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WO2025235420A1 - Methods of treating or preventing sarbecovirus with antibodies or antigen-binding fragments thereof - Google Patents

Methods of treating or preventing sarbecovirus with antibodies or antigen-binding fragments thereof

Info

Publication number
WO2025235420A1
WO2025235420A1 PCT/US2025/027837 US2025027837W WO2025235420A1 WO 2025235420 A1 WO2025235420 A1 WO 2025235420A1 US 2025027837 W US2025027837 W US 2025027837W WO 2025235420 A1 WO2025235420 A1 WO 2025235420A1
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WO
WIPO (PCT)
Prior art keywords
antibody
antigen
binding fragment
seq
dose
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/US2025/027837
Other languages
French (fr)
Inventor
Adambarage Dinesh DE ALWIS
Francesco BORRIELLO
Kia Wee Gavin KOH
Daria Jean Hazuda
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.)
Generate Biomedicines Inc
Original Assignee
Generate Biomedicines Inc
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Filing date
Publication date
Application filed by Generate Biomedicines Inc filed Critical Generate Biomedicines Inc
Publication of WO2025235420A1 publication Critical patent/WO2025235420A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • C07K16/1002—Coronaviridae
    • C07K16/1003—Severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2 or Covid-19]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • SARS-Coronavirus-2 SARS-CoV-2
  • SARS-CoV-2 SARS-CoV-2
  • a novel coronavirus first caused a cluster of pneumonia cases (COVID-19) in Wuhan, China.
  • COVID-19 SARS-Coronavirus-2
  • COVID-19 has been spreading rapidly throughout the world, resulting in a pandemic.
  • the disclosure provides a method of treating or preventing a sarbecovirus infection in a subject, comprising: (a) administering a first dose of about 100 mg to about 2400 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of the sarbecovirus about every 3 months to about every 12 months to the subject and (b) administering a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of the sarbecovirus about every 3 months to about every 12 months to the subject.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a HCDR1, a HCDR2 and a HCDR3 of an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a heavy chain variable region of SEQ ID NO: 10, and (ii) a LCDR1, a LCDR2 and a LCDR3 of an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a light chain variable region of SEQ ID NO: 20.
  • a first dose is about 300 mg to about 900 mg. In some embodiments, a first dose is about 600 mg or about 650 mg. In some embodiments, a second dose is about 100 mg to about 1400 mg.
  • a second dose is about 300 mg to about 900 mg. In some embodiments, a second dose is about 300 mg, about 600 mg, or about 650 mg.
  • a first dose is administered about every 6 months. In some embodiments, a second dose is administered about every 6 months. In some embodiments, one or both of a first dose and a second dose are administered parenterally. In some embodiments, one or both of a first dose and a second dose are administered intravenously, subcutaneously, intramuscularly, or intraperitoneally. [0008] In some embodiments, one or both of a first dose and a second dose are administered intravenously.
  • a first dose and a second dose are administered intramuscularly.
  • a first dose is administered prior to, substantially simultaneously, or after a second dose.
  • a first dose and a second dose are co-formulated in a pharmaceutical composition.
  • Page 2 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0009]
  • a sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV1.
  • a SARS-CoV-2 is one or more SARS-CoV-2 variants.
  • one or more SARS-CoV-2 variants is one or more of: Delta, Omicron, BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, BA.2.75, BA.2.75.2, BA.2.86, BA.4.6, BA.5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, D614G, EG.5.1, JN.1, XBB.1.5, and XBB.1.16.
  • an S2 is a stem helix region.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 is one or more of: (i) a chimeric antibody, a human antibody, or a humanized antibody, or antigen-binding fragment thereof; (ii) a monospecific antibody or a bispecific antibody, or antigen-binding fragment thereof; and (iii) a monoclonal antibody, or antigen-binding fragment thereof.
  • an antigen-binding fragment thereof that binds specifically to S2 is or comprises an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody.
  • an antibody or antigen-binding fragment that binds specifically to S2 is or comprises an IgG1 isotype.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 11, a LCDR2 of SEQ ID NO: 12, and a LCDR3 of SEQ ID NO: 13; (ii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, and a HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 14, a LCDR2 of SEQ ID NO: 15, and a LCDR3 of SEQ
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 10, and (ii) a light chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 20.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a Page 3 of 120 12756399v1 Attorney Docket No.: 2017408-0046 heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10, and (ii) a light chain variable region comprising an amino acid sequence of SEQ ID NO: 20.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 21, and (ii) a light chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 22.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain comprising an amino acid sequence of SEQ ID NO: 21, and (ii) a light chain comprising an amino acid sequence of SEQ ID NO: 22.
  • an antibody that binds specifically to a Spike protein is bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, cilgavimab, pemivibart, rixagevimab, AZD7442 (tixagevimab-cilgavimab), regdanvimab, sotrovimab, or an antigen- binding fragment thereof of any of the foregoing or a combination thereof.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein binds specifically to receptor binding domain (RBD) of a sarbecovirus.
  • RBD receptor binding domain
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD binds specifically to a class 4 region.
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD is one or more of: (i) a chimeric antibody, a human antibody, or a humanized antibody, or antigen-binding fragment thereof; (ii) a monospecific antibody or a bispecific antibody, or antigen-binding fragment thereof; and (iii) a monoclonal antibody, or antigen-binding fragment thereof.
  • an antigen-binding fragment thereof that binds specifically to RBD is or comprises an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody.
  • an antibody or antigen-binding fragment that binds specifically to RBD is or comprises an IgG1 isotype.
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 34, a LCDR2 of SEQ ID NO: 35, and a LCDR3 of SEQ ID NO: 36; (ii) a heavy chain variable region comprising a Page 4 of 120 12756399v1 Attorney Docket No.: 2017408-0046 HCDR1 of SEQ ID NO: 26, a HCDR2 of SEQ ID NO: 27, and a HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising a LCDR1 of SEQ
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a light chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 32, and (ii) a heavy chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO:43.
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a light chain variable region comprising an amino acid sequence of SEQ ID NO: 32, and (ii) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 43.
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 33, and (ii) a light chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 44.
  • an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain comprising an amino acid sequence that is SEQ ID NO: 33, and (ii) a light chain comprising an amino acid sequence that is at SEQ ID NO: 44.
  • FIG.1 is a graph showing a simulated pharmacokinetic profile following a single dose of 1200 mg of an anti-S2 antibody described herein (AB-1) over 43 weeks.
  • the shown Page 5 of 120 12756399v1 Attorney Docket No.: 2017408-0046 areas cover the 90% prediction intervals of plasma (upper curve) and lung (lower curve). Solid lines represent a median profile. Lung concentrations were set at 10% of those in plasma.
  • FIGS.2A-2F are graphs showing neutralization activity of an antibody that binds specifically to S2 of a sarbecovirus (referred to herein as “AB-1”) and an antibody that binds specifically to a receptor binding domain (RBD; referred to herein as “AB-2”), alone and combination, in VERO-TMPRSS2 cells against SARS-CoV-2 Omicron BQ.1.1 Spike (FIGS.2A-C) and XBB.1.5 Spike (FIGS.2D-F) pseudotyped VSVdG particles when titrated in a checkboard approach to generate two-variable titration curves starting at 18 ⁇ g/ml in a fourfold dilution series.
  • AB-1 sarbecovirus
  • RBD receptor binding domain
  • FIG.2A and FIG.2D depict neutralization of BQ1.1 and XBB.1.5, respectively, at about a .0703 ⁇ g/ml concentration of each antibody tested.
  • FIG.2B and FIG.2E depict neutralization of BQ1.1 and XBB.1.5, respectively, at about a .0175 ⁇ g/ml concentration of each antibody tested.
  • FIG.3 is a series of graphs showing a pharmacokinetic profile following a single intravenous dose of 100 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg of an anti-S2 antibody described herein (AB-1) over 43 weeks.
  • the shown areas cover the 95% prediction intervals of 1,000 simulated profiles.
  • Solid lines represent a median profile. Solid circles show observed concentrations.
  • FIG.4 is a series of graphs showing fold changes in live virus 50% (top panels) and 80% (bottom panels) mean neutralization titer (e.g., MN50 and MN80) following a single dose of 100 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg anti-S2 antibody described herein (AB-1) for the three different variants of interest.
  • FIG.5 is a series of graphs showing fold changes in live virus 50% (left panel) and 80% (right panel) mean neutralization titer (e.g., MN50 and MN80) following a single intravenous dose of 1200 mg anti-S2 antibody described herein (AB-1) in subjects with low titers.
  • FIG.6 is a series of graphs showing a neutralizing index following a 1200 mg dose of anti-S2 antibody described herein (AB-1). The equation used to calculate a neutralizing index is also indicated in FIG.6.
  • FIG.7 is a series of graphs showing percent neutralization of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses. Results are representative of at least 12 technical replicates across at least 3 biological replicates and shown as mean ⁇ SD. Neutralization curves were fitted with a 4-parameter logistic regression.
  • FIG.8 is a schematic depicting relative frequency of mutations of interest (AB-1 epitope region) in prevalent sarbecovirus lineages.
  • FIG.9 depicts neutralization profiles of AB-1 and remdesivir either alone or in combination against live SARS-CoV-2 (England/02/2020) using a cytopathic effect (CPE)- based assay.
  • the x-axis indicates the concentration of test articles as single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates).
  • FIG.10 depicts neutralization profiles of AB-1 and remdesivir either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)-based assay.
  • the x-axis indicates the concentration of test articles as single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates).
  • FIG.11 depicts neutralization profiles of AB-1 and nirmatrelvir either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)- based assay.
  • CPE cytopathic effect
  • FIG.12 depicts neutralization profiles of AB-1 and nirmatrelvir (+ P-gp inhibitor) either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)-based assay.
  • the x-axis indicates the concentration of test articles as Page 7 of 120 12756399v1 Attorney Docket No.: 2017408-0046 single agents and in combination (or of the test article with the highest concentration if the concentrations differ).
  • FIG.13 depicts neutralization profiles of AB-1 either alone or in combination with P-gp inhibitor against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)-based assay.
