ID NO: 259, the human CA1 domain extends from amino acid 6 to amino acid 98, the human IgA2 hinge region extends from amino acid 102 to amino acid 111, the human CA2 domain extends from amino acid 113 to amino acid 206, the human CA3 domain extends from amino acid 215 to amino acid 317, and the tp extends from amino acid 318 to amino acid 340. [0185] As indicated, two IgA binding units can form a complex with two additional polypeptide chains, the J chain (e.g., SEQ ID NO: 305, the mature human J chain) and the secretory component to form a bivalent secretory IgA (sIgA)-derived binding molecule. An exemplary precursor secretory component includes the sequence MLLFVLTCLLAVFPAISTKSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGC ITLISSEGYVSSKYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVS QGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRL DIQGTGQLLFSVVINQLRLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFH CALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKED AGRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIK YWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTN GDTLWRTTVEIKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALP F053-6006PCT / 23-211-WO-PCT SQDEGPSKAFVNCDENSRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAA GSRDVSLAKADAAPDEKVLDSGFREIENKAIQDPRLFAEEKAVADTRDQADGSRASVDSGSSE EQGGSSRALVSTLVPLGLVLAVGAVAVGVARARHRKNVDRVSIRSYRTDISMSDFENSREFGA NDNMGASSITQETSLGGKEEFVATTESTTETKEPKKAKRSSKEEAEMAYKDFLLQSSTVAAEA QDGPQEA (SEQ ID NO: 293). An exemplary mature secretory component includes KSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSSKYAGR ANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVSQGPGLLNDTKVYTVDL GRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQL RLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCR QSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQE GSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLL VDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTNGDTLWRTTVEIKIIEGEP NLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALPSQDEGPSKAFVNCDEN SRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAAGSRDVSLAKADAAPDEK VLDSGFREIENKAIQDPR (SEQ ID NO: 294). While not wishing to be bound by theory, and as indicated above, the assembly of two IgA binding units into a dimeric IgA-derived binding molecule is thought to involve the CA3 and tp domains. See, e.g., Braathen, R., el al., J. Biol. Chem. 277:42755-42762 (2002). Accordingly, a multimerizing dimeric IgA-derived binding molecule provided in this disclosure typically includes IgA constant regions that include at least the CA3 and tp domains. [0186] An engineered IgA heavy chain constant region can additionally include a CA2 domain or a fragment thereof, an IgA hinge region or fragment thereof, a CA1 domain or a fragment thereof, and/or other IgA (or other immunoglobulin, e.g., IgG) heavy chain domains, including, e.g., an IgG hinge region. In certain embodiments, a binding molecule as provided herein can include a complete IgA heavy chain constant region (e.g., SEQ ID NO: 258 or SEQ ID NO: 259), or a variant, derivative, or analog thereof. [0187] In particular embodiments, the IgA heavy chain constant regions can include amino acids 125 to 353 of SEQ ID NO: 258 or amino acids 113 to 340 of SEQ ID NO: 259. In particular embodiments, the IgA heavy chain constant regions can each further include an IgA or IgG hinge region situated N-terminal to the IgA CA2 domains. For example, the IgA heavy chain constant regions can include amino acids 102 to 353 of SEQ ID NO: 258 or amino acids 102 to 340 of SEQ ID NO: 259. In particular embodiments, the IgA heavy chain constant regions can each further include an IgA CA1 domain situated N-terminal to the IgA hinge region. [0188] Each of the strategies discussed above can be used to create IgA antibody-based dimers. F053-6006PCT / 23-211-WO-PCT [0189] Particular embodiments include IgM immunoglobulin constant region domains that allow the binding portion of molecules provided herein to readily multimerize into pentamers or hexamers. [0190] Particular embodiments include IgM constant regions (or variants thereof). These embodiments have the ability to form hexamers, or in association with a J-chain, form pentamers. Embodiments with an IgM constant region typically include at least the Cµ4-tp domains of the IgM constant region but can include heavy chain constant region domains from other antibody isotypes, e.g., IgG, from the same species or from a different species. In particular embodiments, one or more constant region domains can be deleted so long as the IgM antibody is capable of forming hexamers and/or pentamers. Thus, an IgM antibody can be, e.g., a hybrid IgM/IgG antibody or can be a “multimerizing fragment” of an IgM-derived binding molecule. [0191] The assembly of five or six IgM binding units into a pentameric or hexameric IgM antibody is thought to involve the Cµ4 and tp domains. See, e.g., Braathen, R., et al., J Biol. Chem. 277:42755-42762 (2002). Accordingly, a pentameric or hexameric IgM antibody described in this disclosure typically includes at least the Cµ4 and/or tp domains (also referred to herein collectively as Cµ4-tp). A “multimerizing fragment” of an IgM heavy chain constant region thus includes at least the Cµ4-tp domains. An IgM heavy chain constant region can additionally include a Cµ3 domain or a fragment thereof, a Cµ2 domain or a fragment thereof, a Cµ1 domain or a fragment thereof, and/or other IgM heavy chain domains. [0192] Five IgM monomers form a complex with a J-chain to form a native IgM molecule. The J- chain is considered to facilitate polymerization of μ chains before IgM is secreted from antibody- producing cells. Sequences for the human IGJ gene are known in the art, for example, (IGMT Accession: J00256, X86355, M25625, AJ879487). The J chain establishes the disulfide bridges between IgM antibodies to form multimeric structures such as pentamers. See, for example, Sorensen et al. International Immunology, (2000), pages 19-27. While crystallization of IgM has proved to be notoriously challenging, Czajkowsky and Shao (PNAS 106(35): 14960-14965, 2009) published a homology-based structural model of IgM, based on the structure of the IgE Fc domain and the known disulfide pairings. The authors report that the human IgM pentamer is a mushroom- shaped molecule with a flexural bias. The IgM heavy (μ) chain contains five N-linked glycosylation sites: Asn-171, Asn-332, Asn-395, Asn-402 and Asn-563. In an IgM antibody where each binding unit is bivalent, the binding molecule itself can have 10 or 12 valencies. [0193] The Kabat numbering system for the human IgM constant domain can be found in Kabat, et. al. “Tabulation and Analysis of Amino acid and nucleic acid Sequences of Precursors, V- Regions, C-Regions, J-Chain, T-Cell Receptors for Antigen, T-Cell Surface Antigens, b-2 F053-6006PCT / 23-211-WO-PCT Microglobulins, Major Histocompatibility Antigens, Thy-l, Complement, C-Reactive Protein, Thymopoietin, Integrins, Post-gamma Globulin, a-2 Macroglobulins, and Other Related Proteins,” U.S. Dept of Health and Human Services (1991). IgM constant regions can be numbered sequentially (i.e., amino acid #1 starting with the first amino acid of the constant region) or by using the Kabat numbering scheme. [0194] A “full length IgM antibody heavy chain” is a polypeptide that includes, in N- terminal to C- terminal direction, an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CM1 or Cµ1), an antibody heavy chain constant domain 2 (CM2 or Cµ2), an antibody heavy chain constant domain 3 (CM3 or Cµ3), and an antibody heavy chain constant domain 4 (CM4 or Cµ4) that can include a tp, as indicated above. [0195] In particular embodiments, each binding unit of a multimeric binding molecule as provided herein includes two IgM heavy chain constant regions or multimerizing fragments or variants thereof, each including at least an IgM Cµ4 domain and an IgM tp domain. In certain embodiments the IgM heavy chain constant regions can each further include an IgM Cµ3 domain situated N- terminal to the IgM Cµ4 and IgM tp domains. [0196] In particular embodiments, the IgM heavy chain constant regions can each further include an IgM Cµ2 domain situated N-terminal to the IgM Cµ3 domain. Exemplary multimeric binding molecules provided herein include human IgM constant regions that include the wild-type human Cµ2, Cµ3, and Cµ4-tp domains as follows: VIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAE AKESGPTTYKVTSTLTIKESDWLSQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSF ASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWN SGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADV FVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNR VTERTVDKSTGKPTLYNVSLVMSDTAGTCY (SEQ ID NO: 295). [0197] In certain IgM-derived multimeric binding molecules as provided herein each IgM constant region can include, instead of, or in addition to an IgM Cµ2 domain, an IgG hinge region or functional variant thereof situated N-terminal to the IgM Cµ3 domain. An exemplary variant human IgG1 hinge region amino acid sequence in which the cysteine at position 6 is substituted with serine is VEPKSSDKTHTCPPCPAP (SEQ ID NO: 296). An exemplary IgM constant region of this type includes the variant human IgG1 hinge region fused to a multimerizing fragment of the human IgM constant region including the Cµ3, Cµ4, and tp domains, and includes the amino acid sequence: VEPKSSDKTHTCPPCPAPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNG F053-6006PCT / 23-211-WO-PCT EAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHR PDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPG RYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY (SEQ ID NO: 297). [0198] Human IgM constant regions, and also certain non-human primate IgM constant regions, as provided herein typically include five (5) naturally-occurring asparagine (N)-linked glycosylation motifs or sites. As used herein “an N-linked glycosylation motif” includes the amino acid sequence N-X1-S/T, wherein N is asparagine, X1 is any amino acid except proline (P), and S/T is serine (S) or threonine (T). The glycan is attached to the nitrogen atom of the asparagine residue. See, e.g., Drickamer K, Taylor ME (2006), Introduction to Glycobiology (2nd ed.). Oxford University Press, USA. N-linked glycosylation motifs occur in the human IgM heavy chain constant regions of SEQ ID NO: 260 or SEQ ID NO: 261 starting at positions 46 (“N1”), 209 (“N2”), 272 (“N3”), 279 (“N4”), and 440 (“N5”). These five motifs are conserved in non-human primate IgM heavy chain constant regions, and four of the five are conserved in the mouse IgM heavy chain constant region. Each of these sites in the human IgM heavy chain constant region, except for N4, can be mutated to prevent glycosylation at that site, while still allowing IgM expression and assembly into a hexamer or pentamer. [0199] The human IgM heavy chain constant region typically includes the amino acid sequence as set forth in SEQ ID NO: 260; identical to, e.g., GenBank Accession Nos. pir||S37768, CAA47708.1, and CAA47714.1). Referring to this SEQ ID NO: 260, the human Cµ1 region ranges from amino acid 5 to amino acid 102; the human Cµ2 region ranges from amino acid 114 to amino acid 205, the human Cµ3 region ranges from amino acid 224 to amino acid 319, the Cµ4 region ranges from amino acid 329 to amino acid 430, and the tp ranges from amino acid 431 to amino acid 453. [0200] In particular embodiments, an IgM heavy chain constant region includes the sequence: GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL GQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDS VTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTI SRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSA PMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLV MSDTAGTCY (SEQ ID NO: 261; (UniProt ID P01871)—allele IGHM*04). This sequence differs from SEQ ID NO: 260 by one amino acid at position 191. F053-6006PCT / 23-211-WO-PCT [0201] Other forms of the human IgM constant region with minor sequence variations exist, including GenBank Accession Nos. P01871.4, CAB37838.1, and pir||MHHU. The amino acid substitutions, insertions, and/or deletions at positions corresponding to SEQ ID NO: 260 described herein can likewise be incorporated into alternate human IgM sequences, as well as into IgM constant region amino acid sequences of other species, e.g., those shown in FIG.1 of PCT/US2019/020374. [0202] In certain aspects, a variant human IgM constant region includes an amino acid substitution corresponding to the wild-type human IgM constant region at position P311, P313, R344, E345, S401, E402, and/or E403 of SEQ ID NO: 260. These positions correspond to the Kabat numbering system as follows: S401 of SEQ ID NO: 260 corresponds to S524 of Kabat; E402 of SEQ ID NO: 260 corresponds to E525 of Kabat; E403 of SEQ ID NO: 260 corresponds to E526 of Kabat; R344 of SEQ ID NO: 260 corresponds to R467 of Kabat; and E345 of SEQ ID NO: 260 corresponds to E468 of Kabat. [0203] In particular embodiments, “corresponds to” means the designated position of SEQ ID NO: 260 and the amino acid in the sequence of the IgM constant region of any species which is homologous to the specified position. See FIG.1 of PCT/US2019/020374. [0204] In particular embodiments, P311 of SEQ ID NO: 260 can be substituted, e.g., with alanine (P311A), serine (P311S), or glycine (P311G) and/or P313 of SEQ ID NO: 260 can be substituted, e.g., with alanine (P313A), serine (P313S), or glycine (P313G). P311 and P313 of SEQ ID NO: 260 can be substituted with alanine (P311A) and serine (P313S), respectively as shown in the following sequence: (mutations in bold underline) GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLASSLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 298). [0205] In certain aspects, S401 of SEQ ID NO: 260 can be substituted with any amino acid. In certain aspects, S401 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP F053-6006PCT / 23-211-WO-PCT RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVAEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 299). [0206] In certain aspects, E402 of SEQ ID NO: 260 can be substituted with any amino acid. In certain aspects, E402 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSAEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 300). [0207] In certain aspects, E403 of SEQ ID NO: 260 can be substituted with any amino acid. In certain aspects, E403 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEAEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 301). [0208] In certain aspects, R344 of SEQ ID NO: 260 can be substituted with any amino acid. In certain aspects, R344 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL F053-6006PCT / 23-211-WO-PCT SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLAESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 302). [0209] In certain aspects, E345 of SEQ ID NO: 260 can be substituted with any amino acid. In certain aspects, E345 of SEQ ID NO: 260 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline): GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRASATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 303). [0210] As indicated, five IgM binding units can form a complex with a J-chain to form a pentameric IgM antibody. The precursor form of the human J-chain includes: MKNHLLFWGVLAVFIKAVHVKAQEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLN NRENISDPTSPLRTRFVYHLSDLCKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKC YTAVVPLVYGGETKMVETALTPDACYPD (SEQ ID NO: 304). The signal peptide extends from amino acid 1 to amino acid 22 of SEQ ID NO: 304 and the mature human J-chain extends from amino acid 23 to amino acid 159 of SEQ ID NO: 304. [0211] The mature human J-chain includes the amino acid sequence QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 305). [0212] The term “J-chain” as used herein refers to the J-chain of native sequence IgM or IgA antibodies of any animal species. When specified, it can also refer to any functional fragment thereof, derivative thereof, and/or variant thereof, including a mature human J-chain amino acid sequence provided herein as SEQ ID NO: 305. A functional fragment, derivative, and/or variant of a J-chain has at least 90% sequence identity to the reference J-chain and retains the multimerizing function of the reference J-chain. [0213] In certain aspects, the J-chain of the IgM antibody as provided herein includes an amino F053-6006PCT / 23-211-WO-PCT acid substitution at the amino acid position corresponding to amino acid Y102, T103, N49 or S51 of SEQ ID NO: 305. [0214] By “an amino acid corresponding to” a position of SEQ ID NO: 305 is meant the amino acid in the sequence of the J-chain of any species which is homologous to the referenced residue in the human J-chain. For example, the position corresponding to Y102 in SEQ ID NO: 305 is conserved in the J-chain amino acid sequences of at least 43 other species. The position corresponding to T103 in SEQ ID NO: 305 is conserved in the J-chain amino acid sequences of at least 37 other species. The positions corresponding to N49 and S51 in SEQ ID NO: 305 are conserved in the J-chain amino acid sequences of at least 43 other species. See FIG.4 of U.S. Patent No.9,951,134 and FIG.2 of PCT/US2019/020374. [0215] In certain aspects, the amino acid corresponding to Y102 of SEQ ID NO: 305 can be substituted with any amino acid. In certain aspects, the amino acid corresponding to Y102 of SEQ ID NO: 305 can be substituted with alanine (alanine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCATYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 306), With serine (serine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCSTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 307), Or with arginine (arginine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCRTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 308). [0216] In certain aspects, the amino acid corresponding to T103 of SEQ ID NO: 305 can be substituted with any amino acid. In a particular aspect, the amino acid corresponding to T103 of SEQ ID NO: 305 can be substituted with alanine as follows (alanine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYAYDRNKCYTAVVPLVYGGETKMVETALTP DACYPD (SEQ ID NO: 309). [0217] In certain aspects, the variant J-chain or functional fragment thereof of the IgM antibody as provided herein includes an amino acid substitution at the amino acid position corresponding to amino acid N49 or amino acid S51 of SEQ ID NO: 305, provided that S51 is not substituted F053-6006PCT / 23-211-WO-PCT with threonine (T), or wherein the J-chain includes amino acid substitutions at the amino acid positions corresponding to both amino acids N49 and S51 of SEQ ID NO: 305. [0218] The amino acids corresponding to N49 and S51 of SEQ ID NO: 305 along with the amino acid corresponding to 150 of SEQ ID NO: 305 include an N-linked glycosylation motif in the J- chain. Accordingly, mutations at N49 and/or S51 (with the exception of a single threonine substitution at S51) can prevent glycosylation at this motif. In certain aspects, the asparagine at the position corresponding to N49 of SEQ ID NO: 305 can be substituted with any amino acid. In certain aspects, the asparagine at the position corresponding to N49 of SEQ ID NO: 305 can be substituted with alanine (A), glycine (G), threonine (T), serine (S) or aspartic acid (D). In a particular aspect the position corresponding to N49 of SEQ ID NO: 305 can be substituted with alanine (A). In a particular aspect the J-chain is a variant human J-chain and includes the amino acid sequence: QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNREAISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 310). [0219] In certain aspects, the serine at the position corresponding to S51 of SEQ ID NO: 305 can be substituted with any amino acid except threonine. In certain aspects, the serine at the position corresponding to S51 of SEQ ID NO: 305 can be substituted with alanine (A) or glycine (G). In a particular aspect the position corresponding to S51 of SEQ ID NO: 305 can be substituted with alanine (A). In a particular aspect the variant J-chain or functional fragment thereof is a variant human J-chain and includes the amino acid sequence: EDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENIADPTSPLRTRFVYHLSDLC KKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPDA CYPD (SEQ ID NO: 311). [0220] Particular embodiments include a heterologous polypeptide (e.g., a single-domain antibody binding domain) fused to the J-chain or functional fragment thereof via a peptide linker, e.g., a peptide linker including at least 5 amino acids, but no more than 25 amino acids. In certain aspects, the peptide linker includes (GGGGS)n (SEQ ID NO: 262) wherein n is 1-5. [0221] A single-domain antibody binding domain can be introduced into the J-chain at any location that allows the binding of the binding domain to its binding target without interfering with J-chain function or the function of an associated IgA, IgM, or hybrid IgG antibody. Insertion locations include at or near the C- terminus, at or near the N-terminus or at an internal location that, based on the three-dimensional structure of the J-chain, is accessible. In certain aspects, the antigen-binding domain can be introduced into the mature human J-chain of SEQ ID NO: 305 F053-6006PCT / 23-211-WO-PCT between cysteine residues 92 and 101 of SEQ ID NO: 305. In a further aspect, the antigen-binding domain can be introduced into the human J-chain of SEQ ID NO: 305 at or near a glycosylation site. In a further aspect, the antigen-binding domain can be introduced into the human J-chain of SEQ ID NO: 305 within 10 amino acid residues from the C- terminus, or within 10 amino acids from the N-terminus. [0222] In particular embodiments, the single-domain antibody is introduced into the native human J-chain sequence of SEQ ID NO: 305 by chemical or chemo-enzymatic derivatization. In particular embodiments, the single-domain antibody is introduced into the native human J-chain sequence of SEQ ID NO: 305 by a chemical linker. In some embodiments, the chemical linker is a cleavable or non-cleavable linker. In particular embodiments, the cleavable linker is a chemically labile linker or an enzyme-labile linker. In some embodiments, the linker is selected from the group including N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-l-carboxylate (SMCC), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), iminothiolane (IT), afunctional derivatives of imidoesters, active esters, aldehydes, bis-azido compounds, bis-diazonium derivatives, diisocyanates, and bis-active fluorine compounds. In particular embodiments, the modified J-chain is modified by insertion of an enzyme recognition site, and by post-translationally attaching a binding moiety at the enzyme recognition site through a peptide or non-peptide linker. [0223] In certain aspects the modified J-chain can include the formula X[Ln]J or J[Ln]X, where J includes a mature native J-chain or functional fragment thereof, X includes a heterologous binding domain, and [Ln] is a linker sequence including n amino acids, where n is a positive integer from 1 to 100, 1 to 50, or 1 to 25. In certain aspects N is 5, 10, 15, or 20. [0224] J-chains from the following species can also be used in certain embodiments: Pan troglodytes, Pongo abelii, Callithrix jacchus, Macaca mulatta, Papio Anubis, Saimiri boliviensis, Tupaia chinensis, Tursiops truncatus, Orcinus orca, Loxodonta Africana, Leptonychotes weddellii, Ceratotherium simum, Felis catus, Canis familiaris, Ailuropoda melanoleuca, Mustela furo, Equus caballus, Cavia porcellus, Camelus ferus, Capra hircus, Chinchilla lanigera, Mesocricetus auratus, Ovis aries, Myotis lucifugus, Pantholops hodgsonii, Bos taurus, Mus musculus, Rattus norvegicus, Echinops telfairi, Oryctolagus cuniculus, Monodelphis domestica, Alligator mississippiensis, Chrysemys picta, Sarcophilus harrisii, Ornithorhynchus anatinus, Melopsittacus undulatus, Anas platyrhynchos, Gallus gallus, Meleagris gallopavo, Falco peregrinus, Zonotrichia albicollis, and Pteropus alecto. [0225] (IV) Recombinant Production. In particular embodiments, the binding domains disclosed herein are produced from a gene using a protein expression system. Protein expression systems F053-6006PCT / 23-211-WO-PCT can utilize DNA constructs (e.g., chimeric genes, expression cassettes, expression vectors, recombination vectors) including a nucleic acid sequence encoding the protein or proteins of interest operatively linked to appropriate regulatory sequences. In particular embodiments, such DNA constructs are not naturally-occurring DNA molecules and are useful for introducing DNA into host-cells to express selected proteins of interest. In particular embodiments, a DNA construct that encodes a vaccine protein can be inserted into cells (e.g., bacterial, mammalian, insect, etc.), which can produce the vaccine protein encoded by the DNA construct. [0226] Operatively linked refers to the linking of DNA sequences (including the order of the sequences, the orientation of the sequences, and the relative spacing of the various sequences) in such a manner that the encoded protein is expressed. Methods of operatively linking expression control sequences to coding sequences are well known in the art. See, e.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, N. Y., 1982; and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, N. Y., 1989. [0227] Expression control sequences are DNA sequences involved in any way in the control of transcription or translation. Suitable expression control sequences and methods of making and using them are well known in the art. Expression control sequences generally include a promoter. The promoter may be inducible or constitutive. It may be naturally-occurring, may be composed of portions of various naturally-occurring promoters, or may be partially or totally synthetic. Guidance for the design of promoters is provided by studies of promoter structure, such as that of Harley and Reynolds, Nucleic Acids Res., 15, 2343-2361, 1987. Also, the location of the promoter relative to the transcription start may be optimized. See, e.g., Roberts et al., Proc. Natl. Acad. Sci. USA, 76:760-764, 1979. [0228] The promoter may include, or be modified to include, one or more enhancer elements. In particular embodiments, the promoter will include a plurality of enhancer elements. Promoters including enhancer elements can provide for higher levels of transcription as compared to promoters that do not include them. [0229] For efficient expression, the coding sequences can be operatively linked to a 3' untranslated sequence. In particular embodiments, the 3' untranslated sequence can include a transcription termination sequence and a polyadenylation sequence. The 3' untranslated region can be obtained, for example, from the flanking regions of genes. [0230] In particular embodiments, a 5' untranslated leader sequence can also be employed. The 5' untranslated leader sequence is the portion of an mRNA that extends from the 5' CAP site to the translation initiation codon. [0231] In particular embodiments, a “hisavi” tag can be added to the N-terminus or C-terminus of F053-6006PCT / 23-211-WO-PCT a gene by the addition of nucleotides coding for the Avitag amino acid sequence, “GLNDIFEAQKIEWHE” (SEQ ID NO: 312), as well as the 6xhistidine tag “HHHHHH” (SEQ ID NO: 313). The Avitag avidity tag can be biotinylated by a biotin ligase to allow for biotin-avidin or biotin-streptavidin based interactions for protein purification, as well as for immunobiology (such as immunoblotting or immunofluorescence) using anti-biotin antibodies. The 6xhistidine tag allows for protein purification using Ni-2+ affinity chromatography. Other tags include: Flag tag (DYKDDDDK; SEQ ID NO: 314), Xpress tag (DLYDDDDK; SEQ ID NO: 315), Calmodulin tag (KRRWKKNFIAVSAANRFKKISSSGAL; SEQ ID NO: 316), Polyglutamate tag, HA tag (YPYDVPDYA; SEQ ID NO: 317), Myc tag (EQKLISEEDL; SEQ ID NO: 318), Strep tag (which refers the original STREP® tag (WRHPQFGG; SEQ ID NO: 319), STREP® tag II (WSHPQFEK SEQ ID NO: 320 (IBA Institut fur Bioanalytik, Germany); see, e.g., US 7,981,632), Softag 1 (SLAELLNAGLGGS; SEQ ID NO: 321), Softag 3 (TQDPSRVG; SEQ ID NO: 322), and V5 tag (GKPIPNPLLGLDST; SEQ ID NO: 323). [0232] In particular embodiments, the binding domains disclosed herein can be produced using, for example, human suspension cells and/or the Daedalus expression system as described in Pechman et al., Am J Physiol 294: R1234-R1239, 2008. The Daedalus system utilizes inclusion of minimized ubiquitous chromatin opening elements in transduction vectors to reduce or prevent genomic silencing and to help maintain the stability of decigram levels of expression. This system can bypass tedious and time-consuming steps of other protein production methods by employing the secretion pathway of serum-free adapted human suspension cell lines, such as 293 Freestyle. Using optimized lentiviral vectors, yields of 20-100 mg/l of correctly folded and post-translationally modified, endotoxin-free protein of up to 70 kDa in size, can be achieved in conventional, small- scale (100 ml) culture. At these yields, most proteins can be purified using a single size-exclusion chromatography step, immediately appropriate for use in structural, biophysical or therapeutic applications. Bandaranayake et al., Nucleic Acids Res., 2011 (Nov); 39(21). In some instances, purification by chromatography may not be needed due to the purity of manufacture according the methods described herein. [0233] In particular embodiments, the DNA constructs can be introduced into a cell by transfection, a technique that involves introduction of foreign DNA into the nucleus of eukaryotic cells. In particular embodiments, the proteins can be synthesized by transient transfection (DNA does not integrate with the genome of the eukaryotic cells, but the genes are expressed for 24- 96 hours). Various methods can be used to introduce the foreign DNA into the host-cells, and transfection can be achieved by chemical-based means including by the calcium phosphate, by dendrimers, by liposomes, and by the use of cationic polymers. Non-chemical methods of F053-6006PCT / 23-211-WO-PCT transfection include electroporation, sono-poration, optical transfection, protoplast fusion, and hydrodynamic delivery. In particular embodiments, transfection can be achieved by particle-based methods including gene gun where the DNA construct is coupled to a nanoparticle of an inert solid which is then "shot" directly into the target-cell's nucleus. Other particle-based transfection methods include magnet assisted transfection and impalefection. [0234] Nucleic acid sequences encoding proteins disclosed herein can be derived by those of ordinary skill in the art. Nucleic acid sequences can also include one or more of various sequence polymorphisms, mutations, and/or sequence variants (e.g., splice variants or codon optimized variants). In particular embodiments, the sequence polymorphisms, mutations, and/or sequence variants do not affect the function of the encoded protein. [0235] Sequence information provided by public databases can be used to identify additional gene and protein sequences that can be used with the systems and methods disclosed. [0236] (V) Antibody Conjugates. Antibody conjugates include binding domains disclosed herein linked to another molecule, other than an additional binding domain. Examples of antibody conjugates include antibody-particle conjugates, antibody-drug conjugates (ADCs), and antibody- detectable label conjugates. [0237] Antibody-particle conjugates include an antibody linked to a particle. In particular embodiments, particles include microparticles, nanoparticles, nanoshells, nanobeads, microbeads, or nanodots. Particles can include, for example, latex beads, polystyrene beads, fluorescent beads, and/or colored beads, and can be made from organic matter and/or inorganic matter. They can be made of any suitable materials that allow for the conjugation of capture proteins, such as antibodies made from the binding domains disclosed herein, to their surface. Examples of suitable materials include: ceramics, glass, polymers, and magnetic materials. Suitable polymers include polystyrene, poly-(methyl methacrylate), poly-(lactic acid), (poly-(lactic- co -glycolic acid)), polyesters, polyethers, polyolefϊns, polyalkylene oxides, polyamides, polyurethanes, polysaccharides, celluloses, polyisoprenes, methylstyrene, acrylic polymers, thoria sol, latex, nylon, Teflon cross- linked dextrans (e.g., Sepharose), chitosan, agarose, and cross-linked micelles. Additional examples include carbon graphited, titanium dioxide, and paramagnetic materials. See, e.g., "Microsphere Detection Guide" from Bangs Laboratories, Fishers Ind. In particular embodiments, microparticles can be made of one or more materials. In particular embodiments, microparticles are paramagnetic microparticles. Particular embodiments utilize carboxy-modified polystyrene latex (CML) flow cytometry beads and/or magnetic MagPlex® (Luminex, Austin, TX) flow cytometry beads. In particular embodiments, particles can carry a payload. F053-6006PCT / 23-211-WO-PCT [0238] Antibody-drug conjugates allow for the targeted delivery of a drug moiety to an infected cell or viral particle, in particular embodiments intracellular accumulation therein, where systemic administration of unconjugated drugs may result in unacceptable levels of toxicity to normal cells (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387). [0239] In particular embodiments, antibody-drug conjugates refer to targeted molecules which combine properties of both antibodies and drugs by targeting potent drugs to sites of infection. The drug moiety (D) of an antibody-drug conjugate may include any compound, moiety or group that has a toxic effect. Exemplary drugs include antivirals or anti-infection agents. The drug may be obtained from essentially any source; it may be synthetic or a natural product isolated from a selected source, e.g., a plant, bacterial, insect, mammalian or fungal source. The drug may also be a synthetically modified natural product or an analogue of a natural product. [0240] In particular embodiments, the antibody-drug conjugates include an antibody conjugated, i.e., covalently attached, to the drug moiety. In particular embodiments, the antibody is covalently attached to the drug moiety through a linker. A linker can include any chemical moiety that is capable of linking an antibody, antibody fragment (e.g., antigen binding fragments) or functional equivalent to another moiety, such as a drug moiety. Linkers can be susceptible to cleavage (cleavable linker), such as, acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage, at conditions under which the compound or the antibody remains active. Alternatively, linkers can be substantially resistant to cleavage (e.g., stable linker or noncleavable linker). In some aspects, the linker is a procharged linker, a hydrophilic linker, or a dicarboxylic acid-based linker. The antibody-drug conjugate selectively delivers an effective dose of a drug to cells whereby greater selectivity, i.e., a lower efficacious dose, may be achieved while increasing the therapeutic index (“therapeutic window”). [0241] To prepare antibody-drug conjugates, linker-toxin conjugates can be made by conventional methods analogous to those described by Doronina et al. (Bioconjugate Chem.17: 114-124, 2006). Antibody-drug conjugates with multiple (e.g., four) drugs per antibody can be prepared by partial reduction of the antibody with an excess of a reducing reagent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) at 37°C for 30 min, then the buffer can be exchanged by elution through SEPHADEX G-25 resin with 1 mM DTPA in Dulbecco’s phosphate-buffered saline (DPBS). The eluent can be diluted with further DPBS, and the thiol concentration of the antibody can be measured using 5,5'-dithiobis(2-nitrobenzoic acid) [Ellman's reagent]. An excess, for example 5-fold, of the linker-cytotoxin conjugate can be added at 4°C. for 1 hr, and the conjugation reaction can be quenched by addition of a substantial excess, for example 20-fold, of cysteine. The resulting ADC mixture can be purified on SEPHADEX G-25 F053-6006PCT / 23-211-WO-PCT equilibrated in PBS to remove unreacted linker-cytotoxin conjugate, desalted if desired, and purified by size-exclusion chromatography. The resulting ADC can then be sterile filtered, for example, through a 0.2 µm filter, and can be lyophilized if desired for storage. [0242] Antibody-detectable label conjugates include an antibody linked to a detectable label. Detectable labels can include any suitable label or detectable group detectable by, for example, optical, spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. In particular embodiments, detectable labels can include fluorescent labels, chemiluminescent labels, spectral colorimetric labels, enzymatic labels, and affinity tags. [0243] Fluorescent labels can be particularly useful in cell staining, identification, imaging, and isolation uses. Exemplary fluorescent labels include blue fluorescent proteins (e.g. eBFP, eBFP2, Azurite, mKalama1, GFPuv, Sapphire, T-sapphire); cyan fluorescent proteins (e.g. eCFP, Cerulean, CyPet, AmCyanl, Midoriishi-Cyan, mTurquoise); green fluorescent proteins (e.g. GFP, GFP-2, tagGFP, turboGFP, EGFP, Emerald, Azami Green, Monomeric Azami Green (mAzamigreen)), CopGFP, AceGFP, avGFP, ZsGreenl, Oregon Green™(Thermo Fisher Scientific)); Luciferase; orange fluorescent proteins (mOrange, mKO, Kusabira-Orange, Monomeric Kusabira-Orange, mTangerine, tdTomato); red fluorescent proteins (mKate, mKate2, mPlum, DsRed monomer, mCherry, mRuby, mRFP1, DsRed-Express, DsRed2, DsRed- Monomer, HcRed-Tandem, HcRedl, AsRed2, eqFP611, mRaspberry, mStrawberry, Jred, Texas Red™ (Thermo Fisher Scientific)); far red fluorescent proteins (e.g., mPlum and mNeptune); yellow fluorescent proteins (e.g., YFP, eYFP, Citrine, SYFP2, Venus, YPet, PhiYFP, ZsYellowl); and tandem conjugates. [0244] Chemiluminescent labels can include lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt, or oxalate ester. [0245] Spectral colorimetric labels can include colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, and latex) beads. [0246] Enzymatic labels can produce, for example, a chemiluminescent signal, a color signal, or a fluorescent signal. Enzymes can include malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI- phosphate dehydrogenase, glucoamylase and acetylcholinesterase. [0247] Affinity tags are described elsewhere herein. [0248] In particular embodiments, an antibody as disclosed herein can be linked to a conjugate by any method known in the art. In particular embodiments, the constant region can be modified F053-6006PCT / 23-211-WO-PCT to allow for site specific conjugation. Such techniques include the use of naturally occurring or engineered cysteine residues, disulfide bridges, poly-histidine sequences, glycoengineering tags, and transglutaminase recognition sequences. Antibody fragments can also be modified for site- specific conjugation, see for example, Kim et al., Mol Cancer Ther 2008;7(8). [0249] (VI) Compositions or Formulations for Administration. Any of the binding domains described herein (e.g., antibodies, multi-domain binding molecules, antibody conjugates, therapeutics) in any exemplary format can be formulated alone or in combination into compositions for administration to subjects. Additionally, nucleic acids encoding the antibodies can also be formulated into compositions for administration (e.g., nucleic acids encapsulated within nanoparticles (e.g., liposomes or polymer-based nanoparticles) and/or as part of a vector delivery system (e.g., a viral vector or plasmid). Binding domains (e.g., antibodies, multi-domain binding molecules, antibody conjugates) and/or nucleic acids encoding antibodies are collectively referred to herein as “active ingredients”. [0250] Salts and/or pro-drugs of active ingredients can also be used. [0251] A pharmaceutically acceptable salt includes any salt that retains the activity of the active ingredient and is acceptable for pharmaceutical use. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. [0252] Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids. [0253] Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine, lysine, arginine and procaine. [0254] A prodrug includes an active ingredient which is converted to a therapeutically active compound after administration, such as by cleavage of an active ingredient or by hydrolysis of a biologically labile group. [0255] Exemplary generally used pharmaceutically acceptable carriers include any and all absorption delaying agents, antioxidants, binders, buffering agents, bulking agents or fillers, chelating agents, coatings, disintegration agents, dispersion media, gels, isotonic agents, lubricants, preservatives, salts, solvents or co-solvents, stabilizers, surfactants, and/or delivery F053-6006PCT / 23-211-WO-PCT vehicles. [0256] Exemplary antioxidants include ascorbic acid, methionine, and vitamin E. [0257] Exemplary buffering agents include citrate buffers, succinate buffers, tartrate buffers, fumarate buffers, gluconate buffers, oxalate buffers, lactate buffers, acetate buffers, phosphate buffers, histidine buffers, and/or trimethylamine salts. [0258] An exemplary chelating agent is EDTA. [0259] Exemplary isotonic agents include polyhydric sugar alcohols including trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, or mannitol. [0260] Exemplary preservatives include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides, hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol. [0261] Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the active ingredient or helps to prevent denaturation or adherence to the container wall. Typical stabilizers can include polyhydric sugar alcohols; amino acids, such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, and cyclitols, such as inositol; PEG; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, α- monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (i.e., <10 residues); proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides such as xylose, mannose, fructose and glucose; disaccharides such as lactose, maltose and sucrose; trisaccharides such as raffinose, and polysaccharides such as dextran. Stabilizers are typically present in the range of from 0.1 to 10,000 parts by weight based on therapeutic weight. [0262] The compositions disclosed herein can be formulated for administration by, for example, injection, inhalation, infusion, perfusion, lavage, or ingestion. The compositions disclosed herein can further be formulated for intravenous, intradermal, intraarterial, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral and/or subcutaneous administration and more particularly by intravenous, intradermal, intraarterial, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, intrathecal, intratumoral, intramuscular, intravesicular, and/or subcutaneous injection. F053-6006PCT / 23-211-WO-PCT [0263] For injection, compositions can be formulated as aqueous solutions, such as in buffers including Hanks' solution, Ringer's solution, or physiological saline. The aqueous solutions can include formulatory agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the formulation can be in lyophilized and/or powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0264] For oral administration, the compositions can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like. For oral solid formulations such as powders, capsules and tablets, suitable excipients include binders (gum tragacanth, acacia, cornstarch, gelatin), fillers such as sugars, e.g., lactose, sucrose, mannitol and sorbitol; dicalcium phosphate, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxy-methylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, disintegrating agents can be added, such as corn starch, potato starch, alginic acid, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms can be sugar-coated or enteric-coated using standard techniques. Flavoring agents, such as peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc. can also be used. [0265] Compositions can be formulated as an aerosol. In particular embodiments, the aerosol is provided as part of an anhydrous, liquid or dry powder inhaler. Aerosol sprays from pressurized packs or nebulizers can also be used with a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator may also be formulated including a powder mix of active ingredient and a suitable powder base such as lactose or starch. [0266] Compositions can also be formulated as depot preparations. Depot preparations can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salts. [0267] Additionally, compositions can be formulated as sustained-release systems utilizing semipermeable matrices of solid polymers including at least one active ingredient. Various sustained-release materials have been established and are well known by those of ordinary skill in the art. Sustained-release systems may, depending on their chemical nature, release one or F053-6006PCT / 23-211-WO-PCT more active ingredients following administration for a few weeks up to over 100 days. Depot preparations can be administered by injection; parenteral injection; instillation; or implantation into soft tissues, a body cavity, or occasionally into a blood vessel with injection through fine needles. [0268] Depot formulations can include a variety of bioerodible polymers including poly(lactide), poly(glycolide), poly(caprolactone) and poly(lactide)-co(glycolide) (PLG) of desirable lactide:glycolide ratios, average molecular weights, polydispersities, and terminal group chemistries. Blending different polymer types in different ratios using various grades can result in characteristics that borrow from each of the contributing polymers. [0269] The use of different solvents (for example, dichloromethane, chloroform, ethyl acetate, triacetin, N-methyl pyrrolidone, tetrahydrofuran, phenol, or combinations thereof) can alter microparticle size and structure in order to modulate release characteristics. Other useful solvents include water, ethanol, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetone, methanol, isopropyl alcohol (IPA), ethyl benzoate, and benzyl benzoate. [0270] Exemplary release modifiers can include surfactants, detergents, internal phase viscosity enhancers, complexing agents, surface active molecules, co-solvents, chelators, stabilizers, derivatives of cellulose, (hydroxypropyl)methyl cellulose (HPMC), HPMC acetate, cellulose acetate, pluronics (e.g., F68/F127), polysorbates, Span® (Croda Americas, Wilmington, Delaware), poly(vinyl alcohol) (PVA), Brij® (Croda Americas, Wilmington, Delaware), sucrose acetate isobutyrate (SAIB), salts, and buffers. [0271] Excipients that partition into the external phase boundary of microparticles such as surfactants including polysorbates, dioctylsulfosuccinates, poloxamers, PVA, can also alter properties including particle stability and erosion rates, hydration and channel structure, interfacial transport, and kinetics in a favorable manner. [0272] Additional processing of the disclosed sustained release depot formulations can utilize stabilizing excipients including mannitol, sucrose, trehalose, and glycine with other components such as polysorbates, PVAs, and dioctylsulfosuccinates in buffers such as Tris, citrate, or histidine. A freeze-dry cycle can also be used to produce very low moisture powders that reconstitute to similar size and performance characteristics of the original suspension. [0273] In particular embodiments, compositions include active ingredients of at least 0.1% w/v or w/w of the composition; at least 1% w/v or w/w of composition; at least 10% w/v or w/w of composition; at least 20% w/v or w/w of composition; at least 30% w/v or w/w of composition; at least 40% w/v or w/w of composition; at least 50% w/v or w/w of composition; at least 60% w/v or w/w of composition; at least 70% w/v or w/w of composition; at least 80% w/v or w/w of composition; at least 90% w/v or w/w of composition; at least 95% w/v or w/w of composition; or F053-6006PCT / 23-211-WO-PCT at least 99% w/v or w/w of composition. [0274] In certain examples, cells are genetically modified to express a protein including a disclosed binding domain. In particular embodiments, cells genetically modified to express the binding domains described herein include genetically modified B cells. In particular embodiments, the modified B cells are modified according to the teachings of International Publication No. WO2019079772. In these embodiments, genetically modified cells can be prepared as formulations for delivery in buffers such as Hanks' solution, Ringer's solution, or physiological saline. [0275] Therapeutically effective amounts of cells within formulations can be greater than 102 cells, greater than 103 cells, greater than 104 cells, greater than 105 cells, greater than 106 cells, greater than 107 cells, greater than 108 cells, greater than 109 cells, greater than 1010 cells, or greater than 1011 cells. [0276] In particular embodiments, cells are in a formulation volume of a liter or less, 500 ml or less, 250 ml or less, or 100 ml or less. Hence, the density of administered cells is typically greater than 104 cells/ml, 105 cells/ml, 106 cells/ml, 107 cells/ml, or 108 cells/ml. [0277] In certain examples, compositions include an anti-infective agent and/or a secondary treatment. Examples of anti-infective agents and secondary treatments are described elsewhere herein. [0278] Any composition or formulation disclosed herein can advantageously include any other pharmaceutically acceptable carriers which include those that do not produce significantly adverse, allergic, or other untoward reactions that outweigh the benefit of administration. Exemplary pharmaceutically acceptable carriers and formulations are disclosed in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. Moreover, compositions and formulations can be prepared to meet sterility, pyrogenicity, general safety, and purity standards as required by U.S. FDA Office of Biological Standards and/or other relevant foreign regulatory agencies. [0279] (VII) Methods of Use. Methods disclosed herein include treating subjects (e.g., humans, veterinary animals (dogs, cats, reptiles, birds) livestock (e.g., horses, cattle, goats, pigs, chickens) and research animals (e.g., monkeys, rats, mice, fish) with compositions disclosed herein. Treating subjects includes delivering therapeutically effective amounts. Therapeutically effective amounts include those that provide effective amounts, prophylactic treatments and/or therapeutic treatments. [0280] An “effective amount” is the amount of a composition or formulation necessary to result in a desired physiological change in the subject. For example, an effective amount can provide an F053-6006PCT / 23-211-WO-PCT immunogenic effect. Effective amounts are often administered for research purposes. Effective amounts disclosed herein can cause a statistically-significant effect in an in vitro assay, an animal model or clinical study relevant to the assessment of an infection’s development, progression, and/or resolution, as well as the effects of the infection. An immunogenic composition can be provided in an effective amount, wherein the effective amount stimulates an immune response. [0281] A "prophylactic treatment" includes a treatment administered to a subject who does not display signs or symptoms of an infection or displays only early signs or symptoms of an infection such that treatment is administered for the purpose of diminishing or decreasing the risk of developing the infection. Thus, a prophylactic treatment functions as a preventative treatment against an infection and/or the potential effects of an infection. [0282] Therefore, "DENV therapeutic" can refer to a treatment that reduces the severity of infection and/or induces an immune response in a subject to DENV. "D+Z therapeutic" can refer to a treatment that reduces the severity of infection and/or induces an immune response in a subject to DENV serotypes 1-4 and ZIKV. In particular embodiments, a D or D+Z therapeutic may be administered therapeutically to a subject who has been exposed to DENV or ZIKV. Thus, a D or D+Z therapeutic can be used to ameliorate a symptom and/or complication associated with DENV or ZIKV, examples of each of which are described elsewhere herein. [0283] In particular embodiments, a DENV therapeutic is a therapeutically effective composition including binding domains disclosed herein that bind the E protein of DENV that neutralizes DENV and/or induces an immune response in a subject against DENV. In particular embodiments, a D+Z therapeutic is a therapeutically effective composition including binding domains disclosed herein that bind the E protein of DENV and ZIKV and neutralizes DENV and ZIKV and/or induces an immune response in a subject against DENV and ZIKV. The skilled artisan will appreciate that the immune system generally is capable of producing an innate immune response and an adaptive immune response. An innate immune response generally can be characterized as not being substantially antigen specific and/or not generating immune memory. An adaptive immune response can be characterized as being substantially antigen specific, maturing over time (e.g., increasing affinity and/or avidity for antigen), and in general can produce immunologic memory. Even though these and other functional distinctions between innate and adaptive immunity can be discerned, the skilled artisan will appreciate that the innate and adaptive immune systems can be integrated and therefore can act in concert. [0284] In particular embodiments, administration of a D or a D+Z therapeutic can further include administration of one or more adjuvants. The term “adjuvant” refers to material that enhances an immune response and is used herein in the customary use of the term. The precise mode of F053-6006PCT / 23-211-WO-PCT action is not understood for all adjuvants, but such lack of understanding does not prevent their clinical use for a wide variety of therapeutics. [0285] Exemplary adjuvants, include any kind of Toll-like receptor ligand or combinations thereof (e.g. CpG, Cpg-28 (a TLR9 agonist), polyriboinosinic polyribocytidylic acid (Poly(I:C)), α- galactoceramide, MPLA, Motolimod (VTX-2337, a novel TLR8 agonist developed by VentiRx), IMO-2055 (EMD1201081), TMX-101 (imiquimod), MGN1703 (a TLR9 agonist), G100 (a stabilized emulsion of the TLR4 agonist glucopyranosyl lipid A), Entolimod (a derivative of Salmonella flagellin also known as CBLB502), Hiltonol (a TLR3 agonist), and Imiquimod), and/or inhibitors of heat-shock protein 90 (Hsp90), such as 17-DMAG (17-dimethylaminoethylamino-17- demethoxygeldanamycin). [0286] In particular embodiments a squalene-based adjuvant can be used. Squalene is part of the group of molecules known as triterpenes, which are all hydrocarbons with 30 carbon molecules. Squalene can be derived from certain plant sources, such as rice bran, wheat germ, amaranth seeds, and olives, as well as from animal sources, such as shark liver oil. In particular embodiments, the squalene-based adjuvant is MF59® (Novartis, Basel, Switzerland). An example of a squalene-based adjuvant that is similar to MF59® but is designed for preclinical research use is Addavax™ (InvivoGen, San Diego, CA). MF59 has been FDA approved for use in an influenza vaccine, and studies indicate that it is safe for use during pregnancy (Tsai et al. Vaccine.2010. 