  • CPE cytopathic effect
  • FIG.14 depicts neutralization profiles of AB-1 and molnupiravir either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)- based assay.
  • CPE cytopathic effect
  • FIG.15 is a bar graph depicting the binding of AB-1 and reference molecule to SARS-CoV-2 spike S2 peptides (indicated as “S:” followed by amino acid positions) and HIV-1 Env negative control peptide were assessed by SPR. The bars which represent AB-1 binding have an upside-down triangle above them.
  • FIGS.16A-16B are bar graphs depicting binding of AB-1 and the reference molecule to spike trimers (indicated as “S:” followed by the respective virus name).
  • FIG. 16A depicts AB-1 and reference molecule binding to major SARS-CoV-2 variants (SARS- CoV-2).
  • FIG.16B depicts AB-1 and reference molecule binding to non-SARS-CoV-2 Sarbecoviruses (“Sarbecov.” labeled graph) and SARS-CoV-2 variants with polymorphisms in the AB-1 binding epitope (SARS-CoV-2 BA.2+P1162L and BA.2+P1162S) and their parent strain (SARS-CoV-2 BA.2 [parent]) (“AB-1 epitope” labeled graph). Results are expressed as EC50 values ( ⁇ g/mL), shown as mean and 95% confidence interval (CI) and representative of two independent experiments, four technical replicates each.
  • Color-coded dotted lines represent upper 95% confidence internal limits for AB-1 and the reference molecule binding to reference trimers (SARS-CoV-2 D614G for FIG.16A and FIG.16B left graph, SARS-CoV-2 BA.2 [parent] for FIG.16B right graph).
  • the lowest depicted Page 8 of 120 12756399v1 Attorney Docket No.: 2017408-0046 dotted line represents the confidence internal limits for AB-1, and the highest depicted dotted line depicts the confidence internal limits for the reference molecule.
  • bars that represent reference molecule binding are always to the left of bars that represent AB-1 binding.
  • FIG.17 is a series of graphs showing fold changes in live virus 50% mean neutralization titer (MN50) following a single dose of 100 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg anti-S2 antibody described herein (AB-1) for two different variants of interest.
  • MN50 mean neutralization titer
  • AB-1 anti-S2 antibody described herein
  • the term “about” refers to a range of values that fall within about 25%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed about 100% of a possible value).
  • Acute infection refers to an infection that is characterized by relatively sudden or rapid onset of disease (see e.g., Rai et al. “Acute Page 9 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Infection of Viral Pathogens and Their Innate Immune Escape.” Front. Microbiol. 12:672026 (2021), the contents of which is incorporated by reference in its entirety).
  • Antibody refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen.
  • an antibody refers to an anti-Spike protein antibody or antigen-binding fragment thereof.
  • Intact antibodies as produced in nature are approximately 150 kD tetrameric agents comprising two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure.
  • Each heavy chain comprises at least four domains (each about 110 amino acids long) – an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CH1, CH2, and the carboxy-terminal CH3 (located at the base of the Y’s stem).
  • a short region connects the heavy chain variable and constant regions.
  • the “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody.
  • Each light chain comprises two domains – an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”.
  • Intact antibody tetramers comprise two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another so that the dimers are connected to one another and a tetramer is formed.
  • Naturally-produced antibodies are also glycosylated, typically on the CH2 domain.
  • Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., about 3-, about 4-, or about 5- stranded sheets) packed against each other in a compressed antiparallel beta barrel.
  • an antibody or antigen-binding fragment thereof is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain.
  • an antibody or antigen-binding fragment thereof is a polypeptide protein having a binding domain that is homologous or largely homologous to an immunoglobulin-binding domain.
  • Page 10 of 120 12756399v1 Attorney Docket No.: 2017408-0046 When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure.
  • the Fc region of naturally- occurring antibodies binds to elements of the complement system, and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. Affinity and/or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification.
  • antibodies produced and/or utilized in accordance with various aspects described herein include glycosylated Fc domains, such as Fc domains with modified or engineered glycosylation.
  • any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and/or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology.
  • an antibody is polyclonal.
  • an antibody is monoclonal.
  • an antibody has constant region sequences characteristic of mouse, rabbit, primate, or human antibodies.
  • antibody sequence elements are humanized, primatized, or chimeric.
  • an antibody can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation.
  • an antibody provided herein is utilized in accordance with a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bispecific or multi-specific antibodies (e.g., Zybodies®, etc.); and/or antibody fragments (preferably antibody fragments that exhibit desired antigen-binding activity).
  • An antibody described herein can be an immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold with antibody-like properties, as well as any other known immunological binding moiety, e.g., a Fab, Fab', Fab'2, Fab2, Fab3, F(ab’)2 , Fd, Fv, Feb, scFv, SMIP, antibody, diabody, triabody, Page 11 of 120 12756399v1 Attorney Docket No.: 2017408-0046 tetrabody, minibody, maxibody, tandab, DVD, BiTe, TandAb, or any combination thereof.
  • the subunit structures and three-dimensional configurations of different classes of antibodies are known.
  • an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally.
  • an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., poly-ethylene glycol, etc.).
  • a covalent modification e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., poly-ethylene glycol, etc.).
  • a covalent modification e.g., attachment of a glycan
  • a payload e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.
  • other pendant group e.g.,
  • Antibody light chain refers to the smaller of the two types of polypeptide chains present in all antibodies in their naturally occurring conformations.
  • Antigen As used herein, the term “antigen” or “Ag” refers to a molecule that is capable of provoking an immune response. This immune response may involve either antibody production, the activation of specific immunologically-competent cells, or both. A skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA.
  • any DNA that comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response encodes an “antigen” as that term is used herein.
  • an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the various aspects of innovations described herein includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all.
  • an antigen can be generated synthesized or can be derived from a biological sample.
  • a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell, or a biological fluid.
  • Page 12 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0045]
  • Antigen-binding fragment refers to a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • An antigen-binding fragment of an antibody includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Exemplary antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, VHH, camelid, or VH or VL domains only); or multispecific antibodies formed from antibody fragments.
  • the antigen-binding fragments of the antibodies described herein are scFvs.
  • the antigen-binding fragments of the antibodies described herein are VHH domains only. As with full antibody molecules, antigen-binding fragments may be mono- specific or multispecific (e.g., bispecific).
  • a multispecific antigen-binding fragment of an antibody may comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope of the same antigen.
  • An antigen-binding fragment may be produced by any means. For example, in some embodiments, an antigen-binding fragment is enzymatically or chemically produced by fragmentation of an intact antibody. Alternatively, in some embodiments, an antigen- binding fragment is recombinantly produced. In some embodiments, an antigen-binding fragment is wholly or partially synthetically produced.
  • an antigen- binding fragment has a length of at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, or at least about 200 amino acids or more.
  • Binding refers to a non-covalent association between or among two or more entities. “Direct” binding involves physical contact between entities or moieties. Indirect binding involves physical interaction by way of physical contact with one or more intermediate entities.
  • CDR refers to a complementarity determining region within an antibody variable region. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions.
  • a “set of CDRs” or “CDR set” refers to a group of three or six CDRs that occur in either a single variable region capable of binding the antigen or the CDRs of cognate heavy and light chain variable regions capable of binding the antigen.
  • there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, LCDR3).
  • HCDR1, HCDR2, HCDR3 three CDRs in each heavy chain variable region
  • LCDR1, LCDR2, LCDR3 three CDRs in each light chain variable region.
  • the exact definitional CDR boundaries and lengths are subject to different classification and numbering systems. Certain systems have been established for defining CDR boundaries (e.g., Kabat, IMGT, Chothia, or a combination thereof).
  • CDRs may therefore be referred to by Kabat, Chothia, IMGT, or any other known boundary definitions. Despite differing boundaries, each of these systems has some degree of overlap in what constitutes the “hypervariable regions” within the variable sequences. CDR definitions according to these systems may therefore differ in length and boundary areas with respect to the adjacent framework region (see, e.g., Kabat et al., in “Sequences of Proteins of Immunological Interest,” 5th Edition, U.S. Department of Health and Human Services, 1992; Chothia et al. (1987) J. Mol. Biol.196, 901; and MacCallum et al., J. Mol. Biol.
  • Chronic infection refers to a type of persistent infection in which a virus is not cleared but remains in specific cells of infected individuals. Persistent infections may involve stages of both silent and productive infection without rapidly killing or even producing excessive damage of host cells.
  • a persistent infection is a chronic infection.
  • a persistent infection is a latent infection (See, e.g., Boldogh et al., Persistent Viral Infection.
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form – e.g., gas, gel, liquid, or solid.
  • Comprising A composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method.
  • composition or method described as “comprising” (or which “comprises”) one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of” (or which “consists essentially of”) the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method.
  • Dosage unit or dose As used herein, a “dosage unit” or “dose” refers to physically discrete units suited as unitary dosages for the particular subject to be treated, e.g., a human subject.
  • Each unit can contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with a Page 15 of 120 12756399v1 Attorney Docket No.: 2017408-0046 pharmaceutical carrier.
  • the specification for the dosage unit forms can be dictated by: (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s).
  • Fragment refers to a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole structure. In some embodiments, a fragment consists of such a discrete portion.
  • a fragment consists of or comprises a characteristic structural element or moiety found in the whole.
  • an antigen-binding fragment comprises or consists of at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 210, at least about 2
  • an antigen-binding fragment comprises or consists of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 25%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more of the monomeric units (e.g., residues) found in a whole antibody.
  • monomeric units e.g., residues
  • a nucleotide fragment comprises or consists of at least about 5%, at least about 10%, at least about 15%, Page 16 of 120 12756399v1 Attorney Docket No.: 2017408-0046 at least about 20%, at least about 25%, at least about 30%, at least about 25%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more of the monomeric units (e.g., residues) found in the whole nucleotide.
  • monomeric units e.g., residues
  • Identity refers to the subunit sequence identity between two polymeric molecules, particularly between two amino acid molecules, such as between two polypeptide molecules. When two amino acid sequences have the same residues at the same positions; e.g., if a position in each of two polypeptide molecules is occupied by an Arginine, then they are identical at that position. The identity or extent to which two amino acid sequences have the same residues at the same positions in an alignment is often expressed as a percentage.
  • the identity between two amino acid sequences is a direct function of the number of matching or identical positions; e.g., if half of the positions (e.g., five positions in a polymer of 10 amino acids in length) in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., nine positions in a polymer of 10 amino acids in length) are identical, the two amino acids sequences are 90% identical.
  • compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Prevent when used herein, the term “prevent” when used in connection with the occurrence of sarbecovirus infection, refers to reducing the risk of developing a sarbecovirus infection and/or to delaying onset of one or more characteristics or symptoms of a sarbecovirus infection.
  • Non-limiting examples of characteristics or symptoms of a sarbecovirus infection include fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle, body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, diarrhea, or any combination thereof.
  • Prevention may be considered Page 17 of 120 12756399v1 Attorney Docket No.: 2017408-0046 complete when onset of a sarbecovirus infection has been delayed for a predefined period of time.
  • RBD refers to a receptor binding domain within S1 of a Spike protein of a sarbecovirus (e.g., SARS-CoV-2).
  • RBD plays a role in viral entry and infection.
  • RBD binds to angiotensin converting enzyme type-II (ACE2) receptor on a human cell surface to form a fusion complex.
  • ACE2 angiotensin converting enzyme type-II
  • RBD can exhibit some variability among different SARS-CoV-2 variants and mutations in RBD can impair viral replication, facilitate immune escape, and impact vaccine efficacy.
  • the terms “RBD” and “RBD domain” can be used interchangeably herein.
  • SARS-CoV-2 As used herein, the term “SARS-CoV-2” refers to Severe Acute Respiratory Syndrome Coronavirus 2, a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic.
  • SARS-CoV-2 is a positive- sense single-stranded RNA virus that is contagious in humans.
  • SARS-CoV-2 belongs to a group of genetically related viruses that includes SARS-CoV and other coronaviruses.
  • Spike Protein refers to a class I fusion protein that mediates fusion of a viral envelope with a host cell membrane through a series of conformational changes.
  • Spike protein refers to a Spike protein of a sarbecovirus (e.g., SARS-CoV-1, SARS-CoV-2, or WIV1).
  • the Spike protein of sarbecovirus is composed of two main regions or domains known as S1 and S2.
  • S1 contains a receptor-binding domain (RBD) that is responsible for recognition and binding to a host cell receptor.
  • S2 is responsible for membrane fusion.
  • RBD receptor-binding domain
  • a spike protein determines host range and cell tropism of a virus.
  • S2 refers to a S2 subunit of a Spike protein of a sarbecovirus (e.g., SARS-CoV-2).
  • S2 is responsible for fusion to a viral envelope and contains a putative fusion peptide and other fusion infrastructure necessary for membrane fusion with the host cell.
  • S2 can form a flexible “stalk” containing most protein-protein interactions that hold an assembled spike protein trimer in place.
  • S2 contains a stem helix region that is highly conserved among sarbecovirus (e.g., SARS-CoV-1, SARS-CoV-2, or WIV1). Antibodies which bind this stem helix may inhibit membrane fusion, preventing the Page 18 of 120 12756399v1 Attorney Docket No.: 2017408-0046 virus from entering the host cell.
  • an anti-Spike protein antibody or antigen-binding fragment thereof disclosed herein binds to S2 of a Spike protein of sarbecovirus.
  • S2 includes full-length S2 (e.g., having an amino acid sequence of SEQ ID NO: 46 or a variant thereof) and truncated versions thereof as well as mutant, engineered, and modified (e.g., post-translationally) variants thereof of full-length or truncated S2 (e.g., an epitope within S2).
  • subject refers to an animal (e.g., a mammal, such as a human) who is to be administered an antibody or antigen-binding fragment disclosed herein.
  • a subject to be treated according to methods described herein may be one who has been diagnosed with a condition (e.g., a sarbecovirus infection such as a SARS-CoV-2 infection) or one at risk of developing such conditions. Diagnosis may be performed by any method or technique.
  • a subject may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with a condition (e.g., a sarbecovirus infection such as a SARS-CoV-2 infection).
  • a condition e.g., a sarbecovirus infection such as a SARS-CoV-2 infection.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • treat refers to partial or complete alleviation, amelioration, delay of onset of, inhibition, prevention, relief, and/or reduction in incidence and/or severity of one or more symptoms or features of a disease, disorder, and/or condition described herein (e.g., a sarbecovirus infection).
  • treatment is administered to a subject who does not exhibit signs or features of a disease, disorder, and/or condition (e.g., may be prophylactic).
  • treatment is administered to a subject who exhibits only early or mild signs or features of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of Page 19 of 120 12756399v1 Attorney Docket No.: 2017408-0046 developing pathology associated with the disease, disorder, and/or condition.
  • treatment is administered to a subject who exhibits established, severe, and/or late-stage signs of the disease, disorder, or condition (e.g., sarbecovirus).
  • one or more symptoms of a sarbecovirus infection include fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle, body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, diarrhea, or any combination thereof.
  • one or more symptoms of a severe sarbecovirus infection include trouble breathing, constant chest pain or pressure, bluish lips or face, sudden confusion, altered mental status, or any combination thereof.
  • one or more symptoms of a late stage sarbecovirus infection include fatigue, energy crashes, brain fog, chronic cough, organ damage, or any combination thereof.
  • treating comprises administering at least one antibody or antigen- binding fragment thereof described herein to a subject.
  • description of a range such as from about 1 to about 6 should be considered to have specifically disclosed subranges such as from about 1 to about 3, from about 1 to about 4, from about 1 to about 5, from about 2 to about 4, from about 2 to about 6, from about 3 to about 6 etc., as well as individual numbers within that range, for example, about 1, about 2, about 2.7, about 3, about 4, about 5, about 5.3, and about 6. This applies regardless of the breadth of the range.
  • a sarbecovirus infection e.g., SARS-CoV-1, SARS-CoV-2, or WIV1
  • a sarbecovirus infection e.g., SARS-CoV-1, SARS-CoV-2, or WIV1
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 Page 20 of 120 12756399v1
  • Attorney Docket No.: 2017408-0046 of a sarbecovirus in combination with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus.
  • administering allows for a reduced dose to be administered of an antibody or antigen- binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus relative to administration of the antibody or antigen-binding fragment thereof that binds specifically to a Spike protein alone.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD) of a sarbecovirus.
  • RBD receptor binding domain
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus.
  • the genome of SARS-CoV-2 encodes the nucleoprotein (N), the membrane glycoprotein (M), the small envelope glycoprotein (E), and the Spike protein, in addition to 16 non-structural proteins (Song et al. Clin Chim Acta.509:280-7 (2020)).
  • the Spike protein of SARS-CoV-2 facilitates entry of into a host cell, such as a human host cell.
  • the Spike protein is a trimer with protomers composed of S1 and S2 Page 21 of 120 12756399v1 Attorney Docket No.: 2017408-0046 subunits.
  • S1 contains a receptor-binding domain (RBD) that binds ACE2 receptors, and S2 mediates fusion of viral and host membranes.
  • RBD receptor-binding domain
  • a non-limiting example of a wildtype Spike protein sequence of SARS-CoV-2 is NCBI RefSeq YP_009724390: [0068] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHS TQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGT TLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSAN NCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFS ALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLK YNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCP FGEVFNATRFASVY
  • Spike protein of SARS-CoV-2 includes wild-type SARS-CoV-2 Spike proteins (e.g., SEQ ID NO: 45 (RefSeq YP_009724390) or homologs thereof) and truncated forms thereof, mutant, and engineered versions of full-length and truncated SARS- Page 22 of 120 12756399v1 Attorney Docket No.: 2017408-0046 CoV-2 Spike proteins, and modified forms (e.g., post-translationally modified forms) of full- length and truncated SARS-CoV-2 Spike proteins.
  • wild-type SARS-CoV-2 Spike proteins e.g., SEQ ID NO: 45 (RefSeq YP_009724390) or homologs thereof
  • truncated forms thereof mutant, and engineered versions of full-length and truncated SARS- Page 22 of 120 12756399v1
  • modified forms e.g., post-translationally modified forms
  • an antibody or antigen-binding fragment thereof disclosed herein binds to a Spike protein comprising an amino acid sequence of SEQ ID NO: 45.
  • an antibody or antigen-binding fragment thereof described herein binds to a mutant, engineered, and/or modified form of a Spike protein.
  • a mutant, engineered, or modified form of a Spike protein comprises an amino acid sequence that has at least about 90% sequence identity to wildtype Spike protein sequence (e.g., SEQ ID NO: 45) of SARS-CoV-2, for example, having at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about or at least about 99.9% sequence identity to wildtype Spike protein sequence.
  • wildtype Spike protein sequence e.g., SEQ ID NO: 45
  • a mutant, engineered, and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: L5F, S13I, T19R, A67V, del69, del70, del69-70, D80G, T95I, G142D, del142-144, del144, Y145D, W152C, E154K, F157S, del211, L212I, ins214EPE, A222V, D253G, G261D, G339D, V367F, S371L, S371L, S373P, S375F, K417N, N439K, N440K, G446S, L452R, Y453F, S477N, T478K, E484A, E484K, E484Q, F486L, S494P, Q493R, G496S, Q498R, N501T
  • a mutant, engineered, and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: L5F, S13I, T19R, A67V, del69, del70, del69-70, D80G, T95I, G142D, del142-144, del144, Y145D, W152C, E154K, F157S, del211, L212I, ins214EPE, A222V, D253G, G261D, G339D, V367F, S371L, S371L, S373P, S375F, K417N, N439K, N440K, G446S, L452R, Y453F, S477N, T478K, E484A, E484K, E484Q, F486L,
  • a mutant, engineered and/or modified form of a Spike protein further comprises E484K, S494P or K1191N, or a combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:45, one or more mutations selected from: D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G or A701V, or a Page 24 of 120 12756399v1 Attorney Docket No.: 2017408-0046 combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, and A701V.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:45, one or more mutations selected from: T19R, G142D, 156del, 157del, R158G, L452R, T478K, D614G, P681R or D950N, or a combination thereof.