17:28(7):1877-80; Heikkinen et al. Am J Obstet Gynecol. 2012. 207(3):177). In particular embodiments, squalene based adjuvants can include 0.1%-20% (v/v) squalene oil. In particular embodiments, squalene based adjuvants can include 5%(v/v) squalene oil. [0287] In particular embodiments the adjuvant alum can be used. Alum refers to a family of salts that contain two sulfate groups, a monovalent cation, and a trivalent metal, such as aluminum or chromium. Alum is an FDA approved adjuvant. In particular embodiments, therapeutics can include alum in the amounts of 1-1000µg/dose or 0.1mg-10mg/dose. [0288] In particular embodiments, one or more STING agonists are used as an adjuvant. "STING" is an abbreviation of "stimulator of interferon genes", which is also known as "endoplasmic reticulum interferon stimulator (ERIS)", "mediator of IRF3 activation (MITA)", "MPYS" or "transmembrane protein 173 (TM173)". [0289] In particular embodiments, STING agonists include cyclic molecules with one or two phosphodiester linkages, and/or one or two phosphorothioate diester linkages, between two nucleotides. This includes (3',5')-(3',5') nucleotide linkages (abbreviated as (3',3')); (3',5')-(2',5') nucleotide linkages (abbreviated as (3',2')); (2',5')-(3',5') nucleotide linkages (abbreviated as (2',3')); and (2',5')-(2',5') nucleotide linkages (abbreviated as (2',2')). "Nucleotide" refers to any F053-6006PCT / 23-211-WO-PCT nucleoside linked to a phosphate group at the 5', 3' or 2' position of the sugar moiety. [0290] In particular embodiments, STING agonists include c-AIMP; (3’,2’)c-AIMP; (2’,2’)c-AIMP; (2’,3’)c-AIMP; c-AIMP(S); c-(dAMP-dIMP); c-(dAMP-2’FdIMP); c-(2’FdAMP-2’FdIMP); (2’,3’)c- (AMP-2’FdIMP); c-[2’FdAMP(S)-2’FdIMP(S)]; c-[2’FdAMP(S)-2’FdIMP(S)](POM)2; and DMXAA. Additional examples of STING agonists are described in WO2016/145102. [0291] Other immune stimulants can also be used as adjuvants. Additional exemplary small molecule immune stimulants include TGF-β inhibitors, SHP-inhibitors, STAT-3 inhibitors, and/or STAT-5 inhibitors. Exemplary siRNA capable of down-regulating immune-suppressive signals or oncogenic pathways (such as kras) can be used whereas any plasmid DNA (such as minicircle DNA) encoding immune-stimulatory proteins can also be used. [0292] In particular embodiments, the immune stimulant may be a cytokine and or a combination of cytokines, such as IL-2, IL-12 or IL-15 in combination with IFN-α, IFN-β or IFN-γ, or GM-CSF, or any effective combination thereof, or any other effective combination of cytokines. The above- identified cytokines stimulate TH1 responses, but cytokines that stimulate TH2 responses may also be used, such as IL-4, IL-10, IL-11, or any effective combination thereof. Also, combinations of cytokines that stimulate TH1 responses along with cytokines that stimulate TH2 responses may be used. [0293] "Immune response" refers to a response of the immune system to produce to neutralize and/or destroy DENV or DENV AND ZIKV. In particular embodiments, an immune response can be an innate and/or adaptive response. In particular embodiments, the D or D+Z therapeutics described herein are responsible for blocking the entry of a pathogen into a cell so that it is firstly unable to infect healthy cells, and secondly, it is unable to replicate and cause severe infection. Furthermore, in particular embodiments, D or D+Z therapeutics described herein mark D or D+Z for destruction by immune cells such as macrophages and neutrophils through opsonization. [0294] A "therapeutic treatment" includes a treatment administered to a subject who displays symptoms or signs of an infection and is administered to the subject for the purpose of diminishing or eliminating those signs or symptoms of the infection or effects of the infection. The therapeutic treatment can reduce, control, or eliminate the presence or activity of the infection and/or reduce, control or eliminate side effects of the infection. [0295] In particular embodiments a therapeutic treatment can reduce, control, or eliminate a primary infection with DENV or ZIKV. In particular embodiments a therapeutic treatment can reduce or eliminate the symptoms of DENV or ZIKV. In particular embodiments, a therapeutically effective amount reduces or prevents transmission of DENV or ZIKV. [0296] In particular embodiments, a therapeutically effective amount alleviates or reduces the F053-6006PCT / 23-211-WO-PCT severity or occurrence of symptoms and/or complications associated with DENV or ZIKV infection. Exemplary symptoms of infection with DENV include fever, headache, muscle pain, joint pain, bone pain, nausea, vomiting, pain behind eyes, swollen glands, rash, liver enlargement, mucosal bleeding, lethargy or restlessness, abdominal pain, serious bleeding, and shock. Exemplary symptoms of infection with ZIKV include fever, rash, conjunctivitis, muscle pain, joint pain, malaise, headache, sweating, chills, loss of appetite, fatigue, and vomiting. [0297] In particular embodiments, a therapeutically effective amount reduces the duration of hospitalization for a subject infected with the DENV or ZIKV as compared to a subject that has not received a D or D+Z therapeutic disclosed herein. [0298] In particular embodiments, a therapeutically effective amount reduces the time to sustained non-detectable DENV or ZIKV in the blood or urine in a patient infected with the virus as compared to a subject that has not received D or D+Z therapeutic disclosed herein. [0299] In particular embodiments, a therapeutically effective amount reduces organ damage or death as compared to a subject that has not received a D or D+Z therapeutic disclosed herein. [0300] Function as an effective amount, prophylactic treatment or therapeutic treatment are not mutually exclusive, and in particular embodiments, administered dosages may accomplish more than one treatment type. [0301] For administration, therapeutically effective amounts (also referred to herein as doses) can be initially estimated based on results from in vitro assays and/or animal model studies. Such information can be used to more accurately determine useful doses in subjects of interest. The actual dose amount administered to a particular subject can be determined by a physician, veterinarian or researcher taking into account parameters such as physical and physiological factors including target, body weight, severity of infection, stage of infection, effects of infection (e.g., IM, lymphoproliferative disorders), previous or concurrent therapeutic interventions, idiopathy of the subject and route of administration. [0302] Useful doses can range from 0.1 to 5 µg/kg or from 0.5 to 1 µg /kg. In other examples, a dose can include 1 µg /kg, 15 µg /kg, 30 µg /kg, 50 µg/kg, 55 µg/kg, 70 µg/kg, 90 µg/kg, 150 µg/kg, 350 µg/kg, 500 µg/kg, 750 µg/kg, 1000 µg/kg, 0.1 to 5 mg/kg or from 0.5 to 1 mg/kg. In other examples, a dose can include 1 mg/kg, 10 mg/kg, 30 mg/kg, 50 mg/kg, 70 mg/kg, 100 mg/kg, 300 mg/kg, 500 mg/kg, 700 mg/kg, 1000 mg/kg or more. [0303] Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every F053-6006PCT / 23-211-WO-PCT 8 months, every 9 months, every 10 months, every 11 months or yearly). [0304] In some embodiments, the D or D+Z therapeutic described herein can be administered in combination or alternation with a secondary flavivirus treatment. In some embodiments, the secondary treatment can be selected from an mRNA-based vaccine, an adenovirus vaccine, a non-replicating vaccine, a DNA vaccine, a live attenuated vaccine, a plant-based adjuvant vaccine, a multi-epitope peptide-based vaccine, an inactivated virus, and a peptide vaccine, pain medicine or combinations thereof. An exemplary secondary vaccine suitable for use with the vaccines and methods described herein includes Dengvaxia® (Sanofi, France). [0305] The D or D+Z therapeutic described herein can be administered on top of the current standard of care for DENV and/or ZIKV patients, or in combination or alternation with any other compound or therapy that the healthcare provider deems beneficial for the patient. The combination and/or alternation therapy can be therapeutic, adjunctive, or palliative. [0306] In some embodiments, the D or D+Z therapeutic is administered with an anti-infective agent, for example, 1662G07, DN59, NITD448, DV2419-447, DN57opt, 10AN1, rolitetracycline, doxycycline, A5, Compound 6, P02, gg-ww, EF, Geraniin, DET2, DET4, MLH40, pr, Pep14-23, VGTI-A3, VGTI-A3-03, bovine lactoferrin, hippeastrum hybrid (HHA), urtica dioica (UDA), galanthus nivalis (GNA), PD1 CD44, PG545, Fucoidan, PI-88, di-galactan hybrid C2S-3, iota carrageenan G3d, CF-238, sulfated galactomannan, sulfated galactan, curdlan sulfate, chondroitin sulfate E, P4 (Lee et al., Viruses, 15(3): 705, 2023), ribavirin, 4'-fluorouridine, small molecule TMC353121, AVG-388, or analogs thereof. Any of these drugs or vaccines can be used in combination or alternation with the D or D+Z therapeutic provided herein to treat a DENV or ZIKV viral infection. [0307] The pharmaceutical compositions and formulations described herein can be administered by, without limitation, injection, inhalation, infusion, perfusion, lavage or ingestion. Routes of administration can include intravenous, intradermal, intraarterial, intraparenteral, intranasal, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral, subcutaneous, and/or sublingual administration and more particularly by intravenous, intradermal, intraarterial, intraparenteral, intranasal, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral, subcutaneous, and/or sublingual injection. [0308] Compositions and formulations disclosed herein can also be used for research, particularly for research into a vaccine for D or D+Z. In particular embodiments, the binding domains disclosed herein can be used to study and engineer vaccines that elicit the production of antibodies that F053-6006PCT / 23-211-WO-PCT neutralize D or D+Z. [0309] (VIII) Kits. Also disclosed herein are kits including one or more containers including one or more of the binding domains described herein, antibodies described herein, multi-domain binding molecules described herein, antibody conjugates described herein, modified cells (e.g. cells modified to express antibodies disclosed herein), and/or compositions and/or adjuvants, anti- infective agents, or secondary treatments described herein. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration. [0310] The Exemplary Embodiments and Example below are included to demonstrate particular embodiments of the disclosure. Those of ordinary skill in the art should recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure. [0311] (IX) Exemplary Embodiments. 1. A binding domain that binds dengue virus (DENV)1, DENV2, DENV3, DENV4, and zika virus (ZIKV), wherein the binding domain includes a variable heavy chain including a complementarity determining region (CDR) heavy (H)1, a CDRH2, and a CDRH3 and a variable light chain including a CDR light (L)1, CDRL2, and CDRL3; wherein: the CDRH1 includes the sequence as set forth in SEQ ID NO: 18, the CDRH2 includes the sequence as set forth in SEQ ID NO: 19, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 20, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 21, the CDRL2 includes the sequence as set forth in SEQ ID NO: 22, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 23 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 24, the CDRH2 includes the sequence as set forth in SEQ ID NO: 25, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 20, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 21, the CDRL2 includes the sequence as set forth in SEQ ID NO: 22, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 23 according to Chothia; the CDRH1 includes the sequence as set forth in SEQ ID NO: 26, the CDRH2 includes the sequence as set forth in SEQ ID NO: 27, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 28, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 29, the CDRL2 includes the sequence DVT, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 23 according to IMGT; F053-6006PCT / 23-211-WO-PCT the CDRH1 includes the sequence as set forth in SEQ ID NO: 30, the CDRH2 includes the sequence as set forth in SEQ ID NO: 31, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 28, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 21, the CDRL2 includes the sequence as set forth in SEQ ID NO: 32, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 23 according to North; or the CDRH1 includes the sequence as set forth in SEQ ID NO: 33, the CDRH2 includes the sequence as set forth in SEQ ID NO: 34, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 35, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 36, the CDRL2 includes the sequence as set forth in SEQ ID NO: 37, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 38 according to Contact. 2. The binding domain of embodiment 1, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 6 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 6. 3. The binding domain of embodiment 1, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 8 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 8. 4. The binding domain of embodiment 1, wherein the variable light chain includes the sequence as set forth in SEQ ID NO: 7 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 7. 5. The binding domain of embodiment 1, wherein the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 9 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 9. 6. A binding domain that binds DENV1, DENV2, DENV3, and DENV4, wherein the binding domain includes a variable heavy chain including a CDRH1, CDRH2, and CDRH3 and a variable light chain including a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 includes the sequence as set forth in SEQ ID NO: 39, the CDRH2 includes the sequence as set forth in SEQ ID NO: 40, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 41, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 42, the CDRL2 includes the sequence as set forth in SEQ ID NO: 43, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 45, the CDRH2 includes the sequence as set forth in SEQ ID NO: 46, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 41, and the CDRL1 includes the sequence as set forth in SEQ ID F053-6006PCT / 23-211-WO-PCT NO: 42, the CDRL2 includes the sequence as set forth in SEQ ID NO: 43, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 44 according to Chothia; the CDRH1 includes the sequence as set forth in SEQ ID NO: 47, the CDRH2 includes the sequence as set forth in SEQ ID NO: 48, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 49, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 50, the CDRL2 includes the sequence DAS, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 51 according to IMGT; the CDRH1 includes the sequence as set forth in SEQ ID NO: 52, the CDRH2 includes the sequence as set forth in SEQ ID NO: 53, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 49, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 42, the CDRL2 includes the sequence as set forth in SEQ ID NO: 54, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 51 according to North; or the CDRH1 includes the sequence as set forth in SEQ ID NO: 55, the CDRH2 includes the sequence as set forth in SEQ ID NO: 56, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 57, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 58, the CDRL2 includes the sequence as set forth in SEQ ID NO: 59, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 60 according to Contact. 7. The binding domain of embodiment 6, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 10 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 10. 8. The binding domain of embodiment 6, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 12 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 12. 9. The binding domain of embodiment 6, wherein the variable light chain includes the sequence as set forth in SEQ ID NO: 11 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 11. 10. The binding domain of embodiment 6, wherein the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 13 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 13. 11. A binding domain that binds DENV1, DENV2, DENV3, and DENV4, wherein the binding domain includes a variable heavy chain including CDRH1, CDRH2, and CDRH3 and a variable light chain including a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 includes the sequence as set forth in SEQ ID NO: 61, the CDRH2 includes the sequence as set forth in SEQ ID NO: 62, and the CDRH3 includes the sequence F053-6006PCT / 23-211-WO-PCT as set forth in SEQ ID NO: 63, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 64, the CDRL2 includes the sequence as set forth in SEQ ID NO: 65, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 66 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 67, the CDRH2 includes the sequence as set forth in SEQ ID NO: 68, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 63, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 64, the CDRL2 includes the sequence as set forth in SEQ ID NO: 65, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 66 according to Chothia; the CDRH1 includes the sequence as set forth in SEQ ID NO: 69, the CDRH2 includes the sequence as set forth in SEQ ID NO: 70, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 71, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 72, the CDRL2 includes the sequence KAS, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 66 according to IMGT; the CDRH1 includes the sequence as set forth in SEQ ID NO: 73, the CDRH2 includes the sequence as set forth in SEQ ID NO: 74, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 71, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 64, the CDRL2 includes the sequence as set forth in SEQ ID NO: 75, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 66 according to North; or the CDRH1 includes the sequence as set forth in SEQ ID NO: 76, the CDRH2 includes the sequence as set forth in SEQ ID NO: 77, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 78, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 79, the CDRL2 includes the sequence as set forth in SEQ ID NO: 80, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 81 according to Contact. 12. The binding domain of embodiment 11, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 14 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 14. 13. The binding domain of embodiment 11, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 16 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 16. 14. The binding domain of embodiment 11, wherein the variable light chain includes the sequence as set forth in SEQ ID NO: 15 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 15. 15. The binding domain of embodiment 11, wherein the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 17 or a sequence having at least 95% sequence identity to F053-6006PCT / 23-211-WO-PCT the sequence as set forth in SEQ ID NO: 17. 16. A binding domain that binds DENV1, DENV2, DENV3, DENV4, and ZIKV, wherein the binding domain includes a variable heavy chain including CDRH1, CDRH2, and CDRH3 and a variable light chain including a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 includes the sequence as set forth in SEQ ID NO: 162, the CDRH2 includes the sequence as set forth in SEQ ID NO: 163, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 164, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 165, the CDRL2 includes the sequence as set forth in SEQ ID NO: 166, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 167 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 168, the CDRH2 includes the sequence as set forth in SEQ ID NO: 169, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 170, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 21, the CDRL2 includes the sequence as set forth in SEQ ID NO: 171, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 172 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 18, the CDRH2 includes the sequence as set forth in SEQ ID NO: 173, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 174, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 21, the CDRL2 includes the sequence as set forth in SEQ ID NO: 175, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 176 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 177, the CDRH2 includes the sequence as set forth in SEQ ID NO: 178, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 179, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 180, the CDRL2 includes the sequence as set forth in SEQ ID NO: 181, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 182 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 183, the CDRH2 includes the sequence as set forth in SEQ ID NO: 184, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 185, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 21, the CDRL2 includes the sequence as set forth in SEQ ID NO: 22, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 23 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 186, the CDRH2 includes the sequence as set forth in SEQ ID NO: 187, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 188, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 189, the CDRL2 includes the sequence as set forth in SEQ ID NO: 181, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 190 according to Kabat; or F053-6006PCT / 23-211-WO-PCT the CDRH1 includes the sequence as set forth in SEQ ID NO: 191, the CDRH2 includes the sequence as set forth in SEQ ID NO: 192, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 193, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 194, the CDRL2 includes the sequence as set forth in SEQ ID NO: 181, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 195 according to Kabat. 17. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 82 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 82; and the variable light chain includes the sequence as set forth in SEQ ID NO: 83 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 83. 18. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 84 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 84; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 85 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 85. 19. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 86 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 86; and the variable light chain includes the sequence as set forth in SEQ ID NO: 87 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 87. 20. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 88 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 88; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 89 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 89. 21. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 90 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 90; and the variable light chain includes the sequence as set forth in SEQ ID NO: 91 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 91. 22. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 92 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 92; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 93 or a sequence having at least 95% sequence identity to F053-6006PCT / 23-211-WO-PCT the sequence as set forth in SEQ ID NO: 93. 23. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 94 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 94; and the variable light chain includes the sequence as set forth in SEQ ID NO: 95 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 95. 24. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 96 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 96; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 97 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 97. 25. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 98 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 98; and the variable light chain includes the sequence as set forth in SEQ ID NO: 99 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 99. 26. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 100 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 100; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 101 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 101. 27. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 102 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 102; and the variable light chain includes the sequence as set forth in SEQ ID NO: 103 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 103. 28. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 104 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 104; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 105 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 105. 29. The binding domain of embodiment 16, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 106 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 106; and the variable light chain includes the sequence F053-6006PCT / 23-211-WO-PCT as set forth in SEQ ID NO: 107 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 107. 30. The binding domain of embodiment 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 108 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 108; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 109 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 109. 31. A binding domain that binds DENV1, DENV2, DENV3, and DENV4, wherein the binding domain includes a variable heavy chain including CDRH1, CDRH2, and CDRH3 and a variable light chain including a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 includes the sequence as set forth in SEQ ID NO: 196, the CDRH2 includes the sequence as set forth in SEQ ID NO: 197, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 198, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 199, the CDRL2 includes the sequence as set forth in SEQ ID NO: 200, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 201 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 202, the CDRH2 includes the sequence as set forth in SEQ ID NO: 203, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 204, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 205, the CDRL2 includes the sequence as set forth in SEQ ID NO: 206, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 207 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 39, the CDRH2 includes the sequence as set forth in SEQ ID NO: 208, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 41, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 209, the CDRL2 includes the sequence as set forth in SEQ ID NO: 200, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 39, the CDRH2 includes the sequence as set forth in SEQ ID NO: 210, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 198, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 211, the CDRL2 includes the sequence as set forth in SEQ ID NO: 200, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 39, the CDRH2 includes the sequence as set forth in SEQ ID NO: 212, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 41, and the CDRL1 includes the sequence as set forth in SEQ ID F053-6006PCT / 23-211-WO-PCT NO: 211, the CDRL2 includes the sequence as set forth in SEQ ID NO: 200, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 213 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 61, the CDRH2 includes the sequence as set forth in SEQ ID NO: 214, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 215, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 216, the CDRL2 includes the sequence as set forth in SEQ ID NO: 217, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 66 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 218, the CDRH2 includes the sequence as set forth in SEQ ID NO: 219, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 220, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 221, the CDRL2 includes the sequence as set forth in SEQ ID NO: 222, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 223 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 196, the CDRH2 includes the sequence as set forth in SEQ ID NO: 224, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 198, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 211, the CDRL2 includes the sequence as set forth in SEQ ID NO: 200, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 186, the CDRH2 includes the sequence as set forth in SEQ ID NO: 225, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 226, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 189, the CDRL2 includes the sequence as set forth in SEQ ID NO: 181, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 195 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 227, the CDRH2 includes the sequence as set forth in SEQ ID NO: 228, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 229, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 230, the CDRL2 includes the sequence as set forth in SEQ ID NO: 231, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 232 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 233, the CDRH2 includes the sequence as set forth in SEQ ID NO: 234, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 235, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 236, the CDRL2 includes the sequence as set forth in SEQ ID NO: 237, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 238 according to Kabat; the CDRH1 includes the sequence as set forth in SEQ ID NO: 239, the CDRH2 includes the sequence as set forth in SEQ ID NO: 240, and the CDRH3 includes the sequence F053-6006PCT / 23-211-WO-PCT as set forth in SEQ ID NO: 241, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 242, the CDRL2 includes the sequence as set forth in SEQ ID NO: 181, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 243 according to Kabat; or the CDRH1 includes the sequence as set forth in SEQ ID NO: 244, the CDRH2 includes the sequence as set forth in SEQ ID NO: 245, and the CDRH3 includes the sequence as set forth in SEQ ID NO: 246, and the CDRL1 includes the sequence as set forth in SEQ ID NO: 247, the CDRL2 includes the sequence as set forth in SEQ ID NO: 248, and the CDRL3 includes the sequence as set forth in SEQ ID NO: 249 according to Kabat. 32. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 110 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 110; and the variable light chain includes the sequence as set forth in SEQ ID NO: 111 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 111. 33. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 112 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 112; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 113 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 113. 34. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 114 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 114; and the variable light chain includes the sequence as set forth in SEQ ID NO: 115 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 115. 35. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 116 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 116; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 117 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 117. 36. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 118 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 118; and the variable light chain includes the sequence as set forth in SEQ ID NO: 119 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 119. 37. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by F053-6006PCT / 23-211-WO-PCT the sequence as set forth in SEQ ID NO: 120 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 120; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 121 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 121. 38. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 122 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 122; and the variable light chain includes the sequence as set forth in SEQ ID NO: 123 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 123. 39. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 124 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 124; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 125 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 125. 40. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 126 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 126; and the variable light chain includes the sequence as set forth in SEQ ID NO: 127 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 127. 41. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 128 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 128; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 129 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 129. 42. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 130 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 130; and the variable light chain includes the sequence as set forth in SEQ ID NO: 131 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 131. 43. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 132 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 132; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 133 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 133. F053-6006PCT / 23-211-WO-PCT 44. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 134 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 134; and the variable light chain includes the sequence as set forth in SEQ ID NO: 135 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 135. 45. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 136 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 136; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 137 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 137. 46. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 138 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 138; and the variable light chain includes the sequence as set forth in SEQ ID NO: 139 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 139. 47. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 140 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 140; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 141 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 141. 48. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 142 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 142; and the variable light chain includes the sequence as set forth in SEQ ID NO: 143 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 143. 49. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 144 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 144; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 145 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 145. 50. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 146 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 146; and the variable light chain includes the sequence as set forth in SEQ ID NO: 147 or a sequence having at least 95% sequence identity to the F053-6006PCT / 23-211-WO-PCT sequence as set forth in SEQ ID NO: 147. 51. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 148 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 148; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 149 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 149. 52. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 150 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 150; and the variable light chain includes the sequence as set forth in SEQ ID NO: 151 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 151. 53. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 152 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 152; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 153 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 153. 54. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 154 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 154; and the variable light chain includes the sequence as set forth in SEQ ID NO: 155 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 155. 55. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 156 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 156; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 157 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 157. 56. The binding domain of embodiment 31, wherein the variable heavy chain includes the sequence as set forth in SEQ ID NO: 158 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 158; and the variable light chain includes the sequence as set forth in SEQ ID NO: 159 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 159. 57. The binding domain of embodiment 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 160 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 160; and the variable light chain is encoded by the F053-6006PCT / 23-211-WO-PCT sequence as set forth in SEQ ID NO: 161 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 161. 58. A binding molecule including the binding domain of any of the preceding embodiments. 59. The binding molecule of embodiment 58, wherein the binding molecule is an IgG antibody, an IgA antibody, an IgM antibody, an IgD antibody, or an IgE antibody. 60. The binding molecule of embodiments 58 or 59, wherein the binding molecule is an IgA antibody. 61. The binding molecule of embodiment 60, wherein the IgA antibody includes an IgA1 antibody or an IgA2 antibody. 62. The binding molecule of embodiments 60 or 61, wherein the IgA antibody includes an IgA1 antibody. 63. The binding molecule of embodiments 58 or 59, wherein the binding molecule is an IgG antibody. 64. The binding molecule of embodiment 63, wherein the IgG antibody includes an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. 65. The binding molecule of embodiments 63 or 64, wherein the IgG antibody includes an IgG1 antibody. 66. The binding molecule of any of embodiments 58-65, wherein the binding molecule is a neutralizing antibody. 67. The binding molecule of any of embodiments 58-66, wherein the binding molecule is an scFV or a Fab. 68. The binding molecule of any of embodiments 58-67, including a thioMab. 69. The binding molecule of any of embodiments 58-68, including one or more modified amino acids. 70. The binding molecule of embodiment 69, wherein the one or more modified amino acids include a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, or an amino acid conjugated to an organic derivatizing agent. 71. The binding molecule of any of embodiments 58-70, including one or more human serum albumin (HSA)-linkages. 72. The binding molecule of any of embodiments 58-71, wherein the binding molecule includes one or more Fc modifications. 73. The binding molecule of embodiment 72, wherein the one or more Fc modifications includes a LALA mutation. F053-6006PCT / 23-211-WO-PCT 74. The binding molecule of embodiments 72 or 73, wherein the one or more Fc modifications includes an Fc region with reduced fucose content or lacking fucose. 75. The binding molecule of any of embodiments 58-74, wherein the binding molecule is a part of a multi-domain binding molecule. 76. A multi-domain binding molecule including at least two binding domains wherein at least one binding domain includes the binding domain of any of embodiments 1-57. 77. The multi-domain binding molecule of embodiment 76, wherein the multi-domain binding molecule is a dimer, trimer, tetramer, pentamer, hexamer, or heptamer. 78. The multi-domain binding molecule of embodiments 76 or 77, including an Fc region. 79. The multi-domain binding molecule of embodiment 78, wherein the Fc region is an IgA Fc region or an IgM Fc region. 80. The multi-domain binding molecule of embodiments 78 or 79, wherein the Fc region is an IgA Fc region having the sequence as set forth in SEQ ID NOs: 258 and 259. 81. The multi-domain binding molecule of embodiments 78 or 79, wherein the Fc region is an IgM Fc region having the sequence as set forth in SEQ ID NOs: 260, 261, or 295-304. 82. The multi-domain binding molecule of any of embodiments 78-81, wherein the Fc region includes a multimerizing fragment of the IgA Fc region or a multimerizing fragment of the IgM Fc region. 83. The multi-domain binding molecule of embodiment 82, wherein the multimerizing fragment of the IgA Fc region includes the IgA tailpiece. 84. The multi-domain binding molecule of embodiment 83, wherein the IgA tailpiece has the sequence of residues 331-352 as set forth in SEQ ID NO: 258 or the sequence of residues 318- 340 as set forth in SEQ ID NO: 259. 85. The multi-domain binding molecule of any of embodiments 82-84, wherein the multimerizing fragment of the IgA Fc region includes the IgA CA3 domain and the IgA tailpiece. 86. The multi-domain binding molecule of any of embodiments 82-85, wherein the multimerizing fragment of the IgA Fc region includes the IgA CA2 domain, the IgA CA3 domain, and the IgA tailpiece. 87. The multi-domain binding molecule of any of embodiments 82-86, wherein the multimerizing fragment of the IgA Fc region includes the IgA CA1 domain, the IgA CA2 domain, the IgA CA3 domain, and the IgA tailpiece. 88. The multi-domain binding molecule of embodiment 82, wherein the multimerizing fragment of the IgM Fc region includes the IgM tailpiece. 89. The multi-domain binding molecule of embodiments 82 or 88, wherein the multimerizing F053-6006PCT / 23-211-WO-PCT fragment of the IgM Fc region includes the Cµ4 domain and the IgM tailpiece. 90. The multi-domain binding molecule of any of embodiments 82-89, wherein the multimerizing fragment of the IgM Fc region includes the Cµ3 domain, the Cµ4 domain, and the IgM tailpiece. 91. The multi-domain binding molecule of any of embodiments 82-90, wherein the multimerizing fragment of the IgM Fc region includes the Cµ2 domain, the Cµ3 domain, the Cµ4 domain, and the IgM tailpiece. 92. The multi-domain binding molecule of any of embodiments 82-91, wherein the multimerizing fragment of the IgM Fc region includes the Cµ1 domain, the Cµ2 domain, the Cµ3 domain, the Cµ4 domain, and the IgM tailpiece. 93. The multi-domain binding molecule of any of embodiments 82-92, wherein the multimerizing fragment of the IgM Fc region has the sequence as set forth in any of SEQ ID NOs: 295-304. 94. A single-chain variable fragment (scFv) including the binding domain of any of embodiments 1-57, wherein the antibody fragment includes a humanized light chain variable region and/or a humanized heavy chain variable region and lacks a constant region. 95. A conjugate including the binding domain of any of embodiments 1-57, linked to a particle, a drug, or a detectable label. 96. A composition including the binding molecule of any of embodiments 1-57 and a pharmaceutically acceptable carrier. 97. The composition of embodiment 96, further including one or more adjuvants. 98. The composition of embodiment 97, wherein the one or more adjuvants are selected from alum, a squalene-based adjuvant, a STING agonist, or a liposome-based adjuvant. 99. The composition of any of embodiments 96-98, further including a second type of binding molecule. 100. The composition of embodiment 99, further including a third type of binding molecule. 101. A nucleic acid sequence encoding the binding domain of any of embodiments 1-57 or the binding molecule of any of embodiments 58- 75. 102. A vector including the nucleic acid sequence of embodiment 101. 103. A cell genetically modified to express the binding molecule of any of embodiments 58-75. 104. A method of treating a subject in need thereof including administering to the subject a therapeutically effective amount of a composition of any of embodiments 96-100 thereby treating the subject in need thereof. 105. The method of embodiment 104, wherein the subject has DENV. F053-6006PCT / 23-211-WO-PCT 106. The method of embodiments 104 or 105, wherein the subject has ZIKV. 107. The method of any of embodiments 104-106, wherein the subject has previously been infected with DENV or ZIKV. 108. The method of any of embodiments 104-107, wherein the administering is through intravenous, intradermal, intraarterial, intranodal, intravesicular, intrathecal, intraperitoneal, intraparenteral, intranasal, intralesional, intramuscular, oral, intrapulmonary, subcutaneous, or sublingual administering. 109. The method of any of embodiments 104-108, wherein the administering precedes or follows administration of a secondary treatment. [0312] (X) Experimental Example. [0313] Summary. Sequential dengue virus (DENV) infections often generate neutralizing antibodies against all four DENV serotypes and sometimes, Zika virus. Characterizing cross- flavivirus broadly neutralizing antibody (bnAb) responses can inform rational vaccine design to avoid infection enhancement associated with non-neutralizing antibodies. In this Example, single cell transcriptomics were used to mine the bnAb repertoire following secondary DENV infection. Several new bnAbs with comparable or superior breadth and potency to known bnAbs were identified, and with distinct recognition determinants. Unlike all known flavivirus bnAbs, which are IgG1, one newly identified cross-flavivirus bnAb (F25.S02) was derived from IgA1. Although F25.S02 and known bnAbs displayed similar neutralizing activity as IgG1 and IgA1, only IgG1 enhanced infection in monocytes expressing IgG and IgA Fc receptors. Moreover, IgG-mediated enhancement of infection was inhibited by IgA1 versions of bnAbs. A role for IgA in flavivirus infection and immunity is demonstrated with implications for vaccine and therapeutic strategies. [0314] Introduction. Zika virus (ZIKV) and the four circulating serotypes of dengue virus (DENV1- 4) are mosquito-borne flaviviruses with overlapping geographic distributions (Pierson, and Diamond, (2020). Nat Microbiol 5, 796–812). Climate change is predicted to further expand the geographic range of mosquito vectors (Kraemer, et al. (2019). Nat Microbiol 4, 854–863; Messina, et al. (2019). Nat Microbiol 4, 1508–1515; Iwamura, et al. (2020). Nat. Commun. 11, 2130), highlighting the need for effective clinical interventions to curb epidemics. The complex antibody response to DENV1-4 has hampered the development of safe and effective vaccines. A first exposure to a given DENV serotype generates potently neutralizing antibodies that typically provide long-term, though sometimes incomplete protection against reinfection by that serotype (Waggoner, et al. (2016). J. Infect. Dis.214, 986–993; Forshey, et al. (2016). PLoS Negl. Trop. Dis.10; Snow, et al. (2014). Am. J. Trop. Med. Hyg.91, 1203–12175–7). However, antibodies that are cross-reactive in binding but not neutralizing activity against other DENV serotypes are F053-6006PCT / 23-211-WO-PCT also elicited (Beltramello, et al. (2010). Cell Host Microbe 8, 271–283 (“Bellatramello”); de Alwis, et al. (2011). PLoS Negl. Trop. Dis. 5; Lai, et al. (2008). J. Virol. 82, 6631–6643; Smith, et al. (2013). J. Infect. Dis.207, 1898–1908) and pre-existing non-neutralizing antibodies predict the risk of severe disease following secondary exposure to a different DENV serotype (Katzelnick, L.C., et al. (2017). Science 358, 929–932 (“Katzelnick 1”); Salje, et al. (2018). Nature 557, 719– 723; Sangkawibha, et al. (1984). Am. J. Epidemiol.120, 653–669; Guzmán, et al. (2000). Am. J. Epidemiol.152, 793–799, 804; Chau, et al. (2008). J. Infect. Dis.198, 516–524 (“Chau”)). This phenomenon is attributed to a process called antibody-dependent enhancement (ADE), in which non-neutralizing IgG antibodies (Katzelnick 1; Wang, et al. (2017). Science 355, 395–398 (“Wang 1”)) facilitate the uptake of bound DENV particles into relevant myeloid target cells via Fc-Fc gamma receptor (FcɣR)-dependent pathways (Guzman and Harris, (2015). Lancet 385, 453– 465). ADE-related safety concerns derailed the widespread use of the first licensed DENV vaccine, which increased the risk of severe dengue disease following subsequent infection in previously DENV-naive recipients (Hadinegoro et al. (2015). N. Engl. J. Med.373, 1195–1206; Villar, et al. (2015). N. Engl. J. Med.372, 113–123). As pre-existing IgG antibodies from one prior exposure to ZIKV can also enhance subsequent dengue disease risk (Katzelnick, L.C., et al. (2020). Science 369, 1123–1128 (“Katzelnick 2”)), a safe vaccine would ideally induce durable antibodies that can broadly and potently neutralize DENV1-4 and ZIKV to minimize the risk of ADE. [0315] In contrast to primary DENV exposure, secondary exposure to a different DENV serotype typically elicits broadly neutralizing antibody responses associated with protection against subsequent disease (Beltramello; Katzelnick 2; Tsai, et al. (2013). J. Virol. 