  • a modified Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: A67V, del69-70, T95I, del142-144, Y145D, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K or L981F, or a combination thereof.
  • a modified Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.
  • a modified Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, L452R, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: 69del, 70del, 144del, A222V, G261D, V367F, K417N, N439K, Y453F, S477N, E484K, F486L, N501T, N501Y, A570D or D614G, or a combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: E484K, N501Y or D614G, or a combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: F817P, A892P, A899P, A942P, K986P or V987P, or a combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:1, one or more mutations selected from: L452R, F486V or R493Q, or a combination thereof.
  • a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: A67V, del69-70, T95I, del142-144, Y145D, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N85
  • the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.
  • the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, L452R, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.
  • the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, K444T, L452R, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.
  • the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, R346T, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, K444T, L452R, N460K, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.
  • Additional modified Spike proteins of SARS-CoV-2 can be found at https://covariants.org/shared-mutations, the contents of which are incorporated herein by reference.
  • Non-limiting examples include Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and/or Omicron, for example, AY.3, AY.4, AY.41, AY.44, AY.64, AY.103, B.1, B.1.1, B.1.1.1, B.1.1.529, B.1.1.7, B.1.177, B.1.2, B.1.351, B.1.427/429, B.1.525, B.1.526, B.1.533, B.1.617.1, B.1.617.2, B.1.621, BA.1, BA.1.1, BA.1.15, BA.1.17.2, BA.2, BA.2+P1162L, and BA.2+P1162S, BA.2.3.20, BA.2.10, BA.2.12.1, BA.2.7
  • an antibody or antigen-binding fragment thereof disclosed herein binds to S2 of a Spike protein of SARS-CoV-2.
  • S2 includes full- length S2 (e.g., having the amino acid sequence of SEQ ID NO: 46 (PLQPELDSFKEELDKYFKNHTSPDVDL) or homologs thereof) and truncated forms thereof, mutant, and engineered versions of full-length and truncated S2 (e.g., an epitope within S2), and modified forms (e.g., post-translationally modified forms) of full-length and truncated S2.
  • full- length S2 e.g., having the amino acid sequence of SEQ ID NO: 46 (PLQPELDSFKEELDKYFKNHTSPDVDL) or homologs thereof
  • truncated forms thereof mutant, and engineered versions of full-length and truncated S2 (e.g., an epitope within S2)
  • modified forms e.g.
  • an antibody or antigen-binding fragment thereof disclosed herein binds to a mutant, engineered and/or modified form of S2.
  • the mutant, engineered and/or modified form of S2 comprises an amino acid sequence that has at least about 90% sequence identity to a wild-type full length S2 domain (e.g., SEQ ID NO: 46), for example, having at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at Page 27 of 120 12756399v1 Attorney Docket No.: 2017408-0046 least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% sequence identity.
  • Antibodies and antigen-binding fragments thereof are antibodies or antigen-binding fragments thereof that bind a Spike protein of a sarbecovirus.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD) of a sarbecovirus.
  • RBD receptor binding domain
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus. In some embodiments, an antibody or antigen- binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus.
  • an antibody that binds specifically to a Spike protein is bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, cilgavimab, pemivibart, rixagevimab, AZD7442 (tixagevimab- cilgavimab), regdanvimab, sotrovimab, or an antigen-binding fragment of any of the foregoing or a combination thereof.
  • an antibody or antigen-binding fragment thereof described herein can be or comprise an immunoglobulin, heavy chain antibody, light chain antibody, or other protein scaffold with antibody-like properties, as well as other immunological binding moiety, including a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a disulfide-bonded Fv fragment, a scFv fragment, a diabody, a triabody, a tetrabody, a minibody, a maxibody, a tandab, BiTe, or any combination thereof.
  • an antibody or antigen-binding fragment thereof described herein comprises or is a monoclonal antibody. In some embodiments, antibody or antigen-binding fragment thereof described herein comprises or is a full-length antibody, e.g., comprising an immunoglobulin Fc region.
  • an antibody or antigen-binding fragment thereof described herein comprises or is a multispecific antibody, Page 28 of 120 12756399v1 Attorney Docket No.: 2017408-0046 e.g., comprising a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope.
  • an antibody or antigen-binding fragment thereof described herein comprises or is a bispecific antibody molecule.
  • an antibody or antigen-binding fragment thereof described herein is or has been affinity matured.
  • An antibody or antigen-binding fragment thereof can include a heavy chain variable domain sequence (VH), and a light chain variable domain sequence (VL).
  • an antibody or antigen-binding fragment thereof comprises an immunoglobulin molecule of four polypeptide chains, e.g., two heavy chains and two light chains.
  • a heavy chain can include a VH and a heavy chain constant domain.
  • a heavy chain constant domain can include CH1, hinge, CH2, CH3, and optionally, a CH4 region.
  • a light chain can include a VL and a light chain constant domain.
  • a light chain constant domain can include a CL domain.
  • a VH and/or a VL can be further subdivided into regions of variability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Such VH and/or VL domains can each include three CDRs and four framework regions, arranged from amino-terminus to carboxyl- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, one or more of which can be engineered as described herein.
  • FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 one or more of which can be engineered as described herein.
  • there are three CDRs in each VH HCDR1, HCDR2, and HCDR3
  • CDRs in each VL LCDR1, LCDR2, and LCDR3
  • the extent of the framework region and CDRs can be defined using a number of well-known schemes (see, e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242; Chothia, C. et al. (1987) J. Mol. Biol.196:901-917; and the AbM definition used by Oxford Molecular’s AbM antibody modeling software, each of which is hereby incorporated by reference in its entirety).
  • An antibody or antigen-binding fragment thereof described herein can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from Page 29 of 120 12756399v1 Attorney Docket No.: 2017408-0046 any subclass (e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies.
  • An antibody or antigen- binding fragment thereof described herein can be or comprise a human, humanized, CDR- grafted, or in vitro generated antibody.
  • An antibody or antigen-binding fragment thereof described herein can have or comprise a heavy chain constant region chosen from, e.g., IgG1, IgG2, IgG3, or IgG4.
  • an antibody or antigen-binding fragment thereof can have or comprise a light chain chosen from, e.g., kappa or lambda.
  • a heavy chain constant region (e.g., IgG1) comprises an LS mutation.
  • a heavy chain constant region (e.g., IgG1) comprises an LS mutation comprising an M428L mutation, numbering is according to the EU index in Kabat et al. (1991).
  • a heavy chain constant region (e.g., IgG1) comprises an LS mutation comprising an N434S mutation, numbering is according to the EU index in Kabat et al. (1991).
  • a heavy chain constant region (e.g., IgG1) comprises an LS mutation comprising a M428L mutation and a N434S mutation, numbering is according to the EU index in Kabat et al. (1991).
  • an antibody or antigen-binding fragment thereof described herein is or comprises a monoclonal antibody.
  • monoclonal antibodies are obtained from a population of substantially homogeneous antibodies, such that the individual antibodies comprising the population are substantially identical, except for possible naturally occurring mutations that may be present in minor amounts.
  • the modifier “monoclonal” as used herein indicates the character of the antibody as not being a mixture of discrete antibodies.
  • monoclonal antibodies directed to a particular epitope are derived from a single cell line (e.g., a B cell line).
  • an antibody or antigen-binding fragment thereof described herein is or comprises a polyclonal antibody.
  • polyclonal antibodies are typically obtained from a population of heterogeneous antibodies, such that the antibodies in a particular population include structural variation, for example, affinity for different epitopes on a particular target (e.g., Spike protein of sarbecovirus, such as S2 of a Spike protein).
  • polyclonal antibodies include use of multiple subcutaneous and/or intraperitoneal injections of the Page 30 of 120 12756399v1 Attorney Docket No.: 2017408-0046 relevant antigen into an animal, optionally including co-administration of one or more adjuvants.
  • Examples of antibodies or antigen-binding fragments thereof described herein can include: (i) a Fab fragment, a monovalent fragment comprising VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at a hinge region; (iii) a Fab fragment comprising VH and CH1 domains; (iv) a Fv fragment comprising VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment comprising a VH domain; (vi) a camelid or camelized variable domain; (vii) a scFv, a fusion protein of VH and VL regions; or (viii) a single domain antibody.
  • a Fab fragment a monovalent fragment comprising VL, VH, CL, and CH1 domains
  • a F(ab')2 fragment a bivalent fragment comprising two
  • an antibody or antigen-binding fragment thereof described herein comprises or is a heavy chain and a light chain (e.g., a half antibody).
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising one, two, or three VH CDR sequences in Table 1; and/or (b) a VL comprising one, two, or three VL CDR sequences in Table 1.
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VH in Table 1 (e.g., in areas outside of CDR regions); and/or (a) a VL with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VL in Table 1 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a heavy chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more identity to a heavy chain in Table 1 (e.g., in areas outside of CDR regions); and/or (a) a light chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more identity to a light chain in Table 1 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 1, a VH CDR2 amino acid sequence of SEQ ID NO: 2, and a VH CDR3 amino acid sequence of SEQ ID NO: 3; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 11, a VL CDR2 amino acid sequence of SEQ ID NO: 12, and a VL CDR3 amino acid sequence of SEQ ID NO: 13.
  • an antibody or antigen- binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 4, a VH CDR2 amino acid sequence of SEQ ID NO: 5, and a VH CDR3 amino acid sequence of SEQ ID NO: 6; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 14 a VL CDR2 amino acid sequence of SEQ ID NO: 15, and a VL CDR3 amino acid sequence of SEQ ID NO: 16.
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 7, a VH CDR2 amino acid sequence of SEQ ID NO: 8, and a VH CDR3 amino acid sequence of SEQ ID NO: 9; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 17, a VL CDR2 amino acid sequence of SEQ ID NO: 18, and a VL CDR3 amino acid sequence of SEQ ID NO: 19.
  • an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 10 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a VL comprising an amino acid sequence of SEQ ID NO: 20, or an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 20 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 10 and a VL comprising an amino acid sequence of SEQ ID NO: 20.
  • an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID Page 32 of 120 12756399v1 Attorney Docket No.: 2017408-0046 NO: 21, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 21 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 22, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 22 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 10 and a light chain comprising an amino acid sequence of SEQ ID NO: 21.
  • An antibody or antigen-binding fragment thereof described herein can include any amino acid sequences disclosed in WO2023215910A1, which is hereby incorporated by reference in its entirety. Table 1.
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VH in Table 2 (e.g., in areas outside of CDR regions); and/or (a) a VL with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VL in Table 2 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a heavy chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about Page 35 of 120 12756399v1 Attorney Docket No.: 2017408-0046 97%, at least about 98%, at least about 99%, or more identity to a heavy chain in Table 2 (e.g., in areas outside of CDR regions); and/or (a) a light chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more identity to a light chain in Table 2 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 23, a VH CDR2 amino acid sequence of SEQ ID NO: 24, and a VH CDR3 amino acid sequence of SEQ ID NO: 25; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 34, a VL CDR2 amino acid sequence of SEQ ID NO: 35, and a VL CDR3 amino acid sequence of SEQ ID NO: 36.
  • an anti-Spike protein antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 26, a VH CDR2 amino acid sequence of SEQ ID NO: 27, and a VH CDR3 amino acid sequence of SEQ ID NO: 28; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 37 a VL CDR2 amino acid sequence of SEQ ID NO: 38, and a VL CDR3 amino acid sequence of SEQ ID NO: 39.
  • an anti-Spike protein antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 29, a VH CDR2 amino acid sequence of SEQ ID NO: 30, and a VH CDR3 amino acid sequence of SEQ ID NO: 31; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 40, a VL CDR2 amino acid sequence of SEQ ID NO: 41, and a VL CDR3 amino acid sequence of SEQ ID NO: 42.
  • an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 32, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, at least about or at least about 99% identical or higher to SEQ ID NO: 32 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a VL comprising an amino acid sequence of SEQ ID NO: 43, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, or at Page 36 of 120 12756399v1 Attorney Docket No.: 2017408-0046 least about 99% identical or higher to SEQ ID NO: 43 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 32 and a VL comprising an amino acid sequence of SEQ ID NO: 43.
  • an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 33, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical or higher to SEQ ID NO: 33 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 44, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical or higher to SEQ ID NO: 44 (e.g., in areas outside of CDR regions).
  • an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 33 and a light chain comprising an amino acid sequence of SEQ ID NO: 44.
  • Table 2 Amino acid sequences of an exemplary antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus.
  • an antibody or antigen-binding fragment thereof described herein is identified using a display technology, such as yeast display, phage display, or ribosome display.
  • an antibody or antigen-binding fragment thereof described herein is identified using a hybridoma library (e.g., a mammalian hybridoma library, e.g., a mouse hybridoma library), followed by supernatant screening.
  • a hybridoma library e.g., a mammalian hybridoma library, e.g., a mouse hybridoma library
  • Page 39 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0110]
  • Combinatorial methods for generating antibodies or antigen-binding fragments thereof are described in, for example, Ladner et al. U.S. Patent No.5,223,409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271; Winter et al.
  • an antibody or antigen-binding fragment thereof described herein may be derived from other species.
  • a humanized antibody is an antibody produced by recombinant DNA technology, in which some or all amino acids of a human immunoglobulin light chain or heavy chain that are not required for antigen binding (e.g., constant regions and/or framework regions of variable domains) are used to substitute for the corresponding amino acids from light chain or heavy chain of the cognate, nonhuman antibody.
  • a humanized version of a murine antibody to a given antigen has on both heavy and light chains: (1) constant regions of a human antibody; (2) FRs from the variable domains of a human antibody; and (3) CDRs from the murine antibody.
  • Human FRs may be selected based on their highest sequence homology to mouse FR sequence.
  • transplantation of non-human (e.g., murine) CDRs onto a human antibody is achieved as follows.
  • cDNAs encoding VH and VL are isolated from a hybridoma, and nucleic acid sequences encoding VH and VL including CDRs are determined by sequencing.
  • Nucleic acid sequences encoding CDRs are inserted into corresponding regions of a human antibody VH or VL coding sequences and attached to human constant region gene segments of a desired isotype (e.g., ⁇ l for CH and for CL).
  • Humanized heavy and light chain genes are co-expressed in mammalian host cells (e.g., CHO or NSO cells) to produce soluble humanized antibody.
  • an antibody or antigen-binding fragment thereof described herein comprises or is a human antibody.
  • Completely human antibodies may be particularly desirable for therapeutic treatment of human subjects.
  • Human antibodies can be made by a variety of methods including phage display methods described above using antibody libraries derived from human immunoglobulin sequences (see, e.g., U.S. Pat. Nos.
  • nucleic acids encoding antibodies or antigen-binding fragments thereof that bind a Spike protein of a sarbecovirus.
  • a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to S1 of a sarbecovirus.
  • a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to a receptor binding domain (RBD) of a sarbecovirus.
  • RBD receptor binding domain
  • a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus. In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to a stem helix region of a sarbecovirus. [0115] In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to S2 of the sarbecovirus.
  • nucleic acids encoding one or more heavy chains, VH domains, heavy chain FRs, heavy chain CDRs, heavy chain constant domains, light chains, VL domains, light chain FRs, light chain CDRs, light chain constant domains, or other immunoglobulin-like sequences, antibodies, or antigen-binding fragments thereof disclosed herein.
  • Such nucleic acids may be present in a vector.
  • Such nucleic acids may be present in the genome of a cell, e.g., a cell of a subject in need of treatment or a cell for production of an antibody, e.g., a mammalian cell for production of an antibody or antigen-binding fragment thereof described herein.
  • Nucleic acids encoding antibodies or antigen-binding fragments thereof described herein may be modified to include codons that are optimized for expression in a particular cell type or organism. Codon optimized sequences are synthetic sequences, and preferably encode an identical polypeptide (or biologically active fragment of a full-length polypeptide which has substantially the same activity as the full-length polypeptide) encoded by a non-codon optimized parent polynucleotide.
  • a coding region of a nucleic acid encoding an antibody or antigen-binding fragment thereof described herein, in whole or in part may include an altered sequence to optimize codon usage for a particular cell type (e.g., a eukaryotic or prokaryotic cell).
  • a coding sequence for a humanized heavy or light chain variable region as described herein may be optimized for expression in a bacterial cell.
  • the coding sequence may be optimized for Page 42 of 120 12756399v1 Attorney Docket No.: 2017408-0046 expression in a mammalian cell (e.g., a CHO cell).
  • Such a sequence may be described as a codon-optimized sequence.
  • Nucleic acid constructs described herein may be inserted into an expression vector or viral vector by methods known to the art, and nucleic acids may be operably linked to an expression control sequence.
  • a vector comprising any nucleic acids or fragments thereof described herein is further provided herein.
  • nucleic acids or fragments thereof described herein can be cloned into any suitable vector and can be used to transform or transfect any suitable host. Selection of vectors and methods to construct them are commonly known to persons of ordinary skill in the art (see, e.g., “Recombinant DNA Part D,” Methods in Enzymology, Vol.153, Wu and Grossman, eds., Academic Press (1987)). [0118] Conventionally used techniques including, for example, electrophoresis, calcium phosphate precipitation, DEAE-dextran transfection, or lipofection, may be used to introduce a foreign nucleic acid (e.g., DNA or RNA) into a prokaryotic or eukaryotic host cell.
  • a foreign nucleic acid e.g., DNA or RNA
  • a vector may include regulatory sequences, such as transcription and/or translation initiation and/or termination codons, which are specific to the type of host (e.g., bacterium, fungus, plant, or animal) into which a vector is to be introduced, as appropriate and taking into consideration whether a vector is DNA or RNA.
  • a vector comprises regulatory sequences that are specific to a genus of a host cell.
  • a vector comprises regulatory sequences that are specific to a species of a host.
  • a nucleic acid construct can include one or more marker genes, which allow for selection of transformed or transfected hosts.
  • Exemplary marker genes include, e.g., biocide resistance (e.g., resistance to antibiotics or heavy metals) or complementation in an auxotrophic host to provide prototrophy.
  • An expression vector can comprise a native or nonnative promoter operably linked to an isolated or purified nucleic acid as described above. Selection of promoters, e.g., strong, weak, inducible, tissue-specific, and/or developmental-specific, is within the skill of one in the art. Similarly, combining a nucleic acid as described above with a promoter is also within the skill of one in the art.
  • Suitable vectors include those designed for propagation and expansion and/or for expression.
  • a cloning vector may be selected from the pUC series, the pBluescript series (Stratagene, LaJolla, Calif.), the pET series (Novagen, Madison, Wis.), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), or the pEX series (Clontech, Palo Alto, Calif.).
  • Bacteriophage vectors such as GT10, GT11, ZapII (Stratagene), EMBL4, and NM1149, may be used.
  • Examples of plant expression vectors that can be used include pBI110, pBI101.2, pBI101.3, pBI121, or pBIN19 (Clontech).
  • Examples of animal expression vectors that can be used include pEUK-C1, pMAM, or pMAMneo (Clontech).
  • the TOPO cloning system (Invitrogen, Carlsbad, Calif.) also can be used in accordance with the manufacturer's recommendations.
  • Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation of a nucleic acid encoding an antibody or antigen-binding fragment thereof described herein, or to improve introduction of a nucleic acid into a cell.
  • Use of cloning vectors, expression vectors, adapters, and linkers have been described (see, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 2d edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989); and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y.
  • nucleic acids and vectors described herein are isolated and/or purified.
  • a composition comprising an isolated or purified nucleic acid, optionally in the form of a vector.
  • Isolated nucleic acids and vectors may be prepared using standard techniques including, for example, alkali/SDS treatment, CsCl binding, column chromatography, agarose gel electrophoresis, and/or other techniques.
  • the composition can comprise other components as described further herein.