87, 12562–12575 (“Tsai”); Lai, et al. (2013). PLoS Negl. Trop. Dis.7; Andrade, et al. (2020). J. Infect. Dis.222, 590– 600; Zompi, et al. (2012). PLoS Negl. Trop. Dis.6 (“Zompi”); Gibbons, et al. (2007). Am. J. Trop. Med. Hyg.77, 910–913). Studying the antibody repertoire in individuals who have experienced multiple DENV infections can thus provide insight into the properties of cross-reactive neutralizing antibody responses that an effective vaccine seeks to mimic. Indeed, a handful of monoclonal broadly neutralizing antibodies (bnAbs) that can potently neutralize DENV1-4 and in some cases, ZIKV, have been isolated from naturally infected individuals living in endemic regions (Xu, et al. (2017). NPJ Vaccines 2, 2 (“Xu 1”); Dejnirattisai, et al. (2015). Nat. Immunol. 16, 170–177 (“Dejnirattisai”); Tsai; Smith, et al. (2013). MBio 4). The most well-characterized class of flavivirus bnAbs targets a quaternary E-dimer epitope (EDE) spanning both E protein monomers within the dimer subunit (Dejnirattisai; Rouvinski, et al. (2015). Nature 520, 109–113 (“Rouvinski”)). There are two subclasses of EDE bnAbs, of which EDE1 but not EDE2 antibodies can potently neutralize F053-6006PCT / 23-211-WO-PCT ZIKV in addition to DENV1-4 (Barba-Spaeth, et al. (2016). Nature 536, 48–53 (“Barba-Spaeth”)). A few antibodies that can cross-neutralize ZIKV and some DENV serotypes have also been described (Kotaki, et al. (2021). Sci. Rep.11, 12987; Dussupt, et al. (2020). Nat. Med.26, 228– 235 (“Dussupt”); Robbiani, et al. (2017). Cell 169, 597–609 (“Robbiani”); Rogers, et al. (2017). Sci Immunol 232–35 (“Rogers”)), but other than those of the EDE1 subclass, SIgN-3C is the only known naturally occurring antibody that can potently neutralize ZIKV and all four DENV serotypes (Xu 1; Kam, et al. (2017). JCI Insight 2 (“Kam”); Zhang, S., et al. (2020). Cell Rep.31 (“Zhang 1”)). [0316] The above antibodies were discovered by sorting hundreds of single B cells from individuals infected with DENV and/or ZIKV, followed by either immortalization or PCR amplification of variable heavy and light chain genes for recombinant IgG production and characterization (Boonyaratanakornkit and Taylor, (2019). Front. Immunol. 10, 1694 “Boonyaratanakornkit”). Although these approaches have successfully identified bnAbs against many viruses, they are laborious, typically requiring robots and/or large teams to increase throughput. As an alternative method, a proof-of-principle for a single cell RNA sequencing (scRNAseq)-based approach was provided to identify multiple DENV1-4 bnAbs, of which two somatic IgG variants, J8 and J9, were the most potent (Durham, et al. (2019). Elife 8 (“Durham”)). [0317] This Example improves upon the scRNAseq-based method to systematically profile the antibody response in 4 individuals whose sera potently cross-neutralized DENV1-4 and ZIKV. Twenty-three bnAbs were identified, of which a subset displayed neutralization breadth and potency comparable or superior to leading bnAbs in the field but with distinct epitopes. Moreover, one of the identified bnAbs neutralized DENV1-4 and ZIKV and is derived from the IgA1 isotype, thus representing the first non-IgG bnAb described against flaviviruses. Notably, monomeric IgA1 versions of newly and previously characterized bnAbs not only retained IgG neutralization breadth and potency, but also inhibited IgG-mediated enhancement of infection in cells expressing both IgG and IgA Fc receptors. [0318] Methods. Cohort Samples. The study’s use of samples from DENV and ZIKV infected human donors was approved by the Stanford University Administrative Panel on Human Subjects in Medical Research (Protocol #35460) and the Fundación Valle del Lili Ethics committee in biomedical research (Cali, Colombia). All participants, their parents, or legal guardians provided written informed consent, and subjects 6 years of age and older provided assent. Blood samples were collected from individuals who presented with symptoms compatible with dengue between 2016 and 2017 to the Fundación Valle del Lili in Cali, Colombia. Each blood sample was centrifuged to separate serum and peripheral blood mononuclear cells (PBMCs). Sera was stored F053-6006PCT / 23-211-WO-PCT at -80°C and corresponding PBMCs were cryopreserved and stored in liquid nitrogen. Cohort details have been previously described (Zanini, et al. (2018). Proc. Natl. Acad. Sci. U. S. A.115 (“Zanini”); Robinson, et al. (2019). Cell Rep.26, 1104–1111 (“Robinson”)). [0319] Cell lines. Expi-CHO-S Cells (Cat# A29127; ThermoFisher Scientific, Waltham MA) were cultured in ExpiCHO Expression Medium (Cat# A2910001; ThermoFisher Scientific) and maintained at 37°C in 8% CO2 on a platform rotating at 125 rotations per minute (rpm) with a rotational diameter of 19 cm. They were subcultured according to the manufacturer’s instructions. HEK-293T/17 cells (Cat# CRL-11268, American Type Culture Collection (ATCC), Manassas, VA) and Vero-C1008 cells (Cat# CRL-1586, ATCC) were maintained in Dulbecco's Modified Eagle Medium (DMEM) (Cat# 11965118; ThermoFisher Scientific) supplemented with 7% fetal bovine serum (FBS) (Cat# 26140079, lot 2358194RP, ThermoFisher) and 100 U/mL penicillin- streptomycin (Cat# 15140–122; ThermoFisher Scientific). Raji cells stably expressing DCSIGNR (Raji-DCSIGNR) (Davis, et al. (2006). J. Virol.80, 1290–1301) (provided by National Institutes of Health), K562 cells (Cat# CCL-243, ATCC), and U937 cells (Cat# CRL-1593.2, ATCC) were maintained in RPMI 1640 supplemented with GlutaMAX (Cat# 72400–047; ThermoFisher Scientific), 7% FBS and 100 U/mL penicillin-streptomycin. C6/36 cells (Cat# CRL-1660, ATCC ) were maintained in EMEM (Cat# 30–2003, ATCC) supplemented with 10% FBS at 30°C in 5% CO2. All cell lines were maintained at 37°C in 5% CO2 unless otherwise stated. [0320] Preparation of cells for single-cell RNA sequencing. Cryopreserved PBMCs were thawed quickly in a 37°C water bath and transferred to a 50 mL conical tube. Thirty mL of RPMI 1640 supplemented with 10% FBS (no antibiotics) was added to the cells dropwise while gently swirling. Cells were counted and CD19+ B cells were isolated using the EasySep Human Pan-B cell enrichment kit (Cat# 19554, StemCell Technologies, Vancouver, Canada) according to the manufacturer’s instructions. The resulting cells were incubated in a cocktail containing a live/dead stain (Cat# L34957, Thermo Scientific) and fluorescently labeled antibodies for CD20-eFluor450 (Cat# 48-0209-42, Invitrogen, Waltham, MA), CD38-FITC (Cat# 303504, Biolegend, San Diego, CA), CD27-PE-Cy7 (Cat# 25-0271-82, Invitrogen), CD19-APC (Cat# 555415, BD Biosciences), CD3-APC-Cy7 (Cat# 300318, Biolegend), CD8-APC-Cy7 (Cat# 344714) and CD14-APC-Cy7 (Cat# 301820) for 30 min at 4°C. Stained cells were washed twice in Fluorescent Activated Cell Sorting (FACS) wash buffer (10% FBS in PBS) and strained through FACS tubes with strainer caps (Cat# 352235, BD). The cells were analyzed on a BD FACS Aria flow cytometer to assess the purity of B cells (CD19+) and determine the fraction of cells that were plasmablasts (CD3-, CD8-, CD14-, CD19 mid to hi, CD20-, CD27+, CD38+). If the fraction of plasmablasts in the B cell sample was <10% (Donor 012), the plasmablasts were sorted via flow cytometry. If the fraction F053-6006PCT / 23-211-WO-PCT of plasmablast in the B cell sample was >10% (Donors 001, 002, 014), further enrichment was not performed. [0321] The cells were prepared for RNA library generation using the Chromium Next GEM Single Cell 5’ Library and Gel Bead Kit v1.1 (Cat# PN-1000167, 10X Genomics, Pleasanton, CA) according to the manufacturer’s instructions. A library enriched for variable regions of B cell receptors (BCR library) was generated using the Chromium Single Cell V(D)J Enrichment Kit, Human B Cell (Cat# PN-1000016, 10X Genomics) and the global gene expression library (GEX library) was generated using the Chromium Single Cell 5’ Library Construction Kit (Cat# PN- 1000020, 10X Genomics), both according to the manufacturer’s instructions. Both libraries from the sample D014 were sequenced on an Illumina HiSeq (Illumina, San Diego, CA), The libraries for the samples D001 (donor 001), D002 (donor 002), and D012 (donor 012) were sequenced on Illumina NovaSeq 6000. Sequencing data were demultiplexed and aligned to the human transcriptome GRCh38-2020-A using cellranger (10X genomics) version 5.0.1 (D001, D002, D012) or 5.0.0 (D014, donor 014), which also identified the isotype of each antibody. The “filtered” cellranger output was then passed to partis for paired heavy/light chain clustering and annotation with default parameters (Ralph). This included the default partis disambiguation of incomplete and ambiguous heavy/light pairing information, which for instance resolved an atypically large number of droplets in D014 with reads from more than one cell. After grouping all sequences from an individual donor into clonal families, partis estimated the V, D, and J gene segments that composed the naive antibody sequence.-B cell subtypes were identified using previously described gene markers (Waickman, et al. (2020). EBioMedicine 54, 102733 (“Waickman”)) in the AUCell package (1.12.0). [0322] Selection of candidate bnAbs from single-cell RNA sequencing data. The variable regions of the paired heavy and light chain sequences were grouped into clusters based on inferred shared ancestry (clonal families) using partis, as described previously (Ralph). For the first round of screening intended to find families that encode bnAbs, the largest clonal families from each donor were selected, excluding those in which the mean somatic hypermutation (measured by nucleotide sequence) was below 2%. Within the selected families, 1-2 sequences that had the lowest Hamming distance to consensus (i.e., the sequence consisting the most common amino acid present at each position) were selected, excluding those that were not encoded by plasmablasts. The selected antibodies were screened for their ability to neutralize DENV1-4 and ZIKV (described below) and those that neutralized >50% of infection of 3 or more viruses were considered “hits”. A second round of screening of antibodies was initiated from clonal families that had produced hits in the first round. Within each family, antibodies were selected in ascending F053-6006PCT / 23-211-WO-PCT order of Hamming distance to the consensus, again excluding those that were not encoded by plasmablasts. [0323] Expression of recombinant antibodies. Heavy and light chain constructs for recombinant IgG1 expression have been described previously (Dussupt) and were provided by the Walter Reed Army Institute of Research. For other antibodies, heavy and light chain variable regions were synthesized (Twist Bioscience, South San Francisco, CA). Variable region sequences for disclosed antibodies were selected from the scRNAseq data; those for control bnAbs were determined based on the protein database (PDB) entries 4UT9 (EDE1-C10), 4UTA (EDE1-C8), 4UT6 (EDE2-B7), 4UT6 (EDE2-A11), and 7BUD (SIgN-3C). All variable regions were cloned into the expression vectors: AbVec-hIgG1 (GenBank accession # FJ475055), AbVec-hIgKappa (GenBank accession# FJ475056) and AbVec-hIgLambda (GenBank accession # FJ517647), respectively . The variable regions were synthesized with overlapping sequences to their respective vectors. The sequence that was appended to the 5’ end was the same for all vectors: TAGTAGGAACTGCAACCGGTT (SEQ ID NO: 324). The sequence appended to 3’ ends was specific to each vector: for AbVec heavy: CGGTCGACCAAGGGCCCATCGG (SEQ ID NO: 325), for AbVec kappa: CGTACGGTGGCTGCACCATC (SEQ ID NO: 326), and for AbVec lambda: GGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCACCCTCGAGTGAGGAGCTTCAA GC (SEQ ID NO: 327). Heavy, kappa, and lambda vectors were linearized by digestion with SalI/AgeI, BsiWI/AgeI, and XhoI/AgeI, respectively as described in Guthmiller, et al. (2019). Methods Mol. Biol.1904, 109–145). Synthesized fragments and linearized vectors were ligated using NEBuilder HiFi DNA Assembly Master Mix (Cat# E2612L, New England Biolabs, Ipswich, MA) according to the manufacturer’s instructions. [0324] IgA1 heavy chains were generated by cloning the variable regions of selected antibodies into the expression vector pFUSEss-CHIg-hA1 (Cat# pfusess-hcha1, Invivogen, San Diego, CA). Variable regions of the antibody coding sequences were PCR amplified using the IgG1 heavy chain expression plasmid as a template and custom primers that appended an EcoRI site and an NheI site at the 5’ and 3’ ends respectively. Primer sequences were as follows: for F25.S02 GTACACGAATTCGCAGGTGCAGCTGGTGC (forward) (SEQ ID NO: 328) and GACTCTGCTAGCTGAGGAGACGGTGACC (reverse) (SEQ ID NO: 329); for EDE1-C10 GTACACGAATTCGGAGGTCCAACTTGTTG (forward) (SEQ ID NO: 330) and GACTCTGCTAGCAGAGCTTACGGTTACG (reverse) (SEQ ID NO: 331); and for SIgN-3C GTACACGAATTCGGAAGTACAACTGGTGC (forward) (SEQ ID NO: 332) and GACTCTGCTAGCTGAACTAACAGTTACCAG (reverse) (SEQ ID NO: 333). The PCR amplicons F053-6006PCT / 23-211-WO-PCT and the vector were digested with EcoRI and NheI and the resulting fragments were ligated using T7 DNA ligase (Cat# M0318, New England Biolabs). [0325] All AbVec antibody expression plasmids (IgG1-heavy, kappa, and lambda) were confirmed by Sanger sequencing using the primer “AbVec sense”: GCTTCGTTAGAACGCGGCTAC (SEQ ID NO: 334). IgA1 expression plasmids were confirmed by whole plasmid nanopore sequencing (Plasmidsaurus, Eugene, OR). To produce IgG1 and monomeric IgA1, heavy and light chain expression vectors were co-transfected into cultures of ExpiCHO-S cells at 0.8 ng/mL total DNA concentration at 1:1 mass ratio using OptiPro serum free medium (Cat#12309, Gibco) and Expifectamine CHO Transfection Kit (Cat# A29130, Gibco) according to the manufacturer’s instructions. To produce IgA1 dimers, plasmids encoding heavy, light, and joining chain (Cat# pUNO4-hJCHAIN, InvivoGen) were co-transfected at 0.8 ng/mL total DNA concentration at 1:1:1 mass ratio. Supernatant containing secreted antibodies was collected 8 days post transfection, centrifuged at 3220 x gravity (g) for 10 minutes and filtered through a 0.45 µm Steriflip filter (Cat# SE1M003M00, Millipore-Sigma). [0326] Purification of antibodies. The hybridoma D1-4G2-4-15, which expresses the antibody 4G2 was obtained from ATCC (Cat# HB-112). The hybridoma was expanded and IgG was purified from culture supernatant by the Fred Hutchinson Cancer Center Antibody Technology Core. The purified antibody was conjugated to APC using the Lighting-Link APC-conjugation kit (Cat# ab201807, Abcam) according to the manufacturer’s instructions. Recombinant IgG1 produced in transfected ExpiCHO-S cells as described above was purified using MabSelect Sure LX protein A agarose beads (Cat# 17-5474-01, Cytiva Life Sciences, Marlborough, MA) according to the manufacturer’s instructions. Recombinant IgA1 produced in ExpiCHO-S cells as described above was purified using protein M agarose beads (Cat# gel-pdm-2, InvivoGen US, San Diego, CA) according to the manufacturer’s instructions. IgA1 multimers were separated from monomers via size exclusion chromatography on a HiLoad 16/600 Superdex 200 pg column using 70 mL PBS as the eluate. A monomeric IgA1 antibody (Cat# 31148, ThermoFisher) was used as a standard for SDS-PAGE and as a negative control for ADE assays as indicated. [0327] Production of reporter virus particles. Reporter virus particles were produced by co- transfection of HEK-293T/17 cells with (i) a plasmid expressing a WNV subgenomic replicon encoding GFP in place of structural genes (Pierson, et al. (2006). Virology 346, 53–65 (“Pierson 1”)), and (ii) a plasmid encoding (capsid) C-(precursor membrane) prM-(envelope) E structural genes from the following viruses: DENV1 Western Pacific-74 (WP-74) (Ansarah-Sobrinho, et al. (2008). Virology 381, 67–74), DENV116007 (Dowd, et al. (2014). J. Virol. 88, 11726–11737), DENV2 16681 (Ansarah-Sobrinho, et al. (2008). Virology 381, 67–74), DKE-121 (Chen, et al. F053-6006PCT / 23-211-WO-PCT (2021). Cell Host Microbe 29, 1634–1648.e5 (“Chen 1”)), WNV NY99 (Pierson), and ZIKV H/PF/2013 (Dowd, et al. (2016). Cell Rep. 16, 1485–1491). Briefly, 8 x 105 HEK-293T/17 cells were plated in each well of a 6-well plate, The following day each well was co-transfected with 1 µg of replicon-encoding plasmid and 3 µg of C-prM-E-encoding plasmid using Lipofectamine 3000 (Cat# L3000-015; ThermoFisher Scientific) according to the manufacturer’s instructions. Four hours post-transfection, media was replaced with low-glucose DMEM (Cat# 12320–032; ThermoFisher Scientific) containing 7% FBS and 100 U/mL penicillin-streptomycin (i.e., low- glucose DMEM complete) and cells were transferred to 30°C in 5% CO2. Virus-containing supernatant was harvested twice per day at days 3 through 8 post-transfection, centrifuged at 700 x g for 5 minutes. The clarified supernatant was passed through a 0.45 µm Steriflip filter (Cat# SE1M003M00, Millipore-Sigma, St. Louis, MO), pooled, aliquoted, and stored at -80°C. [0328] Reporter virus particles with increased efficiency of prM cleavage were produced as above by co-transfecting plasmids encoding the replicon, structural genes, and human furin (provided by NIH) at a 1:3:1 mass ratio. DENV3 strain CH53489 (Cat# RVP-301; Integral Molecular, Philadelphia, PA) and DENV4 strain TVP376 reporter viruses (Cat# RVP-401; Integral Molecular) were obtained commercially and were produced by co-transfection of the DENV3 or DENV4 CprME plasmid with the DENV2 strain 16681 replicon as previously described (Mattia, et al. (2011). PLoS One 6, e27252). [0329] Infectious titers of reporter viruses were determined by infection of Raji-DCSIGNR cells. At 2 days post-infection, cells were fixed in 2% paraformaldehyde (Cat# 15714S; Electron Microscopy Sciences, Hatfield, PA), and GFP positive cells quantified by flow cytometry (Intellicyt iQue Screener PLUS, Sartorius AG, Gottingen, Germany). [0330] Generation of E protein variants. Construction of DENV216681 reporter virus variants in which E protein sites were substituted with corresponding ZIKV H/PF/2013 amino acid residues individually or in combination have been previously described. Similar methods to generate individual alanine mutations were used in this Example. Specifically, the DENV216681 CprME expression construct (Ansarah-Sobrinho, et al. (2008). Virology 381, 67–74) was used as a template for Q5 site-directed mutagenesis (Cat# E0554S; New England Biolabs, Ipswich, MA) and primers generated by NEBaseChanger (New England Biolabs, Ipswich, MA). The entire plasmid was sequenced (Plasmidsaurus, Eugene, OR) to confirm the presence of the desired mutation(s) only. [0331] ELISA. DENV216681 reporter virus particles were concentrated by ultracentrifugation through 20% sucrose at 166,880 x g for 4 hours at 4°C, resuspended in 1/100 volume of HNE buffer (5 mM HEPES, 150 mM NaCl, 0.1 mM EDTA, pH 7.4), and stored at -80°C. Nunc 384-Well F053-6006PCT / 23-211-WO-PCT Clear Polystyrene Plates (Cat# 164688 ThermoFisher) were coated with 20 uL/well of recombinant E monomers (Cat#DENV2-ENV, Native Antigen Co, Kidlington, United Kingdom) at 3 µg/mL or 20 µL/well of antibody 4G2 at 50 ug/mL overnight. The next day plates were washed once with 50 µL wash buffer (0.05% Tween-20 in PBS) and blocked with 50 uL of blocking buffer (3% nonfat milk in PBS) at 37°C for 45 min. Blocking buffer was aspirated from wells that had received 4G2 and replaced with 20uL of 100X concentrated reporter virus particles diluted 1:1 in blocking buffer. Wells that had received E monomers were left in blocking buffer and plates were incubated at 37°C for 45 min. Wells were washed 3 times with 50 uL of wash buffer, received 30 µL of primary antibody at 100 µg/mL, and were incubated at 37°C for 45 minutes. Wells were washed 6 times with 50 µL wash buffer, received 30 µL of mouse anti-human Ab (Cat# 05-4220, ThermoFisher) at 1 µg/mL, and were incubated at 37°C for 45 minutes. Finally, wells were washed 6 times with 50 µL wash buffer, received 30 µL of TMB (Cat# 34028 ThermoFisher), and were incubated until a color change was apparent. The reaction was stopped with 15 uL of 1N HCl and absorbance at 450 nm was read on SpectraMax i3x plate reader (Molecular Devices, San Jose, CA). [0332] Binding screen against alanine library. Binding of antibodies F25.S02 and F05.S03 to a DENV2 16681 library where each prM/E polyprotein residue was mutated to alanine (or alanine residues to serine) was screened (Davidson and Doranz, (2014). Immunology 143, 13–20 (“Davidson”)). In total, 559 sequence confirmed DENV2 mutants (99.6% coverage of the prM/E protein) were arrayed into 384-well plates (one mutation per well). The optimal screening condition was determined using an independent immunofluorescence titration curve against wild- type prM/E expressed in HEK293T cells to ensure that signals were within the linear range of detection and that signal exceeded background by at least 5-fold. F25.S02 and F05.S03 bound sufficiently well for screening only when the prM/E expression plasmid was co-transfected with a furin expression plasmid to enhance cleavage of prM to M. Thus, for antibody screening, plasmids encoding the DENV protein variants were individually co-transfected with furin expression plasmid into HEK-293T cells and expressed for 22 hours before incubation with purified IgG1 antibodies (0.1-2.0 µg/mL) diluted in 10% normal goat serum (NGS) (Sigma-Aldrich, St. Louis, MO) in PBS plus calcium and magnesium (PBS++). [0333] Antibodies were detected using 3.75 µg/mL Alexa Fluor 488-conjugated secondary antibody (Jackson ImmunoResearch Laboratories) in 10% NGS. Cells were washed three times with PBS++ followed by 2 washes in PBS, then fixed in 4% paraformaldehyde, washed in PBS (Electron Microscopy Sciences), and resuspended in Cellstripper (Corning) plus 0.1% BSA F053-6006PCT / 23-211-WO-PCT (Sigma-Aldrich, St. Louis, MO). Mean cellular fluorescence was detected by flow cytometry (Intellicyt iQue Screener PLUS, Sartorius AG, Gottingen, Germany). [0334] Antibody reactivity against each mutant was calculated relative to reactivity with wild-type prM/E, by subtracting the signal from mock-transfected controls and normalizing to the signal from wild-type protein-transfected controls. The entire library data for each antibody was compared to control antibodies. Mutations were identified as critical to the antibody epitope if they did not support reactivity of the test antibody, but supported reactivity of other control antibodies. This counter-screen strategy facilitates the exclusion of DENV prM/E protein mutants that impact folding or expression. [0335] Neutralization and antibody-dependent enhancement assays using reporter virus particles. All neutralization and ADE assays using the following strains were performed with reporter virus particles: DENV1 West-Pac 74, DENV116607, DENV216681, DENV3 CH53489, DENV4 TVP376, DKE-121, ZIKV H/PF/2013. Depending on the assay, stocks of reporter virus particles diluted to 5–10% final infectivity were incubated with either heat-inactivated serum (56°C for 30 min), 1/10 diluted ExpiCHO-S cell supernatant containing recombinant IgG1, or 5-fold serial dilutions of purified monoclonal antibodies for 1 hr at room temperature before addition of 2 x 105 Raji-DCSIGNR cells (neutralization assays), K562 cells (ADE assays), or U937 cells (ADE assays). After a 48 hour incubation at 37°C, cells were fixed in 2% paraformaldehyde and GFP positive cells were quantified by flow cytometry (Intellicyt iQue Screener Plus, Sartorius AG). For experiments using single dilutions of serum or ExpiCHO-S cell supernatant, infection was normalized to conditions without serum/supernatant and expressed as % infection of the untreated condition. For experiments using serial dilutions of serum or of purified monoclonal antibodies, infection was normalized to conditions without serum/antibody and analyzed by non- linear regression with a variable slope and the bottom and top of the curves constrained to 0% and 100%, respectively (Graph-PadPrism v8, GraphPad Software Inc). Results from experiments using serially diluted serum were reported as the reciprocal dilution at which 50% of infection was neutralized (NT50). Results from experiments using serially diluted purified antibodies were reported as the concentration at which 50% of infection was neutralized (IC50). [0336] Production, titer and neutralization of fully infectious virus. DENV1 UIS 998 (isolated in 2007, Cat# NR-49713), DENV2 US/BID-V594/2006 (isolated in 2006, Cat# NR-43280), DENV3/US/BID- V1043/2006 (isolated in 2006, Cat# NR-43282), and DENV4 strain UIS497 (isolated in 2004, Cat# NR-49724) were obtained from BEI Resources (Manassas, VA). Viral stocks were expanded by infecting 70% confluent C6/36 cells and virus-containing supernatant was collected and pooled at days 3 to 8 post infection. DENV4 H241 (isolated in 1956, Cat# F053-6006PCT / 23-211-WO-PCT TVP17463) was obtained from the World Reference Center for Emerging Viruses and Arboviruses at the University of Texas Medical Branch (Galveston, TX). The seed stock was expanded by infecting 90% confluent Vero cells and virus-containing supernatant was collected 7 days post infection. All virus-containing supernatants were centrifuged at 500 x g for 5 min, filtered