  • Any method known to one skilled in the art for the insertion of nucleic acids into a vector may be used to construct expression vectors encoding an antibody or antigen- binding fragment thereof described herein under control of transcriptional and/or translational control signals. These methods may include in vitro recombinant DNA and Page 44 of 120 12756399v1 Attorney Docket No.: 2017408-0046 synthetic techniques and in vivo recombination (see, e.g., Ausubel, supra or Sambrook, supra). Methods of use [0125] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection in a subject comprising administering an antibody or antigen-binding fragment thereof described herein.
  • sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV.
  • an antibody or antigen-binding fragment thereof described herein binds specifically to S2 of a sarbecovirus.
  • Pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof described herein can be for use in the manufacture of a medicament for treating or preventing sarbecovirus infection in a subject.
  • various aspects of innovations described herein provide methods of neutralizing a sarbecovirus infection in a subject.
  • sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV.
  • an antibody or antigen-binding fragment thereof described herein binds specifically to S2 of a sarbecovirus.
  • Pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof described herein can be for use in the manufacture of a medicament for treating or preventing a chronic sarbecovirus infection (e.g., long COVID-19) in a subject.
  • various aspects of innovations described herein provide methods of neutralizing a chronic sarbecovirus infection (e.g., long COVID-19) in a subject.
  • a sarbecovirus infection is an acute infection.
  • a sarbecovirus infection is a chronic infection (e.g., long COVID-19).
  • Long COVID-19 refers to a group of health problems persisting or developing after an initial period of sarbecovirus infection.
  • long COVID-19 can persist for weeks.
  • long COVID-19 can persist for months.
  • long COVID-19 can persist for years.
  • long COVID-19 begins at one week after initial infection.
  • long COVID-19 begins at two weeks after initial infection.
  • long COVID-19 begins at three weeks after initial infection.
  • long COVID-19 begins at four weeks after initial infection.
  • long COVID-19 begins at five weeks after initial infection.
  • long COVID-19 begins at six weeks after initial infection.
  • long COVID-19 begins at seven weeks after initial infection.
  • long COVID-19 begins at eight weeks after initial infection.
  • long COVID-19 begins at nine weeks after initial infection.
  • long COVID-19 begins at ten weeks after initial infection.
  • long COVID-19 begins at 11 weeks after initial infection.
  • long COVID-19 begins at 12 weeks after initial infection.
  • long COVID-19 is characterized by fatigue.
  • long COVID-19 is characterized by fatigue and/or memory problems.
  • long COVID-19 is characterized by fatigue, memory problems, and/or shortness of breath.
  • long COVID-19 is characterized by fatigue, memory problems, shortness of breath, and/or sleep disorders.
  • long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, and/or headaches. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, headaches, and/or initial loss of smell and/or taste. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, headaches, initial loss of smell and/or taste, and/or muscle weakness. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, headaches, initial loss of smell and/or taste, muscle weakness, and/or fever (See Chen et al.
  • a sarbecovirus infection is an acute infection.
  • a sarbecovirus infection is a chronic infection (e.g., long COVID-19).
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1 of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD) of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus.
  • RBD receptor binding domain
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus are co- formulated in a pharmaceutical composition.
  • an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus are formulated in separate pharmaceutical compositions.
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is administered prior to, substantially simultaneously, or after an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus.
  • a Spike protein e.g., RBD
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein e.g., Page 47 of 120 12756399v1 Attorney Docket No.: 2017408-0046 RBD
  • a Spike protein e.g., Page 47 of 120 12756399v1 Attorney Docket No.: 2017408-0046 RBD
  • an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is administered prior to, substantially simultaneously, or after an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to RBD. [0133] In some embodiments, an additional therapeutic agent is administered with an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus in combination with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus.
  • Non-limiting examples of additional therapeutic agents include antibiotics (e.g., azithromycin), antibodies or antigen-binding fragments thereof (e.g., other SARS-CoV-2-binding antibodies or antigen-binding fragments), antimalarial agents (e.g., chloroquine or hydroxychloroquine), antiviral agents (e.g., Molnupiravir (LAGEVRIO, Merck), PF-07817883 (Pfizer), STI-1558 (Sorrento Therapeutics), PBI-0451 (Pardes Biosciences), EDP-235 (Enanta Pharmaceuticals), favipiravir, lopinavir and/or ritonavir), cytokines (e.g., type 1 interferons, such as interferon beta-1a), nucleotide analogs (e.g., remdesivir), protease inhibitors (e.g., danoprevir), Renin-Angiotensin-Aldosterone
  • an additional therapeutic agent is administered with an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus.
  • an additional therapeutic comprises a nucleotide analog (e.g., remdesivir).
  • administration of a combination of additional therapeutic agent and antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus reduces the likelihood of a SARS-CoV-2 infection as compared to administration of the additional therapeutic agent alone.
  • administering increases anti-viral activity of the additional therapeutic and/or the antibody or antigen-binding fragment thereof.
  • an additional therapeutic agent and antibody or antigen- binding fragment thereof are co-administered.
  • an additional therapeutic agent comprises remdesivir.
  • an additional therapeutic agent comprises a pro-drug of GS-441524, the parent nucleoside of remdesivir.
  • an additional therapeutic agent comprises a pro-drug of remdesivir. In some embodiments, an additional therapeutic agent comprises obeldesivir (GS-5245). In some embodiments, an additional therapeutic agent comprises GS-621763. In some embodiments, an additional therapeutic agent comprises molnupiravir. [0135] In some embodiments, an additional therapeutic agent is a protease inhibitor (e.g., nirmatrelvir). In some embodiments, an additional therapeutic agent comprises nirmatrelvir. In some embodiments, an additional therapeutic agent is nirmatrelvir comprising P-glycoprotein (P-gp) inhibitor.
  • P-gp P-glycoprotein
  • an additional therapeutic agent comprises a P-glycoprotein (P-gp) inhibitor.
  • P-gp P-glycoprotein
  • a likelihood of sarbecovirus infection in a subject is reduced by at least about 10%, e.g., by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% at least about or at least about 99% after administration of an antibody or antigen-binding fragment thereof described herein.
  • a subject has (e.g., confirmed by testing, such as by PCR or rapid test), or is suspected of having, sarbecovirus. In some embodiments, a subject has sarbecovirus. In some embodiments, the subject has been diagnosed with sarbecovirus. In some embodiments, the subject is at risk of developing sarbecovirus. [0138] In some embodiments, a subject is a mammal.
  • a subject is a mammal selected from the group consisting of a dog, a cat, a mouse, a rat, a hamster, a guinea pig, a horse, a pig, a sheep, a cow, a chimpanzee, a macaque, a cynomolgus, and a Page 49 of 120 12756399v1 Attorney Docket No.: 2017408-0046 human.
  • a subject is a primate.
  • a subject is a human.
  • a subject has a heart disease.
  • a subject has a heart disease selected from the group consisting of a congenital heart disease, a coronary artery disease, a hypertensive heart disease, an inflammatory heart disease, a pulmonary heart disease, a rheumatic heart disease, a valvular heart disease, a cardiomyopathy, heart failure, and combinations thereof.
  • a subject has a congestive heart failure.
  • a subject has an inflammatory heart disease selected from the group consisting of endocarditis, cardiomegaly, myocarditis, and combinations thereof.
  • a subject has diabetes.
  • a subject has a lung disease.
  • Non-limiting examples of lung diseases include acute respiratory distress syndromes, asthma, bronchitis, COPD, emphysema, lung tumors, pleural cavity diseases (e.g., pleural mesothelioma or tension pneumothorax), pulmonary vascular diseases (e.g., embolisms, edema, arterial hypertension or hemorrhage), and respiratory tract infections (e.g., pneumonia or other upper or lower respiratory tract infections).
  • a subject is a tobacco smoker.
  • a subject is immune compromised (e.g., has an underlying disorder or is on immunosuppressive therapy). In some embodiments, a subject is not immune compromised.
  • a subject is a recipient of an organ transplant.
  • a subject is at least about 40 years or older, e.g., at least about 45 years old, at least about 50 years old, at least about 55 years old, at least about 60 years old, at least about 65 years old, at least about 70 years old, at least about 75 years old, at least about 80 years old, at least about 85 years old, or at least about 90 years old.
  • the subject is older than about 90 years old.
  • Administration of an antibody or antigen-binding fragment thereof described herein may be carried out in any convenient manner (e.g., injection, ingestion, transfusion, inhalation, implantation, or transplantation).
  • an antibody or antigen-binding fragment thereof described herein is administered by injection or infusion.
  • an antibody or antigen-binding fragment thereof described herein is administered transarterially, subcutaneously, intravenously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, or intraperitoneally.
  • an antibody or antigen-binding fragment thereof described herein is administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or intramuscularly).
  • an antibody or antigen-binding fragment thereof described herein described herein is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally by infusion or injection. In some embodiments, an antibody or antigen- binding fragment thereof described herein is administered intramuscularly. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered intravenously. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered subcutaneously. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered by intramuscular injection. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered by intravenous injection.
  • an antibody or antigen-binding fragment thereof described herein is administered by subcutaneous injection.
  • a 100mg, 300 mg, 600 mg, 1200 mg, or 2400 mg dose of an antibody or antigen-binding fragment thereof described herein achieves at least about a 1- fold, at least about a 5-fold, at least about a 10-fold, at least about a 15-fold, at least about a 20-fold, at least about a 25-fold, at least about a 30-fold, at least about a 35-fold, at least about a 40-fold, at least about a 50-fold, at least about a 55-fold, at least about a 60-fold, at least about a 65-fold, at least about a 70-fold, at least about a 75-fold, at least about a 80- fold, at least about a 85-fold, at least about a 90-fold, at least about a 95-fold, or at least about a 100-fold increase from baseline in sarbe
  • a 1200 mg dose of an antibody or antigen-binding fragment thereof described herein achieves at least about a 10-fold increase in sarbecovirus neutralizing titer.
  • a 100mg, 300 mg, 600 mg, 1200 mg, or 2400 mg dose of an antibody or antigen-binding fragment thereof described herein achieves a half-life of at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at Page 51 of 120 12756399v1 Attorney Docket No.: 2017408-0046 least about 50 days, at least about 55 days, at least about 60 days, at least about 65 days, at least about 70 days, at least about 75 days, at least about 80 days, at least about 85 days, at least about 90 days, at least about 95 days, or at least about 100 days.
  • a dose of an antibody or antigen-binding fragment thereof described herein achieves a half- life of at least about 55 days.
  • a 1200 mg dose of an antibody or antigen-binding fragment thereof described herein achieves a neutralizing index against SARS-CoV-2 of at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, or at least about 200.
  • a 1200 mg dose of an antibody or antigen-binding fragment thereof described herein achieves a neutralizing index against SARS-CoV-2 of at least about 30 to greater than 100 against omicron variants of interest.
  • Dosing [0149] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection in a subject comprising administering a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus in combination with a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus allows for a reduced second dose to be administered of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus relative to the dose administered of the antibody or antigen-binding fragment thereof that binds specifically to a Spike protein as a monotherapy.
  • first dose and second dose is not indicative of the order of administration of any combination disclosed herein, particularly an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus.
  • Page 52 of 120 12756399v1 Attorney Docket No.: 2017408-0046
  • a first dose and a second dose can be administered in any order or substantially simultaneously.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is from 25 mg to about 2400 mg, about 25 mg to about 1800mg, about 25 mg to about 900mg, about 25 mg to about 600mg, about 25 mg to about 300mg, about 25 mg to about 200mg, about 50 mg to about 2400 mg, about 50 mg to about 1800 mg, about 50mg to about 1200 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 600 mg, about 100 mg to about 2400 mg, about 100 mg to about 1800 mg, about 100 mg to about 1500 mg, about 100 mg to about 1200 mg, about 100 mg to about 900 mg, about 100mg to about 700 mg, about 300 mg to about 2400 mg, about 300 mg to about 1800 mg, about 300 mg to about 1500 mg, about 300 mg to about 1200 mg, about 300mg to about 1000 mg, about 300mg to about 800 mg, about 300m
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 25 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 50 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 75 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 100 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 125 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 150 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 175 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 200 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus Page 53 of 120 12756399v1 Attorney Docket No.: 2017408-0046 is about 225 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 250 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 275 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 300 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 325 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 350 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 375 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 400 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 425 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 450 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 475 mg. [0153] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 500 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 625 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 650 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that Page 54 of 120 12756399v1 Attorney Docket No.: 2017408-0046 binds specifically to S2 of a sarbecovirus is about 675 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 700 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 725 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 750 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 775 mg.
  • a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 800 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 825 mg. [0154] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 850 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 875 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 900 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 925 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 950 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 975 mg.
  • a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1000 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1025 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1050 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1075 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1100 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1125 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1150 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1175 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1200 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1225 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1250 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1275 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1300 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1325 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1350 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1375 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1400 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1425 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1450 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1475 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1500 mg. In some Page 56 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1525 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1650 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1675 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1700 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1725 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1750 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1775 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1800 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1825 mg.
  • a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1850 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1875 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus is from about 25 mg to about 2400 mg, 25 mg to about 1800mg, about 25 mg to about 900mg, about 25 Page 57 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg to about 600mg, about 25 mg to about 300 mg, about 25 mg to about 200mg, about 50 mg to about 2400 mg, about 50 mg to about 1800 mg, about 50mg to about 1200 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 100 mg to about 2400 mg, about 100 mg to about 1800 mg, about 100 mg to about 1500 mg, about 100 mg to about 1200 mg, about 100 mg to about 900 mg, about 100 mg to about 700 mg, about 200 mg to about 2400 mg, about 200 mg to
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 25 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 50 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 75 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 100 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 125 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 150 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 175 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 200 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 225 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 250 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 275 mg. In some Page 58 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 300 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 325 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 350 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 375 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 400 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 425 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 450 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 475 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 500 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 525 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 550 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 575 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 600 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 625 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 650 Page 59 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 675 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 700 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 725 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 750 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 775 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 800 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 825 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 850 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 875 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 900 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 925 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 950 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 975 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1000 Page 60 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1025 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1050 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1075 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1100 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1125 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1150 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1175 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1200 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1225 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1250 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1275 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1300 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1325 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1350 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1375 Page 61 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1400 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1425 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1450 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1475 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1500 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1525 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1550 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1575 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1600 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1625 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1650 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1675 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1700 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1725 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1750 Page 62 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1775 mg.
  • a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1800 mg.
  • a combination of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus can be administered on multiple occasions. Administration of doses described herein can be repeated various times. Intervals between a combination of doses can be weekly, monthly, quarterly, or yearly. Administration of doses described herein can be repeated various times. Intervals between doses described herein can be weekly, monthly, quarterly, or yearly. Administration of doses described herein can be repeated various times. In some embodiments, doses described herein are administered at least 2 or more times.
  • doses described herein are administered at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times or more. In some embodiments, doses and dosing frequencies described herein are repeated indefinitely. In some embodiments, a single dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a single dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus are administered.
  • a Spike protein e.g., RBD
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 3 months to about every 12 months. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 3 months.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of Page 63 of 120 12756399v1 Attorney Docket No.: 2017408-0046 an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 4 months.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 6 months.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 9 months. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 12 months.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 12 weeks to about every 52 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 13 weeks.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 14 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 15 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 16 weeks.
  • administration of a first dose of an Page 64 of 120 12756399v1 Attorney Docket No.: 2017408-0046 antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 17 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 18 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 19 weeks.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 20 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 21 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 22 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 23 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 24 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of Page 65 of 120 12756399v1 Attorney Docket No.: 2017408-0046 a sarbecovirus is about every 25 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 26 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 27 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 28 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 29 weeks.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 30 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 31 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 32 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 33 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds Page 66 of 120 12756399v1 Attorney Docket No.: 2017408-0046 specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 34 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 35 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 36 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 37 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 38 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 39 weeks.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 40 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 41 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus Page 67 of 120 12756399v1 Attorney Docket No.: 2017408-0046 is about every 42 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 43 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 44 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 45 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 46 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 47 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 48 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 49 weeks.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 50 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that Page 68 of 120 12756399v1 Attorney Docket No.: 2017408-0046 binds specifically to a Spike protein of a sarbecovirus is about every 51 weeks.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 52 weeks.
  • administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 4 times to about 1 time annually.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 4 times annually. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 3 times annually.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about quarterly. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 2 times annually.
  • administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 1 time annually.
  • Any dose or combination of doses described herein can be administered at any frequency described herein.
  • Non-limiting examples of doses and frequencies described herein include: a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 300 mg and a second dose of an antibody or Page 69 of 120 12756399v1 Attorney Docket No.: 2017408-0046 antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 300 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 300 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or
  • kits comprising at least one antibody or antigen-binding fragment thereof described herein, and instructions for use and/or administration.
  • a kit comprises least one antibody or antigen-binding fragment thereof described herein and a pharmaceutically acceptable carrier, and instructions for use and/or administration.
  • a kit comprises an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1.
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD).
  • RBD receptor binding domain
  • an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus.
  • Page 72 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0173]
  • Instructions can comprise a description of administration of a first and second pharmaceutical composition to a subject to achieve an intended activity in a subject.
  • a kit may further comprise a description of selecting a human suitable for treatment based on identifying whether the human is in need of the treatment.
  • the instructions comprise a description of administering at least one antibody or antigen-binding fragment thereof described herein to a subject.
  • Instructions relating to administering a dose comprising at least one antibody or antigen-binding fragment thereof described herein generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • Containers may be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses.
  • kits are typically written instructions on a label or package insert.
  • a label or package insert indicates that pharmaceutical compositions are used for treating or preventing sarbecovirus (e.g., SARS-CoV-2) infection in a subject.
  • Kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Also contemplated are packages for use in combination with a specific device, such as an infusion device.
  • a kit may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierce able by a hypodermic injection needle).
  • a container may also have a sterile access port.
  • Kits optionally may provide additional components such as buffers and interpretive information.
  • a kit can include a container and a label or package insert(s) on or associated with the container.
  • articles of manufacture comprising contents of kits described herein.
  • Example 1 First-in-human study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.
  • This Example demonstrates that an anti-S2 antibody (AB-1) achieves prophylactic efficacy against circulating viral variants of SARS-CoV-2 and related sarbecovirus.
  • AB-1 is a half-life extended monoclonal antibody for prophylaxis of SARS- CoV-2 infection that targets S2 of the SARS-CoV2 spike protein, which contains a stem- helix region, and was selected because S2 is conserved across all SARS-Co-V2 variants to- date.
  • S2 is not immunodominant, and therefore, is not subject to selective pressure due to natural infection or vaccine induced immunity, which suggests that AB-1 will maintain its activity against SARS-Co-V2 and variants.
  • AB-1 is also able to neutralize other sarbecovirus, such as SARS-CoV-1 and WIV1 (Table 3).
  • Page 74 of 120 12756399v1 Attorney Docket No.: 2017408-0046
  • Table 3 AB-1 EC50 against SARS-CoV2 variants and other sarbecovirus in a pseudoneutralization assay.
  • Live virus neutralization against currently circulating strains of SARS-CoV-2 was dose-proportional with clear separation from placebo. Limited anti-drug antibodies were observed in a few participants, but had no impact on PK or viral neutralization titers. Simulated PK of AB-1 confirmed with observed data (assuming 10% lung penetration) are at levels anticipated to protect against COVID-19 infection for at least 150 days (FIG.1). [0183] These preliminary data support that AB-1 will provide at least about a 6 month duration of prophylactic efficacy against currently circulating viral variants when administered.
  • Example 2 First-in-human study of a combination of monoclonal antibodies described herein against SARS-CoV-2 and related sarbecovirus.
  • the present Example will provide a randomized, dose-escalation trial for evaluation of safety, tolerability, and pharmacokinetics of a combination of an antibody that binds specifically to S2 of a sarbecovirus (referred to herein as “AB-1”) and an antibody that binds specifically to a receptor binding domain (RBD; referred to herein as “AB-2”) of a sarbecovirus.