through a 0.45 µm Steriflip filter (Cat# SE1M003M00, Millipore-Sigma), and stored at -80°C. Viral stocks were titered by infecting 2 x 105 Raji-DCSIGNR cells with 2-fold serial dilutions. Two days post infection cells were fixed and permeabilized using BD cytofix/cytoperm (Cat# 554717, BD Biosciences, Franklin Lakes, NJ) according to the manufacturer's instructions before being incubated with APC-conjugated (Cat# ab201807, Abcam, Waltham, MA), flavivirus E protein- specific antibody 4G2 for 30 minutes at 4°C. Cells were washed twice in cytoperm/wash buffer and APC+ positive cells were quantified by flow cytometry. [0337] For dose response neutralization assays using fully infectious virus, stocks were diluted to achieve 5-10% infection in Raji-DCSIGNR cells. Cells were incubated with 5-fold serial dilutions of antibodies for 1 hour, then combined with 2 x 105 Raji-DCSIGNR cells and incubated at 37°C 5% CO2. Before being stained for E protein as described above, IC50 values were calculated (as described above) for neutralization assays using reporter virus particles. [0338] Determining Fc receptor expression. K562 cells and U937 cells were washed in FACS wash (FW, 2% FBS in PBS) and resuspended in 50 µL of staining or isotype control antibody and incubated at 4°C for 30 min. For FcγRII, anti-CD32-FITC (Cat# 60012.FI, StemCell) and corresponding mouse IgG2b-FITC isotype control were used for staining. For FcαRI, anti-CD89/- PE (cat# 555686, BD Biosciences) and corresponding mouse IgG1-PE isotype control (cat# 12- 4714-42, ThermoFisher) were used for staining. Cells were washed twice in FW and analyzed by flow cytometry. [0339] Statistical analysis. All data were analyzed and plotted in Prism 8.4.3 (GraphPad Software, San Diego, CA). Where indicated, p-values for comparisons of IgG- versus IgA-mediated neutralization were obtained from one-way ANOVA using Tukey’s multiple comparisons tests. [0340] Results. Profiling the antibody repertoire of naturally infected individuals. BbnAbs against DENV1-4 (Durham) were previously identified from secondary analyses of available scRNAseq data of antibody genes encoded by 350 B cells obtained from an unrelated study (Zanini). The analysis was focused on B cells from individuals with broadly neutralizing antibody responses to specifically leverage scRNAseq for bnAb discovery (summarized in FIGs. 1A-1F). These individuals were enrolled in a prospective cohort in Colombia with confirmed acute DENV or ZIKV infection (FIG. 2) (Robinson; Zhang, et al. (2017). Nat. Med. 23, 548–550 (“Zhang 2”)). Longitudinal serum samples from 38 cohort participants were screened for their ability to F053-6006PCT / 23-211-WO-PCT neutralize prototype DENV1-4 and ZIKV strains in two independent experiments. When tested at a single dilution, no serum sample reproducibly neutralized West Nile virus (WNV), a more distantly related flavivirus included as a control. In contrast, even at the earliest available time point (range: 0 to 7 days after fever onset), serum samples from 26/38 individuals inhibited infection by two or more DENV serotypes by >50% in both experiments (FIG. 2). This high prevalence of cross-serotype neutralizing activity likely reflects repeated DENV exposures, as confirmed by IgG avidity testing (Robinson; Zhang 2). In addition to broad neutralizing activity against DENV1-4, serum samples from 11/38 individuals reproducibly neutralized >50% infection by ZIKV. [0341] To investigate the properties of broad and potent neutralizing antibody responses, 4 individuals were chosen with cross-flavivirus serum neutralizing activity, as confirmed by dose- response neutralization assays (FIG. 1A). In addition to broad and potent serum neutralizing activity, these individuals were selected due to the availability of corresponding peripheral blood mononuclear cells (PBMCs) at early time points during which bnAb responses were detected (within 11 days post-fever onset) (FIG. 2). Early time points were chosen to maximize the likelihood of detecting transiently circulating plasmablasts, which undergo a large expansion following acute DENV exposure (peaking between 4-14 days after onset of fever (Zompi; Xu, et al. (2012). J. Immunol. 189, 5877–5885 (“Xu 2”); Priyamvada, et al. (2016). J. Virol. 90, 5574– 5585 (“Priyamvada”); Wrammert, et al. (2012). J. Virol.86, 2911–2918 (“Wrammert”); Nivarthi, et al. (2019). EBioMedicine 41, 465–478; Garcia-Bates, et al. (2013). J. Immunol. 190, 80–8725) and often encode neutralizing antibodies against multiple DENV serotypes and in some cases, ZIKV after repeated exposures (Zompi; Xu 1; Dejnirattisai; Durham). Moreover, unlike memory B cells, plasmablasts constitutively secrete antibodies so their antibody repertoire likely closely mimics that of contemporaneous serum. [0342] CD19+ B cells were isolated from PBMCs of these 4 donors (FIG.1B) for single cell RNA sequencing (scRNAseq) of B cell receptor-specific and overall gene expression libraries (FIG. 1C). A total of 25,293 paired antibody coding sequences were obtained, with a mean of 6,323 per donor (range 4,644-9,249), comparable to previous studies that profiled antibody repertoires using this method (Waickman; Setliff, et al. (2019). Cell 179, 1636–1646; Cao, et al. (2020). Cell 182, 73–84 (“Cao”)). Antibodies were first grouped into clonally related sequences derived from the same rearrangement event (i.e., clonal families, FIG.1D) using partis (Ralph) paired clustering with default parameters. As shown in FIG.3A, the sizes of clonal families and the distributions of B cell subtypes within these samples varied substantially. Samples from donors 001 and 012 were dominated by naive B cells that were not members of any clonal family could be discerned. F053-6006PCT / 23-211-WO-PCT By contrast, samples from donors 002 and 014 were composed mostly of plasmablasts in large (4-50 members) or very large (50+ members) clonal families. Antibody isotype distribution also varied by donor: samples from donors 001 and 012 were mostly IgM while those from donors 002 and 014 were primarily IgG1 (FIG.3B). [0343] Functional characterization of antibodies. To downselect antibodies for functional characterization, a set of criteria that predicts antibody affinity and/or neutralizing activity was applied (summarized in FIG.1E and detailed in Methods). Briefly, antibodies were chosen that were 1) encoded by plasmablasts as these are often broadly neutralizing (Zompi; Xu 1; Dejnirattisai; Durham), 2) clonally expanded with >2% somatic hypermutation at the family level, indicating antigen-specific selection (Durham; Cao; Croote, D., et al. (2018). Science 362, 1306– 1309) and 3) most similar to their family’s amino acid consensus sequence, indicating high affinity (Ralph and Matsen, 4th (2020). PLoS Comput. Biol.16). [0344] One to three antibodies were selected from up to 28 clonal families per donor to identify families encoding bnAbs. These antibodies were recombinantly expressed as IgG1 by transfection of mammalian cells and the antibody-containing supernatant screened at a single dilution for neutralization of DENV1-4 and ZIKV. As shown in FIG. 4, the number and neutralization profile of clonal family ‘hits’ varied by donor. For example, of 14 total families tested from donor 001, only two (F05, F07) encoded neutralizing antibodies: F05 antibodies displayed weak ZIKV-specific neutralization, while F07 antibodies neutralized DENV1-3 and ZIKV, but not DENV4. Similarly, only two of the selected families from donor 012 (F12, F15) encoded neutralizing antibodies. In contrast, almost all 26 families from donor 002 neutralized DENV1 and DENV3, though only one (F09) neutralized DENV1-4 and ZIKV. Donor 014 antibodies displayed the broadest neutralization profile: almost all 28 selected clonal families neutralized DENV1-4 and, in some cases, ZIKV with varying potencies. Of these, antibodies from two families (F05 and F09) neutralized DENV1-4 by a mean of 97% and one family (F25) neutralized DENV1-4 and ZIKV by a mean of 92%. [0345] Having identified clonal families encoding bnAbs, additional members within these families were screened, and it was found that antibodies within a given family generally displayed similar neutralization profiles. For example, all 10 selected antibodies from family F07 of donor 001 neutralized DENV1, DENV2, DENV3, and ZIKV, but not DENV4. Similarly, all tested antibodies from donor 014 family F09 neutralized all four DENV serotypes but not ZIKV, while those from family F25 broadly neutralized DENV1-4 and ZIKV, though the level of DENV2 and DENV4 inhibition was variable (FIG. 4). These results demonstrate that the disclosed bioinformatics- F053-6006PCT / 23-211-WO-PCT based approach successfully identified clonal families encoding multiple broadly neutralizing antibodies. [0346] Identifying antibodies with potent and cross-reactive neutralizing activity. Based on the above crude screens with transfection supernatant, 23 IgG1 antibodies were purified that inhibited DENV1-4 and in some cases ZIKV by >50%. Their neutralizing activity was confirmed in dose- response assays and the concentration at which each antibody inhibits 50% of virus infection (IC50) was calculated. All but one (F15.S01 from donor 012) of these antibodies were from donor 014 and neutralization profiles from dose-response assays were overall concordant with those from the crude screen. It was confirmed that the selected antibodies fell into two main categories based on neutralization: 1) those that cross-neutralized DENV1-4 and ZIKV, and 2) those that cross-neutralized DENV1-4 but not ZIKV (FIG.5). [0347] The neutralization breadth and potencies of the disclosed antibodies were compared to each other and to previously identified bnAbs tested in parallel. EDE1-C10 (Dejnirattisai; Barba- Spaeth) and SIgN-3C (Xu 1; Zhang 1) represent the only known classes of bnAbs that simultaneously neutralize ZIKV in addition to DENV1-4 (category 1). J9, an antibody that was previously isolated from a different donor in the same cohort, potently neutralizes DENV1-4, but not ZIKV (category 2) (Durham). EDE2-A11 was also included, which weakly neutralizes ZIKV, unlike EDE1 subclass antibodies (Barba-Spaeth), and MZ4, which neutralizes ZIKV and some DENV serotypes (Dussupt). [0348] Among all category 1 antibodies tested, the most potent was F25.S02 from donor 014 based on geometric mean IC50 value (FIG. 5). The potency of F25.S02 against ZIKV was comparable to EDE1-C10 (IC50 of 18 and 14 ng/ml, respectively) but was 39 times higher than that of SIgN-3C (IC50 of 694 ng/ml). The geometric mean potency of F25.S02 against DENV1-4 was also 2-fold higher than that of EDE1-C10 (IC50 of 96 ng/ml versus 207 ng/ml, respectively). Family F25 contained 3 other antibodies that broadly neutralized DENV1-4 and ZIKV. These antibodies (F25.S03, F25.S04, F25.S06) neutralized DENV1, DENV2, DENV3, and ZIKV with relatively similar potency as F25.S02, but they were less potent against DENV4 (IC50 of 1 μg/ml). [0349] Among the newly identified category 2 antibodies, F09.S05 was most potent; its geometric mean IC50 against DENV1-4 was comparable to the previously identified J9 (Durham) within the same category (36 ng/ml and 33 ng/ml, respectively). Additional high-ranking category 2 antibodies include others from family F09 and antibody F05.S03 from family F05. [0350] Thus, several neutralizing antibodies were identified with similar or better breadth and potency compared to existing bnAbs. Even within the same donor, these bnAbs were derived from multiple germline genes and did not display unusually high levels of somatic hypermutation F053-6006PCT / 23-211-WO-PCT (Table 1), as has been reported for some bnAbs against other viruses (Wang, et al. (2020). Cell Host Microbe 28, 335–349; Kwong and Mascola, (2012). Immunity 37, 412–425). For subsequent detailed characterization, the top-ranking antibody from each clonal family of donor 014 was chosen, namely F25.S02, F09.S05, and F05.S03. FIG.6A shows representative dose-response neutralization assays demonstrating that these disclosed bnAbs are roughly as potent, and in some cases, more potent, than previously published bnAbs (FIGs.6B and 5). [0351] FIG. 16 provides genetic characteristics of broadly neutralizing antibodies whose IC50 values are displayed in FIG. 7. Bold = chosen for detailed characterization; triangle = non-IgG isotype; ? = insufficient sequence coverage of constant gene to determine isotype information; pb = plasmablast. [0352] Newly identified antibodies neutralize flavivirus antigenic variants. There is antigenic variation even within a given DENV serotype (Katzelnick, et al. (2015). Science 349, 1338–1343; Bell, et al. (2019). Elife 8 (“Bell”); Martinez, et al. (2020). Cell Rep. 33, 108226), which is composed of distinct genotypes (Rico-Hesse, (1990). Virology 174, 479–493; Holmes and Twiddy, (2003). Infect. Genet. Evol.3, 19–28). For example, the DENV1 strain West Pac-74 (WP- 74) used in the above screens belongs to genotype IV, which is the most antigenically distinct within this serotype (Bell). Additionally, this DENV1 strain is thought to display altered structural dynamics that globally affect antigenicity (Dowd, et al. (2015). MBio 6; VanBlargan, et al. (2021). J. Virol. 95). To rule out the possibility that DENV1 inhibition was limited to an unusually neutralization-sensitive strain, it was confirmed that the disclosed bnAbs also potently neutralized the genotype II DENV1 strain 16007 (IC50 range of 4 to 30 ng/ml, FIG.6C). DENV4 also displays antigenic variation across genotypes (I and II) that circulate in humans (Chen and Vasilakis, (2011). Viruses 3, 1562–1608; Gallichotte, et al. (2018). Cell Rep.25, 1214–1224 (Gallichotte)). Many of the disclosed lower-ranking antibodies and some known bnAbs neutralized the DENV4 genotype II TVP376 strain used in the above screens with modest potency (FIG.4). When tested against the DENV4 genotype I strain H241, category 1, but not category 2 bnAbs retained neutralization potency (FIG.6C). This preferential neutralization of DENV4 genotype II by most antibodies is consistent with previous observations (Gallichotte; Henein, et al. (2017). J. Infect. Dis.215, 351–358; Juraska, et al. (2018). Proc. Natl. Acad. Sci. U. S. A.115 (Juraska); Rabaa, et al. (2017). Elife 6 (“Rabaa”)). The disclosed bnAbs were also tested against DKE-121, a recently identified strain that is so distantly related to existing serotypes that some have proposed a fifth serotype (Normile, (2013). Science 342, 415; Young, et al. (2017). Parasit. Vectors 10, 406; “Chen 1”). Excitingly, F25.S02 and F09.S05 potently neutralized DKE-121(IC50 of 212 and 59 F053-6006PCT / 23-211-WO-PCT ng/ml, respectively), though F05.S03’s neutralization of this strain was relatively weak (IC50 of 4500 ng/ml) (FIG.6C). [0353] Except for DKE-121, most strains used above were lab-adapted and isolated many decades ago (1956 - 1982). Additionally, most were tested as single-round infectious reporter virus particles (with the exception of H241, which was tested as a replication competent virus). Reassuringly, F25.S02, F09.S05, and F05.S03 also neutralized more contemporaneous, fully infectious DENV1-4 clinical isolates collected between 2004 and 2007 with geometric mean IC50 values lower than for the known bnAb EDE1-C10 but higher than SIgN-3C and J9 (FIG.6D). [0354] Aside from genetic diversity, flavivirus antigenic variation can also arise from heterogeneous virion maturation states resulting from inefficient cleavage of prM, a chaperone for the E protein. Many but not all flavivirus-specific antibodies preferentially neutralize incompletely mature virions that retain prM on the surface (Cherrier, et al. (2009). EMBO J.28, 3269–3276; Nelson, et al. (2008). PLoS Pathog.4 (“Nelson”); Goo, et al. (2019). Nat Microbiol 4, 71–77). Importantly, there is increasing evidence that the ability to neutralize the structurally mature form of flaviviruses is important for in vivo protection (Raut, et al. (2019). Proc. Natl. Acad. Sci. U. S. A.116, 227–232; Maciejewski, et al. (2020). Sci. Transl. Med.12 (“Maciejewski”)). The ability of the disclosed bnAbs to neutralize either partially mature DENV2 or ZIKV produced under standard conditions or more fully mature viruses produced in the presence of excess furin to enhance prM cleavage was tested (Nelson) (FIG.7). As controls, antibodies E60 and ZV-67 were included, which poorly neutralize mature forms of DENV2 and ZIKV, respectively, resulting in a large fraction of infectious virions even at high antibody concentrations, consistent with previous studies (Nelson; Goo, et al. (2017). PLoS Pathog.13, e1006178; Goo, et al. (2018). Virology 515, 191–202). In contrast to these control antibodies, whose IC50s against mature virus is 15-30 fold higher than against partially mature virus (FIG. 7), F25.S02, F09.S05, and F05.S03 potently neutralized DENV2 regardless of maturation state (maximum IC50 fold change of 2.7). Moreover, F25.S02 was more potent against the mature form of ZIKV (15-fold decrease in IC50). Preferential neutralization of mature ZIKV by known bnAbs EDE1-C10 and SIgN-3C was also observed. Overall, these results demonstrate that the disclosed bnAbs can neutralize flavivirus antigenic variants arising from both genetic and structural heterogeneity that are relevant for vaccine efficacy (Juraska; Rabaa; Maciejewski), though the ability to broadly neutralize multiple DENV4 genotypes was restricted to F25.S02. [0355] Mapping E protein determinants of antibody binding. Many potently neutralizing flavivirus antibodies target complex epitopes displayed optimally on virions and not on soluble monomeric E protein (VanBlargan, et al. (2016). Microbiol. Mol. Biol. Rev.80, 989–1010). To determine the F053-6006PCT / 23-211-WO-PCT E protein oligomeric form recognized by the dislosed bnAbs, ELISA was performed to assess binding to soluble monomeric E protein or to virus particles of the prototype DENV216681 strain. Unlike antibody B10, which was previously shown to efficiently bind E proteins displayed in both contexts (Durham), F25.S02, F09.S05, and F05.S03 bound efficiently to E proteins displayed on virus particles only, similar to the known bnAb EDE1-C10 (Dejnirattisai) (FIGs. 8A, 8B). These results indicate that the disclosed bnAbs preferentially recognize quaternary epitopes. [0356] To identify E protein amino acid residues critical for binding, antibodies were screened against a shotgun alanine-scanning mutagenesis library of DENV2 prM/E proteins (Durham; Davidson). As controls, known bnAbs EDE1-C10 and J9 were included. Alanine mutations were identified that specifically reduced F25.S02 or F05.S03 binding by >70% relative to wild type DENV2 (FIGs.8C-8F; FIG.17 shows screen results against the entire library). [0357] For F25.S02, all E residues identified as important for binding were located in domain II (G78, L82, V97, I113, N242) with the exception of M6 in domain I (FIGs. 7C, 7D). Mutation at these residues minimally impacted binding by the known bnAb EDE1-C10, which retained 50- 85% of wild type binding reactivity (FIG.7D). EDE1-C10 and F25.S02 are further distinguished by their dependence on K310A, which abolished binding by EDE1-C10, but not by F25.S02 (FIG. 7D). Thus, although F25.S02 and EDE1-C10 display a similar neutralization profile against DENV1-4 and ZIKV, their binding determinants on DENV2 are distinct. [0358] For F05.S03, mutation at E residue N153 or T155 in domain I, each of which abolishes a potential N-linked glycosylation site, reduced binding efficiency by 85% (FIGs. 7E, 7F). The presence of this potential N-linked glycosylation site has also been shown to be important for recognition by J9 (Durham) (FIG.7F) and by the EDE2 subclass of bnAbs 28. A shared feature of these antibodies is potent neutralization of DENV1-4, but not ZIKV (FIGs. 5A-5D). Other residues important for F05.S03 binding include V308, V309, and K310 in E domain III. Of these, K310A also strongly reduced binding efficiency by J9 (FIG.7F). [0359] Despite testing multiple conditions (data not shown), binding of F09.S05 to wild type DENV2 was not detected in this format. Thus, an alternative mapping approach was used, as described below, for this antibody. [0360] FIG.17 provides antibody binding reactivity to a DENV216681 E protein alanine scanning mutagenesis library. Mean percentage and range of binding reactivity to alanine mutant relative to wild type DENV2 from at least two independent experiments are shown. [0361] Mapping neutralization determinants. As F09.S05 neutralized DENV1-4 but not ZIKV, neutralizing activity was screened against a previously described DENV2 library encoding mutations at solvent accessible E residues that were identical or similar across representative F053-6006PCT / 23-211-WO-PCT DENV1-4 strains but different from ZIKV (Durham). Specifically, amino acids at these E protein sites in DENV2 16681 were substituted with corresponding ZIKV H/PF/2013 amino acids individually or in combination to identify those that reduce antibody potency against DENV2 and thus comprise the neutralization epitope. A subset of identified DENV2 alanine mutations were also tested in the binding screen above to validate their role in neutralization. [0362] Most mutations that strongly impacted F09.S05 neutralizing activity were located in E domain I (FIG.9A). Removing the potential N-linked glycosylation site through mutation at residue N153 or T155 abrogated neutralization, while the nearby V151T mutation reduced F09.S05 potency by 20-fold. Combining V151T with H149S abolished neutralizing activity. The glycosylation site mutations also abolished neutralization by F05.S03 (FIG.9C) and J9 (FIG.9E), consistent with results from the binding screen described above (FIG. 8F) and a previously described study with J9 (Durham). In addition to these shared residues important for neutralization, unique determinants were identified that distinguished F09.S05 and F05.S03 from each other and from the previously characterized J9. For example, although the individual S145A and H149S mutations minimally impacted F09.S05 and J9 (≤ 4-fold change in IC50), each mutation reduced F05.S03 neutralization potency by 20-fold. Moreover, the combination of K47T+F279S mutations in domain I minimally impacted F09.S05 and F05.S03 (≤ 4-fold IC50 change, FIGs.9A, 9B), but reduced J9 potency by 76-fold (FIG.9C). [0363] As mentioned, the N153 and T155 glycosylation site mutants abolished neutralization by F09.S05, F05.S03, and J9, which neutralize DENV1-4 but not ZIKV. In contrast, when tested against EDE1-C10 and F25.S02, both of which neutralize ZIKV in addition to DENV1-4, these mutations increased neutralization potency by up to 50-fold (FIGs. 9B, 9D). Another shared feature between EDE1-C10 and F25.S02 is a large reduction in neutralization potency against the K47T+F279S double mutation in E domain. However, there were distinct neutralization determinants for these bnAbs. Specifically, the I113A and N242A mutations in domain II strongly reduced F25.S02 potency (30-fold, FIG.9D) but had a modest effect on EDE1-C10 potency (4- fold IC50 increase, FIG. 9E). Moreover, the K310A mutation in domain III resulted in a 80-fold reduction in EDE1-C10 potency (FIG. 9D), but slightly increased F25.S02 potency (FIG. 9B). These results validate those from the alanine binding screen (FIG. 8D). Thus, despite some similarities, E residues were identified that distinctly impact neutralization by newly discovered bnAbs relative to each other and to known bnAbs. [0364] Effect of antibody valency on neutralizing activity. To gain insight into the epitope arrangement on virions, the neutralization potency of F25.S02, F09.S05, and F05.S03 tested as bivalent IgG or monovalent Fab against DENV2 and ZIKV was compared (FIGs. 10A-10E). F053-6006PCT / 23-211-WO-PCT Except for F09.S05, the Fab versions of all antibodies tested, including known bnAb controls, EDE1-C10 and SIgN-3C, failed to neutralize DENV2 by at least 50% at the highest antibody concentration tested (400 nM), indicating that bivalent engagement is important for potent DENV2 neutralization by these antibodies (Sharma, et al. (2021). Cell 184, 6052–6066). Although SIgN- 3C IgG neutralized ZIKV with moderate potency, no neutralization was detected with Fab, consistent with previous findings (Zhang 1). In contrast, EDE1-C10 and F25.S02 retained the ability to completely neutralize ZIKV as Fab. Although IgG versions of EDE1-C10 and F25.S02 neutralized ZIKV with similar potency, their Fab neutralization profiles were more distinct; unlike EDE1-C10 Fab, which retained relatively potent neutralization consistent with previous findings (<10-fold increase in IC50 compared to IgG) F25.S02 neutralized ZIKV with much reduced potency as Fab (64-fold increase in IC50 compared IgG). These results indicate that EDE1-C10 and F25.S02 target distinct epitopes on ZIKV. [0365] Neutralizing activity of IgA1 antibodies is similar to or better than IgG1 versions. As neutralizing activity is traditionally thought to be dependent mainly on changes within the antibody variable region, neutralizing antibodies have typically been tested as the IgG1 subclass, regardless of their native isotype (Scheepers, et al. (2022). Trends Mol. Med. 28, 979–988 (“Scheepers 1”)). Moreover, most studies profiling the neutralizing antibody repertoire against flaviviruses have specifically isolated IgG antibodies (Dejnirattisai; Dussupt; Robbiani; Rogers; Xu 2; Priyamvada). While the scRNAseq-based approach was not biased towards a particular antibody isotype, all antibodies were initially expressed and screened as IgG1, similar to previous studies. Given increasing evidence that antibody Fc isotype can impact neutralizing activity against many viruses (Scheepers, et al. (2020). Cell Rep.33, 1084309 (“Scheepers 2”); Wang, et al. (2021). Sci. Transl. Med.13 (“Wang 2”); Bolton, et al. (2022). bioRxiv (“Bolton”); Hale, et al. (2022). J. Exp. Med. 219 (“Hale”); Singh, T., et al. (2022). Cell 185, 4826–4840 (“Singh”)), scRNAseq data was used to confirm that the native isotype of almost all 23 antibodies downselected for detailed characterization was indeed IgG1 (FIG. 16). However, unlike other flavivirus bnAbs described here or previously, the disclosed top-ranking bnAb, F25.S02 was derived from the IgA1 isotype. [0366] To investigate the impact of isotype on neutralizing activity, F25.S02, EDE1-C10, and SIgN-3C were expressed as monomeric or dimeric IgA1 and their neutralization profile was compared to IgG1 versions. Although IgA1 dimers were purified by size-exclusion chromatography, the presence of higher order polymers (Woof and Russell, (2011). Mucosal Immunol.4, 590–597) could not be excluded by SDS-PAGE analysis (FIGs.11A-11C) so these antibodies were referred to as polymeric IgA1 hereafter. F053-6006PCT / 23-211-WO-PCT [0367] As shown in FIGs.12A and 12B, all 3 bnAbs retained neutralization breadth and potency as monomeric IgA1. Moreover, while F25.S02 monomeric IgA1 and IgG1 displayed comparable potency against DENV1-4 and ZIKV (maximum of 2-fold IC50 change), monomeric IgA1 versions of EDE1-C10 and SIgN-3C were more potent against some viruses (FIG. 12B). For example, compared to their IgG1 versions, EDE1-C10 and SIgN-3C monomeric IgA1 antibodies were 4 times more potent against DENV3, though sample sizes were too small to achieve statistical significance (p = 0.15 and p = 0.22, respectively). SIgN-3C potency against ZIKV was also 9 times higher as monomeric IgA1 compared to IgG1 (p = 0.07). [0368] Antibody expression as polymeric IgA1 further increased potency compared to IgG1 to varying extents. This effect was most apparent for viruses against which the IgG1 version of the particular antibody was the least potent; for F25.S02, EDE1-C10 and SIgN-3C polymeric IgA1, the largest IC50 reduction compared to IgG1 was observed against DENV2 (20-fold, p = 0.03), DENV3 (9-fold, p = 0.15), and ZIKV (167-fold, p = 0.1), respectively (FIG.12B). This increased potency of IgA1 bnAbs is unlikely due to non-specific effects as none neutralized the more antigenically distant WNV (FIG.12A). [0369] IgA1 antibodies inhibit enhancement of infection by IgG1. Virtually all IgG antibodies can enhance flavivirus infection in vitro at sub-neutralizing concentrations, presumably by facilitating uptake of IgG-virus complexes into FcɣR-expressing cells (Pierson, et al. (2007). Cell Host Microbe 1, 135–145). Accordingly, IgG1 versions of newly and previously identified bnAbs enhanced infection to various extents in K562 cells (FIG.13) commonly used to study ADE as they express FcɣRIIa (FIG.14) and are poorly permissive to flavivirus infection in the absence of IgG (Littaua, et al. (1990). J. Immunol.144, 3183–3186). Enhancement of ZIKV infection by J9, F09.S05, and F05.S03 was not detected (FIG.14), indicating that the lack of ZIKV neutralizing activity by these antibodies (FIGs.6A-6D) is due to their inability to bind ZIKV. [0370] FIGs.12A and 12B demonstrate that regardless of native isotype, F25.S02, EDE1-C10, and SIgN-3C bnAbs expressed as IgA1 retained IgG1 neutralization breadth and potency. As existing studies of ADE of viral infection or disease have focused on the role of IgG-FcɣR interactions (Katzelnick 1; Wang 1; Katzelnick 2; Thulin, et al. (2020). Cell Rep. 31, 107642 (Thulin); Bournazos, et al. (2020). Nat. Rev. Immunol.20, 633–643; Arvin, et al. (2020). Nature 584, 353–363), the role of IgA in enhancing DENV infection was investigated. Specifically, the ability of IgA1 versions of F25.S02, EDE1-C10, and SIgN-3C to enhance DENV1 and DENV4 infection was tested; these viruses were chosen as the infectivity curves obtained across the concentration range of IgG1 versions of bnAbs of interest fully captured both enhancement and neutralization in K562 cells (FIG.13). F053-6006PCT / 23-211-WO-PCT [0371] As expected, IgG1 but not IgA1 versions of F25.S02, EDE1-C10, and SIgN-3C enhanced DENV infection in K562 cells (FIG.15A), which do not express Fc alpha receptor (FcɑR1) (FIG. 14). Surprisingly, monomeric IgA1 antibodies failed to enhance DENV infection even in U937 monocytes (FIG.15B), which express FcɑR1 in addition to FcɣRs (FIG.14) (Boltz-Nitulescu, et al. (1995). J. Leukoc. Biol.58, 256–262; Geissmann, et al. (2001). J. Immunol. 166, 346–352). Moreover, ADE assays using mixtures of IgG1 and IgA1 antibodies at various ratios demonstrated that autologous IgA1 antibodies inhibited IgG1-mediated ADE of DENV infection in U937 cells (FIG. 15B) in a dose-dependent manner, as revealed by area under the curve analyses (FIG. 15C). That this effect was observed for all 3 bnAbs regardless of native isotype and epitope specificity indicates that IgA1 antibodies can broadly interfere with IgG1-mediated ADE. Crucially, an isotype control IgA1 antibody had virtually no effect on ADE mediated by IgG, indicating that inhibition was due neither to a reduction in IgG1 concentration in IgG1/IgA1 mixtures nor the presence of non-specific IgA1. Rather, this indicates that IgA1 inhibits ADE mediated by IgG1 via direct competition of binding to virions. [0372] Discussion. Unlike most antibody discovery approaches that involve screening large panels of antibodies expressed by sorted and baited B cells (Boonyaratanakornkit), a proof-of- concept for a bioinformatics-based strategy has been established to identify not only antigen- specific antibodies, as shown previously by other groups (Cao; Parola, et al. (2018). Immunology 153, 31–41; Gilchuk, et al. (2020). Nat Biomed Eng 4, 1030–1043), but also those with broadly neutralizing activity (Durham). In this Example, previous approaches have been improved upon, and scRNAseq of B cells was leveraged to identify multiple antibodies that broadly and potently neutralized DENV1-4 and in some cases, ZIKV. This Example demonstrates a promising platform for accelerating the discovery of flavivirus bnAbs whose characterization can reveal the basis of desirable antibody properties to inform strategies for novel vaccines and therapeutics. Although most of the disclosed bnAbs were of the IgG1 isotype, consistent with previous findings (Xu 1; Dejnirattisai; Durham), an IgA1 antibody with broadly neutralizing activity against DENV1-4 and ZIKV is also described for the first time. [0373] Despite broad and potent serum neutralizing activity in all 4 donors selected for antibody repertoire analysis, almost all monoclonal bnAbs were isolated from only one donor (014). The basis for donor-dependent effects was investigated, consistent with previous findings (Wrammert; Waickman), and antibody neutralizing activity could be partly explained by sample collection time (FIG.2), which likely affected the ability to capture transiently circulating plasmablasts (FIG.3A), many of which encode bnAbs (Zompi; Xu 1; Dejnirattisai; Boonyaratanakornkit). Alternatively, the observed serum neutralization breadth and potency across donors was due to a combination of F053-6006PCT / 23-211-WO-PCT antibodies with multiple specificities. However, within a given donor, an obvious pattern of complementary neutralizing activity among antibodies from distinct clonal families was not detected (FIG. 4). The number and order of prior flavivirus exposures also impact bnAb development (Katzelnick 2). It is interesting that unlike other donors analyzed, donor 014 was confirmed to have been acutely co-infected with two DENV serotypes (FIG.2). Prior studies have documented concurrent infection by multiple DENV serotypes in hyperendemic regions (Senaratne, et al. (2020). Epidemiol. Infect.148, e119; Gubler, et al. (1985). Am. J. Trop. Med. Hyg.34, 170–173; Bharaj, et al. (2008). Virology Journal 5; Figueiredo, de, Naveca, F.G., et al. (2011). Rev. Inst. Med. Trop. Sao Paulo 53, 321–323; Colombo, et al. (2013). Revista do Instituto de Medicina Tropical de São Paulo 55, 275–281; Dewi, et al. (2014). Southeast Asian J. Trop. Med. Public Health 45, 53–61). [0374] Although neutralizing activity is thought to be primarily determined by somatic hypermutation within IgG antibody variable regions, Fc isotype can also impact neutralization potency and/or breadth against many viruses (Scheepers 2; Wang 2; Bolton; Hale; Singh). For example, a recent study described a naturally occurring ZIKV-specific pentameric IgM antibody (DH1017.IgM) whose potency depended on the IgM isotype (Singh). Unlike DH1017.IgM, which did not neutralize DENV, this Example describes F25.S02, an IgA1 antibody that potently cross- neutralized ZIKV and DENV1-4 and retained its potency as IgG1. While IgA bnAbs have been described for other antigenically distinct viruses such as HIV (Scheepers 1) and SARS-CoV-2 (Wang 2), F25.S02 is the first known IgA bnAb against flaviviruses. In addition to its distinct isotype, the disclosed epitope mapping results demonstrate that despite some similarities, F25.S02 has unique binding and neutralization determinants compared to EDE1-C10 (Dejnirattisai; Rouvinski; Barba-Spaeth) and SIgN-3C (Xu 1; Kam; Zhang 1) IgG1 antibodies, which represent the only 2 known classes of bnAbs that potently neutralize ZIKV and DENV1-4. [0375] Human IgA antibodies in serum and mucosal sites exist primarily as monomeric or dimeric/polymeric forms, respectively (Woof and Russell, (2011). Mucosal Immunol.4, 590–597). As monomeric IgA1, F25.S02 displayed comparable neutralizing activity to IgG1 against DENV1- 4 and ZIKV. In contrast, expression of EDE1-C10 and SIgN-3C bnAbs as monomeric IgA1 improved potency against some viruses, despite their native IgG1 isotype (Dejnirattisai; Xu 2). These findings are consistent with epitope- and virus-dependent effects of antibody isotype on neutralization (Scheepers 1). Expression of all 3 bnAbs as polymeric IgA1 increased potency against DENV1-4 and ZIKV relative to corresponding monomeric IgA1 or IgG1 versions. This observation indicates that the epitope arrangement of these bnAbs allows multivalent engagement by polymeric IgA on the same virion. Alternatively or in addition to this mechanism, F053-6006PCT / 23-211-WO-PCT polymeric IgA could bind the same epitope on multiple virions to cause aggregation. Both mechanisms of virion engagement have been shown for DH1017.IgM, depending on the particular antibody conformation (Singh). [0376] Compared to other isotypes, IgA1 antibodies have a greater distance between Fabs relative to each other and to the Fc domain (Correa, et al. (2013). Acta Crystallogr. D Biol. Crystallogr.69, 388–397; Pan, et al. (2021). Int. J. Mol. Sci.22), providing a possible mechanism for unique neutralizing and Fc-dependent effector functions (Scheepers 1). Further, engagement of IgA with FcɑR1 is distinguished from that of other isotypes with their Fc receptors in terms of stoichiometry, orientation, and protein binding sites (Otten and van Egmond, (2004). Immunology Letters 92, 23–31). In this Example, it is demonstrated that that unlike IgG1, IgA1 versions of bnAbs failed to mediate ADE of DENV infection even in cells expressing Fc receptors for both isotypes. Moreover, IgA1 antibodies not only displayed neutralization breadth and potency comparable or superior to IgG1, but also inhibited IgG1-mediated ADE in a dose-dependent manner, likely via competition for binding to virions. Thus, previous results demonstrating the ability of monomeric IgA1 to antagonize IgG-mediated ADE of DENV in cells that express FcɣR but not FcɑR1 are extended in this Example (Wegman, et al. (2021). Front. Immunol.12, 777672). [0377] Existing studies of flavivirus immunity have heavily focused on the role of IgG antibodies and their interactions with FcɣRs (Katzelnick 1; Chau; Wang 1; Katzelnick 2; Thulin; Halstead, (2014). Microbiol Spectr 2). The disclosed results nevertheless highlight an underappreciated role for flavivirus-specific IgA antibodies in infection and immunity. Indeed, recent studies reported a high proportion of DENV-reactive IgA-expressing plasmablasts following acute primary infection and to a lesser extent, secondary infection (Waickman; Rouers, A., et al. (2021). iScience 24, 102482). The disclosed analysis of circulating B cell repertoires here also demonstrates that while IgG dominated the response, IgA and IgM antibodies were prevalent (FIG.3B). Notably, FcɑR1 is expressed on myeloid cells, including monocytes, macrophages, and dendritic cell subsets (Monteiro and Van De Winkel, (2003). Annu. Rev. Immunol.21, 177–204; Chevailler, et al. (1989). J. Immunol.142, 2244–2249; Maliszewski, et al. (1985). J. Immunol.135, 3878–3881; Monteiro, et al. (1990). J. Exp. Med.171, 597–613), all of which also express FcɣRs and are thought to be principal target cells for DENV in vivo (Zanini; Durbin, et al. (2008). Virology 376, 429–435; Fong, et al. (2004). J. Infect. Dis.189, 1411–1418; Kyle, et al. (2007). J. Infect. Dis.195, 1808–1817; Kou, et al. (2008). J. Med. Virol.80, 134–146; Balsitis, et al. (2009). Am. J. Trop. Med. Hyg.80, 416–424). Intriguingly, IgA-FcɑR1 interactions can modulate activating or inhibitory responses mediated by other Fc receptors (Pasquier, et al. (2005). Immunity 22, 31–42; Breedveld and van Egmond, (2019). Front. Immunol. 10, 553). Together, these observations underscore the F053-6006PCT / 23-211-WO-PCT importance of future studies to account for the complex interplay among distinct antibody isotypes and Fc receptors in modulating flavivirus immunity and pathogenesis. Determining whether IgA and other non-IgG isotypes mitigate or potentiate antibody-associated disease in vivo will inform strategies to improve the safety and efficacy of antibody-based countermeasures (Dengue vaccine: WHO position paper, September 2018. Vaccine 37, 4848–4849). [0378] (XI) Closing Paragraphs. The nucleic acid and amino acid sequences provided herein are shown using letter abbreviations for nucleotide bases and amino acid residues, as defined in 37 C.F.R. §1.831-1.835 and set forth in WIPO Standard ST.26 (implemented on July 1, 2022). Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included in embodiments where it would be appropriate. [0379] Variants of the sequences disclosed and referenced herein are also included. Guidance in determining which amino acid residues can be substituted, inserted, or deleted without abolishing biological activity can be found using computer programs well known in the art, such as DNASTAR™ (Madison, Wisconsin) software. Preferably, amino acid changes in the protein variants disclosed herein are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. [0380] In a peptide or protein, suitable conservative substitutions of amino acids are known to those of skill in this art and generally can be made without altering a biological activity of a resulting molecule. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin/Cummings Pub. Co., p.224). Naturally occurring amino acids are generally divided into conservative substitution families as follows: Group 1: Alanine (Ala), Glycine (Gly), Serine (Ser), and Threonine (Thr); Group 2: (acidic): Aspartic acid (Asp), and Glutamic acid (Glu); Group 3: (acidic; also classified as polar, negatively charged residues and their amides): Asparagine (Asn), Glutamine (Gln), Asp, and Glu; Group 4: Gln and Asn; Group 5: (basic; also classified as polar, positively charged residues): Arginine (Arg), Lysine (Lys), and Histidine (His); Group 6 (large aliphatic, nonpolar residues): Isoleucine (Ile), Leucine (Leu), Methionine (Met), Valine (Val) and Cysteine (Cys); Group 7 (uncharged polar): Tyrosine (Tyr), Gly, Asn, Gln, Cys, Ser, and Thr; Group 8 (large aromatic residues): Phenylalanine (Phe), Tryptophan (Trp), and Tyr; Group 9 (non- polar): Proline (Pro), Ala, Val, Leu, Ile, Phe, Met, and Trp; Group 11 (aliphatic): Gly, Ala, Val, Leu, and Ile; Group 10 (small aliphatic, nonpolar or slightly polar residues): Ala, Ser, Thr, Pro, and Gly; and Group 12 (sulfur-containing): Met and Cys. Additional information can be found in Creighton F053-6006PCT / 23-211-WO-PCT (1984) Proteins, W.H. Freeman and Company. [0381] In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982, J. Mol. Biol.157(1), 105-32). Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (Kyte and Doolittle, 1982). These values are: Ile (+4.5); Val (+4.2); Leu (+3.8); Phe (+2.8); Cys (+2.5); Met (+1.9); Ala (+1.8); Gly (−0.4); Thr (−0.7); Ser (−0.8); Trp (−0.9); Tyr (−1.3); Pro (−1.6); His (−3.2); Glutamate (−3.5); Gln (−3.5); aspartate (−3.5); Asn (−3.5); Lys (−3.9); and Arg (−4.5). [0382] It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i.e., still obtain a biological functionally equivalent protein. In making such changes, the substitution of amino acids whose hydropathic indices are within ±2 is preferred, those within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred. It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. [0383] As detailed in US 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: Arg (+3.0); Lys (+3.0); aspartate (+3.0±1); glutamate (+3.0±1); Ser (+0.3); Asn (+0.2); Gln (+0.2); Gly (0); Thr (−0.4); Pro (−0.5±1); Ala (−0.5); His (−0.5); Cys (−1.0); Met (−1.3); Val (−1.5); Leu (−1.8); Ile (−1.8); Tyr (−2.3); Phe (−2.5); Trp (−3.4). It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent, and in particular, an immunologically equivalent protein. In such changes, the substitution of amino acids whose hydrophilicity values are within ±2 is preferred, those within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred. [0384] As outlined above, amino acid substitutions may be based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. As indicated elsewhere, variants of gene sequences can include codon optimized variants, sequence polymorphisms, splice variants, and/or mutations that do not affect the function of an encoded product to a statistically-significant degree. [0385] Variants of the protein, nucleic acid, and gene sequences disclosed herein also include sequences with at least 70% sequence identity, 80% sequence identity, 85% sequence, 90% sequence identity, 95% sequence identity, 96% sequence identity, 97% sequence identity, 98% sequence identity, or 99% sequence identity to the protein, nucleic acid, or gene sequences F053-6006PCT / 23-211-WO-PCT disclosed herein. [0386] “% sequence identity” refers to a relationship between two or more sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between protein, nucleic acid, or gene sequences as determined by the match between strings of such sequences. "Identity" (often referred to as "similarity") can be readily calculated by known methods, including those described in: Computational Molecular Biology (Lesk, A. M., ed.) Oxford University Press, NY (1988); Biocomputing: Informatics and Genome Projects (Smith, D. W., ed.) Academic Press, NY (1994); Computer Analysis of Sequence Data, Part I (Griffin, A. M., and Griffin, H. G., eds.) Humana Press, NJ (1994); Sequence Analysis in Molecular Biology (Von Heijne, G., ed.) Academic Press (1987); and Sequence Analysis Primer (Gribskov, M. and Devereux, J., eds.) Oxford University Press, NY (1992). Methods to determine identity are designed to give the best match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Sequence alignments and percent identity calculations may be performed using the Megalign program of the LASERGENE bioinformatics computing suite (DNASTAR, Inc., Madison, Wisconsin). Multiple alignment of the sequences can also be performed using the Clustal method of alignment (Higgins and Sharp CABIOS, 5, 151-153 (1989) with default parameters (GAP PENALTY=10, GAP LENGTH PENALTY=10). Relevant programs also include the GCG suite of programs (Wisconsin Package Version 9.0, Genetics Computer Group (GCG), Madison, Wisconsin); BLASTP, BLASTN, BLASTX (Altschul, et al., J. Mol. Biol.215:403-410 (1990); DNASTAR (DNASTAR, Inc., Madison, Wisconsin); and the FASTA program incorporating the Smith-Waterman algorithm (Pearson, Comput. Methods Genome Res., [Proc. Int. Symp.] (1994), Meeting Date 1992, 111- 20. Editor(s): Suhai, Sandor. Publisher: Plenum, New York, N.Y.. Within the context of this disclosure it will be understood that where sequence analysis software is used for analysis, the results of the analysis are based on the "default values" of the program referenced. As used herein "default values" will mean any set of values or parameters, which originally load with the software when first initialized. [0387] Variants also include nucleic acid molecules that hybridize under stringent hybridization conditions to a sequence disclosed herein and provide the same function as the reference sequence. Exemplary stringent hybridization conditions include an overnight incubation at 42 °C in a solution including 50% formamide, 5XSSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5XDenhardt's solution, 10% dextran sulfate, and 20 µg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1XSSC at 50 °C. Changes in the stringency of hybridization and signal detection are primarily accomplished through the F053-6006PCT / 23-211-WO-PCT manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature. For example, moderately high stringency conditions include an overnight incubation at 37°C in a solution including 6XSSPE (20XSSPE=3M NaCl; 0.2M NaH2PO4; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 µg/ml salmon sperm blocking DNA; followed by washes at 50 °C with 1XSSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g.5XSSC). Variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility. [0388] "Specifically binds" refers to an association of a binding domain (of, for example, an antibody (e.g., broadly neutralizing antibody) to a virus) to its cognate binding molecule with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M) equal to or greater than 105 M-1, while not significantly associating with any other molecules or components in a relevant environment sample. Binding domains may be classified as "high affinity" or "low affinity". In particular embodiments, "high affinity" binding domains refer to those binding domains with a Ka of at least 107 M-1, at least 108 M-1, at least 109 M-1, at least 1010 M-1, at least 1011 M-1, at least 1012 M-1, or at least 1013 M-1. In particular embodiments, "low affinity" binding domains refer to those binding domains with a Ka of up to 107 M-1, up to 106 M-1, up to 105 M-1. Alternatively, affinity may be defined as an equilibrium dissociation constant (Kd) of a particular binding interaction with units of M (e.g., 10-5 M to 10-13 M). In certain embodiments, a binding domain may have "enhanced affinity," which refers to a selected or engineered binding domains with stronger binding to a cognate binding molecule than a wild type (or parent) binding domain. For example, enhanced affinity may be due to a Ka (equilibrium association constant) for the cognate binding molecule that is higher than the reference binding domain or due to a Kd (dissociation constant) for the cognate binding molecule that is less than that of the reference binding domain, or due to an off-rate (Koff) for the cognate binding molecule that is less than that of the reference binding domain. A variety of assays are known for detecting binding domains that specifically bind a particular cognate binding molecule as well as determining binding affinities, such as Western blot, ELISA, and BIACORE® analysis (see also, e.g., Scatchard, et al., 1949, Ann. N.Y. Acad. Sci.51:660; and U.S. Patent Nos.5,283,173, 5,468,614, or the equivalent). [0389] Unless otherwise indicated, the practice of the present disclosure can employ conventional F053-6006PCT / 23-211-WO-PCT techniques of immunology, molecular biology, microbiology, cell biology and recombinant DNA. These methods are described in the following publications. See, e.g., Sambrook, et al. Molecular Cloning: A Laboratory Manual, 2nd Edition (1989); F. M. Ausubel, et al. eds., Current Protocols in Molecular Biology, (1987); the series Methods IN Enzymology (Academic Press, Inc.); M. MacPherson, et al., PCR: A Practical Approach, IRL Press at Oxford University Press (1991); MacPherson et al., eds. PCR 2: Practical Approach, (1995); Harlow and Lane, eds. Antibodies, A Laboratory Manual, (1988); and R. I. Freshney, ed. Animal Cell Culture (1987). [0390] As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component. Thus, the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.” The transition term “comprise” or “comprises” means has, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase “consisting of” excludes any element, step, ingredient or component not specified. The transition phrase “consisting essentially of” limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment. A material effect would cause a statistically significant increase in dengue virus and/or zika virus infection, as described herein. [0391] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of F053-6006PCT / 23-211-WO-PCT the stated value; or ±1% of the stated value. [0392] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. [0393] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. [0394] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims. [0395] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. F053-6006PCT / 23-211-WO-PCT [0396] Furthermore, numerous references have been made to patents, printed publications, journal articles and other written text throughout this specification (referenced materials herein). Each of the referenced materials are individually incorporated herein by reference in their entirety for their referenced teaching. [0397] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described. [0398] The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and/or examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. [0399] Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the examples or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 3rd Edition or a dictionary known to those of ordinary skill in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology (Eds. Attwood T et al., Oxford University Press, Oxford, 2006).

Claims

F053-6006PCT / 23-211-WO-PCT CLAIMS What is claimed is: 1. A binding domain that binds dengue virus (DENV)1, DENV2, DENV3, DENV4, and zika virus (ZIKV), wherein the binding domain comprises a variable heavy chain comprising a complementarity determining region (CDR) heavy (H)1, a CDRH2, and a CDRH3 and a variable light chain comprising a CDR light (L)1, CDRL2, and CDRL3; wherein: the CDRH1 comprises the sequence as set forth in SEQ ID NO: 18, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 19, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 20, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 21, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 22, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 23 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 24, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 25, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 20, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 21, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 22, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 23 according to Chothia; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 26, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 27, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 28, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 29, the CDRL2 comprises the sequence DVT, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 23 according to IMGT; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 30, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 31, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 28, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 21, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 32, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 23 according to North; or the CDRH1 comprises the sequence as set forth in SEQ ID NO: 33, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 34, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 35, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 36, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 37, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 38 according to Contact. 2. The binding domain of claim 1, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 6 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 6. F053-6006PCT / 23-211-WO-PCT 3. The binding domain of claim 1, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 8 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 8. 4. The binding domain of claim 1, wherein the variable light chain comprises the sequence as set forth in SEQ ID NO: 7 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 7. 5. The binding domain of claim 1, wherein the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 9 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 9. 6. A binding domain that binds DENV1, DENV2, DENV3, and DENV4, wherein the binding domain comprises a variable heavy chain comprising a CDRH1, CDRH2, and CDRH3 and a variable light chain comprising a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 comprises the sequence as set forth in SEQ ID NO: 39, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 40, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 41, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 42, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 43, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 45, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 46, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 41, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 42, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 43, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 44 according to Chothia; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 47, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 48, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 49, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 50, the CDRL2 comprises the sequence DAS, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 51 according to IMGT; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 52, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 53, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 49, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 42, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 54, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 51 according to North; or the CDRH1 comprises the sequence as set forth in SEQ ID NO: 55, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 56, and the CDRH3 comprises the F053-6006PCT / 23-211-WO-PCT sequence as set forth in SEQ ID NO: 57, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 58, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 59, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 60 according to Contact. 7. The binding domain of claim 6, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 10 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 10. 8. The binding domain of claim 6, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 12 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 12. 9. The binding domain of claim 6, wherein the variable light chain comprises the sequence as set forth in SEQ ID NO: 11 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 11. 10. The binding domain of claim 6, wherein the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 13 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 13. 11. A binding domain that binds DENV1, DENV2, DENV3, and DENV4, wherein the binding domain comprises a variable heavy chain comprising CDRH1, CDRH2, and CDRH3 and a variable light chain comprising a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 comprises the sequence as set forth in SEQ ID NO: 61, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 62, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 63, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 64, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 65, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 66 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 67, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 68, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 63, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 64, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 65, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 66 according to Chothia; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 69, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 70, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 71, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 72, the CDRL2 comprises the sequence KAS, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 66 according to IMGT; F053-6006PCT / 23-211-WO-PCT the CDRH1 comprises the sequence as set forth in SEQ ID NO: 73, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 74, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 71, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 64, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 75, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 66 according to North; or the CDRH1 comprises the sequence as set forth in SEQ ID NO: 76, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 77, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 78, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 79, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 80, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 81 according to Contact. 12. The binding domain of claim 11, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 14 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 14. 13. The binding domain of claim 11, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 16 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 16. 14. The binding domain of claim 11, wherein the variable light chain comprises the sequence as set forth in SEQ ID NO: 15 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 15. 15. The binding domain of claim 11, wherein the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 17 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 17. 16. A binding domain that binds DENV1, DENV2, DENV3, DENV4, and ZIKV, wherein the binding domain comprises a variable heavy chain comprising CDRH1, CDRH2, and CDRH3 and a variable light chain comprising a CDRL1, CDRL2, and CDRL3; wherein: the CDRH1 comprises the sequence as set forth in SEQ ID NO: 162, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 163, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 164, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 165, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 166, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 167 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 168, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 169, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 170, and the CDRL1 comprises the sequence as set F053-6006PCT / 23-211-WO-PCT forth in SEQ ID NO: 21, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 171, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 172 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 18, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 173, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 174, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 21, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 175, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 176 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 177, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 178, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 179, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 180, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 181, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 182 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 183, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 184, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 185, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 21, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 22, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 23 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 186, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 187, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 188, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 189, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 181, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 190 according to Kabat; or the CDRH1 comprises the sequence as set forth in SEQ ID NO: 191, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 192, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 193, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 194, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 181, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 195 according to Kabat. 17. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 82 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 82; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 83 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 83. 18. The binding domain of claim 16, wherein the variable heavy chain is encoded by the F053-6006PCT / 23-211-WO-PCT sequence as set forth in SEQ ID NO: 84 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 84; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 85 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 85. 19. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 86 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 86; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 87 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 87. 20. The binding domain of claim 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 88 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 88; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 89 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 89. 21. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 90 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 90; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 91 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 91. 22. The binding domain of claim 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 92 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 92; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 93 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 93. 23. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 94 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 94; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 95 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 95. 24. The binding domain of claim 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 96 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 96; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 97 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 97. F053-6006PCT / 23-211-WO-PCT 25. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 98 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 98; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 99 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 99. 26. The binding domain of claim 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 100 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 100; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 101 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 101. 27. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 102 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 102; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 103 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 103. 28. The binding domain of claim 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 104 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 104; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 105 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 105. 29. The binding domain of claim 16, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 106 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 106; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 107 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 107. 30. The binding domain of claim 16, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 108 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 108; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 109 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 109. 31. A binding domain that binds DENV1, DENV2, DENV3, and DENV4, wherein the binding domain comprises a variable heavy chain comprising CDRH1, CDRH2, and CDRH3 and a variable light chain comprising a CDRL1, CDRL2, and CDRL3; wherein: F053-6006PCT / 23-211-WO-PCT the CDRH1 comprises the sequence as set forth in SEQ ID NO: 196, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 197, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 198, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 199, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 200, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 201 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 202, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 203, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 204, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 205, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 206, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 207 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 39, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 208, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 41, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 209, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 200, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 39, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 210, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 198, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 211, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 200, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 39, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 212, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 41, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 211, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 200, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 213 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 61, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 214, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 215, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 216, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 217, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 66 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 218, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 219, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 220, and the CDRL1 comprises the sequence as set F053-6006PCT / 23-211-WO-PCT forth in SEQ ID NO: 221, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 222, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 223 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 196, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 224, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 198, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 211, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 200, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 44 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 186, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 225, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 226, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 189, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 181, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 195 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 227, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 228, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 229, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 230, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 231, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 232 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 233, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 234, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 235, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 236, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 237, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 238 according to Kabat; the CDRH1 comprises the sequence as set forth in SEQ ID NO: 239, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 240, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 241, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 242, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 181, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 243 according to Kabat; or the CDRH1 comprises the sequence as set forth in SEQ ID NO: 244, the CDRH2 comprises the sequence as set forth in SEQ ID NO: 245, and the CDRH3 comprises the sequence as set forth in SEQ ID NO: 246, and the CDRL1 comprises the sequence as set forth in SEQ ID NO: 247, the CDRL2 comprises the sequence as set forth in SEQ ID NO: 248, and the CDRL3 comprises the sequence as set forth in SEQ ID NO: 249 according to Kabat. 32. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence F053-6006PCT / 23-211-WO-PCT as set forth in SEQ ID NO: 110 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 110; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 111 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 111. 33. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 112 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 112; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 113 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 113. 34. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 114 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 114; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 115 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 115. 35. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 116 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 116; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 117 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 117. 36. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 118 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 118; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 119 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 119. 37. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 120 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 120; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 121 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 121. 38. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 122 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 122; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 123 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 123. F053-6006PCT / 23-211-WO-PCT 39. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 124 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 124; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 125 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 125. 40. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 126 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 126; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 127 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 127. 41. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 128 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 128; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 129 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 129. 42. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 130 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 130; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 131 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 131. 43. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 132 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 132; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 133 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 133. 44. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 134 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 134; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 135 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 135. 45. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 136 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 136; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 137 or a sequence having at least 95% sequence identity F053-6006PCT / 23-211-WO-PCT to the sequence as set forth in SEQ ID NO: 137. 46. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 138 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 138; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 139 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 139. 47. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 140 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 140; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 141 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 141. 48. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 142 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 142; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 143 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 143. 49. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 144 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 144; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 145 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 145. 50. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 146 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 146; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 147 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 147. 51. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 148 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 148; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 149 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 149. 52. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 150 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 150; and the variable light chain comprises the sequence F053-6006PCT / 23-211-WO-PCT as set forth in SEQ ID NO: 151 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 151. 53. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 152 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 152; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 153 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 153. 54. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 154 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 154; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 155 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 155. 55. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 156 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 156; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 157 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 157. 56. The binding domain of claim 31, wherein the variable heavy chain comprises the sequence as set forth in SEQ ID NO: 158 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 158; and the variable light chain comprises the sequence as set forth in SEQ ID NO: 159 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 159. 57. The binding domain of claim 31, wherein the variable heavy chain is encoded by the sequence as set forth in SEQ ID NO: 160 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 160; and the variable light chain is encoded by the sequence as set forth in SEQ ID NO: 161 or a sequence having at least 95% sequence identity to the sequence as set forth in SEQ ID NO: 161. 58. A binding molecule comprising the binding domain of any of claims 1, 6, 11, 16, or 31. 59. The binding molecule of claim 58, wherein the binding molecule is an IgG antibody, an IgA antibody, an IgM antibody, an IgD antibody, or an IgE antibody. 60. The binding molecule of claim 58, wherein the binding molecule is an IgA antibody. 61. The binding molecule of claim 60, wherein the IgA antibody comprises an IgA1 antibody or an IgA2 antibody. 62. The binding molecule of claim 60, wherein the IgA antibody comprises an IgA1 antibody. F053-6006PCT / 23-211-WO-PCT 63. The binding molecule of claim 58, wherein the binding molecule is an IgG antibody. 64. The binding molecule of claim 63, wherein the IgG antibody comprises an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. 65. The binding molecule of claim 63, wherein the IgG antibody comprises an IgG1 antibody. 66. The binding molecule of claim 58, wherein the binding molecule is a neutralizing antibody. 67. The binding molecule of claim 58, wherein the binding molecule is an scFV or a Fab. 68. The binding molecule of claim 58, comprising a thioMab. 69. The binding molecule of claim 58, comprising one or more modified amino acids. 70. The binding molecule of claim 69, wherein the one or more modified amino acids comprise a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, or an amino acid conjugated to an organic derivatizing agent. 71. The binding molecule of claim 58, comprising one or more human serum albumin (HSA)- linkages. 72. The binding molecule of claim 58, wherein the binding molecule includes one or more Fc modifications. 73. The binding molecule of claim 72, wherein the one or more Fc modifications includes a LALA mutation. 74. The binding molecule of claim 72, wherein the one or more Fc modifications includes an Fc region with reduced fucose content or lacking fucose. 75. The binding molecule of claim 58, wherein the binding molecule is a part of a multi-domain binding molecule. 76. A multi-domain binding molecule comprising at least two binding domains wherein at least one binding domain comprises the binding domain of any of claims 1, 6, 11, 16, or 31. 77. The multi-domain binding molecule of claim 76, wherein the multi-domain binding molecule is a dimer, trimer, tetramer, pentamer, hexamer, or heptamer. 78. The multi-domain binding molecule of claim 76, comprising an Fc region. 79. The multi-domain binding molecule of claim 78, wherein the Fc region is an IgA Fc region or an IgM Fc region. 80. The multi-domain binding molecule of claim 78, wherein the Fc region is an IgA Fc region having the sequence as set forth in SEQ ID NOs: 258 and 259. 81. The multi-domain binding molecule of claim 78, wherein the Fc region is an IgM Fc region having the sequence as set forth in SEQ ID NOs: 260, 261, or 295-304. 82. The multi-domain binding molecule of claim 78, wherein the Fc region comprises a F053-6006PCT / 23-211-WO-PCT multimerizing fragment of the IgA Fc region or a multimerizing fragment of the IgM Fc region. 83. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgA Fc region comprises the IgA tailpiece. 84. The multi-domain binding molecule of claim 83, wherein the IgA tailpiece has the sequence of residues 331-352 as set forth in SEQ ID NO: 258 or the sequence of residues 318- 340 as set forth in SEQ ID NO: 259. 85. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgA Fc region comprises the IgA CA3 domain and the IgA tailpiece. 86. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgA Fc region comprises the IgA CA2 domain, the IgA CA3 domain, and the IgA tailpiece. 87. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgA Fc region comprises the IgA CA1 domain, the IgA CA2 domain, the IgA CA3 domain, and the IgA tailpiece. 88. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgM Fc region comprises the IgM tailpiece. 89. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgM Fc region comprises the Cµ4 domain and the IgM tailpiece. 90. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgM Fc region comprises the Cµ3 domain, the Cµ4 domain, and the IgM tailpiece. 91. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgM Fc region comprises the Cµ2 domain, the Cµ3 domain, the Cµ4 domain, and the IgM tailpiece. 92. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgM Fc region comprises the Cµ1 domain, the Cµ2 domain, the Cµ3 domain, the Cµ4 domain, and the IgM tailpiece. 93. The multi-domain binding molecule of claim 82, wherein the multimerizing fragment of the IgM Fc region has the sequence as set forth in any of SEQ ID NOs: 295-304. 94. A single-chain variable fragment (scFv) comprising the binding domain of any of claims 1, 6, 11, 16, or 31, wherein the antibody fragment comprises a humanized light chain variable region and/or a humanized heavy chain variable region and lacks a constant region. 95. A conjugate comprising the binding domain of any of claims 1, 6, 11, 16, or 31, linked to a particle, a drug, or a detectable label. 96. A composition comprising the binding molecule of any of claims 1, 6, 11, 16, or 31 and a pharmaceutically acceptable carrier. 97. The composition of claim 96, further comprising one or more adjuvants. F053-6006PCT / 23-211-WO-PCT 98. The composition of claim 97, wherein the one or more adjuvants are selected from alum, a squalene-based adjuvant, a STING agonist, or a liposome-based adjuvant. 99. The composition of claim 96, further comprising a second type of binding molecule. 100. The composition of claim 99, further comprising a third type of binding molecule. 101. A nucleic acid sequence encoding the binding domain of any of claims 1, 6, 11, 16, or 31 or the binding molecule of claim 58. 102. A vector comprising the nucleic acid sequence of claim 101. 103. A cell genetically modified to express the binding molecule of claim 58. 104. A method of treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition of claim 96 thereby treating the subject in need thereof. 105. The method of claim 104, wherein the subject has DENV. 106. The method of claim 104, wherein the subject has ZIKV. 107. The method of claim 104, wherein the subject has previously been infected with DENV or ZIKV. 108. The method of claim 104, wherein the administering is through intravenous, intradermal, intraarterial, intranodal, intravesicular, intrathecal, intraperitoneal, intraparenteral, intranasal, intralesional, intramuscular, oral, intrapulmonary, subcutaneous, or sublingual administering. 109. The method of claim 104, wherein the administering precedes or follows administration of a secondary treatment.
PCT/US2024/023379 2023-04-07 2024-04-05 Cross-flavivirus binding domains and uses thereof Pending WO2024211789A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363495063P 2023-04-07 2023-04-07
US63/495,063 2023-04-07

Publications (1)

Publication Number Publication Date
WO2024211789A1 true WO2024211789A1 (en) 2024-10-10

Family

ID=92972729

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/023379 Pending WO2024211789A1 (en) 2023-04-07 2024-04-05 Cross-flavivirus binding domains and uses thereof

Country Status (1)

Country Link
WO (1) WO2024211789A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015196192A2 (en) * 2014-06-20 2015-12-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods and compositions relating to dengue virus
US20190023745A1 (en) * 2017-07-19 2019-01-24 The University Of North Carolina At Chapel Hill Methods and compositions for zika virus vaccines
US20190375826A1 (en) * 2018-06-12 2019-12-12 National Defense Medical Center Anti-dengue virus antibodies and applications thereof
US20210363227A1 (en) * 2016-07-13 2021-11-25 Humabs Biomed Sa Novel antibodies specifically binding to zika virus epitopes and uses thereof
US20220306729A1 (en) * 2017-04-07 2022-09-29 The Rockefeller University Neutralizing antibodies that bind to the zika virus domain iii envelope region

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015196192A2 (en) * 2014-06-20 2015-12-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods and compositions relating to dengue virus
US20210363227A1 (en) * 2016-07-13 2021-11-25 Humabs Biomed Sa Novel antibodies specifically binding to zika virus epitopes and uses thereof
US20220306729A1 (en) * 2017-04-07 2022-09-29 The Rockefeller University Neutralizing antibodies that bind to the zika virus domain iii envelope region
US20190023745A1 (en) * 2017-07-19 2019-01-24 The University Of North Carolina At Chapel Hill Methods and compositions for zika virus vaccines
US20190375826A1 (en) * 2018-06-12 2019-12-12 National Defense Medical Center Anti-dengue virus antibodies and applications thereof

Similar Documents

Publication Publication Date Title
ES2920140T3 (en) Human immunodeficiency virus (HIV) neutralizing antibodies
ES2916404T3 (en) Human immunodeficiency virus (HIV) neutralizing antibodies
TW202146442A (en) Antibodies against sars-cov-2 and methods of using the same
US20230331824A1 (en) Single-domain antibodies that bind sars-cov-2
CN115768790A (en) Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
US20240150444A1 (en) Protective antibodies against respiratory viral infections
JP2025506172A (en) Broadly targeted human monoclonal antibodies against coronaviruses
US20230357364A1 (en) Covid-19 antibodies and uses thereof
US20240238405A1 (en) Methods of eliciting antibodies that bind to full-length glycosylated hiv-1 env using multimerized env cores
KR102656738B1 (en) Family, member A5 antibody with anti-sequence similarity 19 and methods of use thereof
CN115315442B (en) SARS-COV-2 antibodies and their applications
KR20150140752A (en) Antibodies targeting m-csf
RS66591B1 (en) ANTIBODIES CAPABLE OF BINDING TO THE SPIKE PROTEIN OF CORONAVIRUS SARS-COV-2
WO2022136685A1 (en) Antibody compositions for treatment of corona virus infection
WO2024211789A1 (en) Cross-flavivirus binding domains and uses thereof
US20220213176A1 (en) Antibodies against sars-cov-2 spike protein
US11359007B2 (en) Anti-SARS-CoV-2 neutralizing antibodies
WO2022068844A1 (en) Neutralizing antibody against sars-cov-2
US20230399385A1 (en) Neutralizing antibodies against sars-cov-2
TWI896628B (en) HUMAN MONOCLONAL ANTIBODIES TO SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-CoV-2)
US20240294611A1 (en) Cross-reactive antibodies recognizing the coronavirus spike s2 domain
WO2025222144A1 (en) Antibodies and vaccines having vh3-21 and vl1-40 binding domains and uses thereof
WO2022053054A1 (en) Neutralizing antibodies against sars-cov-2
WO2024196463A2 (en) Broadly neutralizing human monoclonal antibodies that target the sars-cov-2 receptor binding domain (rbd)
KR20240058167A (en) Synthetic humanized llama nanobody library for identification of SARS-COV-2 neutralizing antibodies and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24785872

Country of ref document: EP

Kind code of ref document: A1