  • AB-1 an antibody that binds specifically to S2 of a sarbecovirus
  • RBD receptor binding domain
  • This study will aim to evaluate AB-1 and AB-2 in combination dose cohorts in 20 healthy volunteers. All subjects will be monitored at periodic clinic visits for 302 days following their dosing. Upon completion of the last subject’s Day 29 clinic visit in the second combination dose cohort, interim analysis will be performed.
  • Combination Cohort 1 650 mg, AB-1 10 (8 active/2 placebo) 650 mg, AB-2
  • subjects will receive an intramuscular (IM) dose of AB-1 and an IM dose of AB-2 (a “combination dose”).
  • the placebo group will receive a dose of 0.9% sodium chloride given intramuscularly.
  • Interim Analysis Assessments [0188] Primary objectives: Assess safety and tolerability of a combination dose of AB-1 and AB-2 administered IM compared to placebo. [0189] Secondary objectives: Assess pharmacokinetics and immunogenicity of a combination dose of AB-1 and AB-2 administered IM compared to placebo.
  • the present Example demonstrates that a combination of an antibody that binds specifically to S2 of a sarbecovirus (referred to herein as “AB-1”) and an antibody that binds specifically to a receptor binding domain (RBD; referred to herein as “AB-2”) achieved strong virus neutralization activity.
  • AB-1 and AB-2 were titrated in a checkboard approach so two-variable titration curves could be generated starting at 18ug/ml in a fourfold dilution series. These dilutions were assayed for neutralization activity in VERO-TMPRSS2 cells against SARS-CoV-2 Omicron BQ.1.1 Spike and XBB.1.5 Spike pseudotyped VSVdG particles.
  • Vero-E6 cells over-expressing TMPRSS2 were seeded in 384 well tissue culture plates. Antibodies were serially diluted and incubated with diluted virus at a desired MOI. After 30 min - 1 hour incubation at 37oC, 5% CO2, pseudovirus/antibody mixture was added to corresponding wells of the culture plates with Vero cells. After 24 hours, luciferase substrate was added directly to culture plates (pseudovirus backbone has a luciferase reporter) and read using the luminescent filter on the Envision.
  • Vero-TMPRSS2 cells were harvested, counted and plated in cell culture plates at 3.5 x 103 cells/well with 20 ⁇ l stimulation medium. Plates were spun down for ⁇ 5 seconds at 50 g and then incubated at 37 degrees Celsius, 5% CO2 for 2-4 hours while dilution and antibody/pseudovirus incubation plates were prepared.
  • AB-1 dilution plates (plates 1-4) were prepared as follows: 40 ⁇ l of PBS-T +BSA + P/S) was added to rows A-H of columns 1-8 of plates 2 and 4 and rows B-H of column 1-8 of plates 1 and 3.
  • AB-2 dilution plates 5-8 were prepared as follows: 40 ⁇ l of PBS-T +BSA + P/S was added to rows A-H of column 8-1 of plates 6 and 8, and rows A-H of column 1-7 of plates 5 and 7. Then, 53.33 ⁇ l of PRO-37587-001 at 72 ⁇ g/ml was added to column 8 of plate 5 and 7. 13.33 ⁇ l was taken from column 8 of plate 5 and serially diluted through column 1 and continued through column 8-1 of plate 6 to create a (row-wise) 16-pt titration curve at a 1:4 dilution.
  • a total of 106.7 ⁇ l of antibody at 72 ug/ml was added to well A1 (AB-1), A3 (AB-2), A5 (Bebtelovimab), and A7 (Isotype).
  • a total of 26.7 ⁇ l of antibody was transferred to B1, B3, B5, B7, respectively, and 26.7 ⁇ l was transferred through columns 1, 3, 5, 7 and through A- H of rows 2, 4, 6, 8 to create a 16-pt curve; 1:4 dilution.
  • Antibody/pseudovirus plates were prepared as follows: 40 ⁇ l of diluted virus was added to each well of the dilution plates. 40 ⁇ l of stimulation media was added to column 11-12 of Plate 10 (as a positive control).
  • Results depicted in FIGs.2A-F demonstrate strong enhancement of protection, at all concentrations tested and as measured by percent neutralization, of AB-1 combined with AB-2.
  • Example 4 Pharmacodynamic study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.
  • pharmacodynamic properties of AB-1 was characterized in subjects with pre-existing SARS -CoV-2 titers (e.g., infection).
  • a subject’s mean neutralization titer of antibodies was measured before and after a 100mg, 300mg, 600mg, 1200mg, or 2400mg dose of AB-1 was administered.
  • live virus 50% and 80% mean neutralization titer e.g., MN50 and MN80
  • Wild Type D614G, Omicron XBB.1.5, and Omicron BA.5.5 strains of live (e.g., infectious) SARS-CoV-2. All doses tested i.e., 100mg, 300mg, 600mg, 1200mg, and 2400mg
  • All doses tested i.e., 100mg, 300mg, 600mg, 1200mg, and 2400mg
  • All doses tested i.e., 100mg, 300mg, 600mg, 1200mg, and 2400mg
  • an AB-1 dose of 1200mg achieved an approximately 10-fold increase in live virus MN50 titer against XBB.1.5 and BA.5.5 (FIG. 4).
  • subjects that received an AB-1 dose of 1200mg achieved a 20-fold increase in live virus MN50 titer and a 15-fold increase in live virus MN80 titer against XBB.1.5, relative to pre-dose (e.g., baseline) titers (FIG.5).
  • pre-dose e.g., baseline
  • Example 5 Neutralizing capacity of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.
  • This Example demonstrates that AB-1 achieves protection against SARS-CoV-2 for over 60 days in subjects with low baseline titer of anti-SARS-Cov2 neutralizing antibodies.
  • an immunocompromised subject has a low baseline titer of antibodies that can neutralize SARS-CoV-2.
  • a neutralizing index was calculated like described in Stadler et al. “Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis.” The Lancet.
  • AB-1 in subjects with low baseline titers achieved a neutralizing index of 30 to greater than 100 over a 60-day period.
  • Neutralizing index data demonstrated that AB-1 achieved protection against hospitalization due to Omicron variant Xbb.1.5 or BA.5.5 infection for over 60 days in subjects with low baseline titer levels (e.g., in immunocompromised subjects).
  • Example 6 Neutralizing capacity of a novel half-life extended monoclonal antibody against SARS-CoV-2 and related sarbecovirus. [0204] This Example demonstrates the percent neutralization of various sarbecoviruses (e.g., SARS-CoV-2 variants) achieved by AB-1.
  • a neutralization assay was performed using an isotype control (i.e., negative control) and commercial antibody, bebtelovimab, for comparison.
  • AB-1 achieved neutralization of SARS CoV-2 variants currently tracked by the CDC as well as non-SARS-CoV-2 sarbecoviruses responsible for previous outbreaks (e.g., SARS-CoV-1) or at risk of zoonotic spillover (e.g., WIV1).
  • AB-1 achieved at least 80% neutralization of all sarbecoviruses tested (FIG.7).
  • AB-1 achieved Page 81 of 120 12756399v1 Attorney Docket No.: 2017408-0046 percent neutralization of non-SARS-CoV-2 sarbecoviruses (e.g., SARS-CoV-1 and WIV1) and SARS-CoV-2 Omicron variants BQ.1, BQ.1.1, and XBBB.1.5 that was superior to bebtelovimab and the isotype control (FIG.7).
  • AB-1 achieved percent neutralization of SARS-CoV-2 D614G, SARS-CoV-2 Delta, and SARS-CoV-2 BA.4/5 that was similar to Bebtelovimab (FIG.7).
  • Table 5 depicts the EC50 (95% CI) value (ng/mL) of AB-1 calculated for each Sarbecovirus tested. Table 5. EC50 values of AB-1 against sarbecoviruses. EC50 (95% SARS- SARS- SARS- SARS- SARS- CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 SARS- WIV1 [0205] Table 5 depicts EC50 values ( ⁇ g/mL), shown as mean (95% confidence interval) and representative of three to six independent experiments, four technical replicates each.
  • the pseudovirus panel included the following: spike (WIV-1) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-033-002, BPS Bioscience, catalog # 78696, lot # 221201); spike (SARS- CoV-1) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-032-001, BPS Bioscience, catalog # 78695, lot #221201); spike (SARS-CoV-2, D614G) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-017-001, BPS Bioscience, catalog # 78642, lot # 220512); spike Page 82 of 120 12756399v1 Attorney Docket No.: 2017408-0046 (SARS-CoV-2, B.1.617.2, Delta) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-016- 002, BPS Bioscience, catalog # 78640, lot # 220512); spike (SARS-CoV-2, BA.4
  • Cell lines TMPRSS2-Vero E6 Recombinant Cell Line (CL-030, BPS Biosciences, catalog # 78081, lot # 210522#20); VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586).
  • Antibodies AB-1 (Lonza, lot # 1100-130922-01), isotype control (GenScript USA, Inc., lot # U799WHJ270-3, palivizumab variable regions targeting RSV F protein and expressed as human IgG1 with LS mutation in the Fc region), bebtelovimab (GenScript USA, Inc., lot # U3767HH180-46).
  • Stimulation medium MEM (catalog # SH30024.02, lot # AH29890509) with 2.5% FBS (catalog # A38403-01, lot # 262908SRP), 0.1 mM nonessential amino acids (catalog #11140-050, lot # 2390759), 1 mM sodium pyruvate (catalog #11360-070, lot #2323639), 1% Penicillin/Streptomycin (catalog # 15140-122, lot # 2441835).
  • Luciferase detection buffer ONE-StepTM Luciferase Assay System, components A and B were mixed at 100:1 ratio respectively (BPS Bioscience, catalog # 60690-3, lot # 221221).
  • Plastics Tissue culture plates were white 384-Well plates, with lid, cell culture, sterile, polystyrene (ThermoFisher, catalog # 164610). Dilution plates were 96 well plate round bottom, non-treated, polypropylene (Corning, catalog# 3365; Greiner, catalog # 650201). Antibody/pseudovirus incubation plates were Nunc 96-Well polystyrene round bottom microwell plates, with lid, non-tissue culture-treated, sterile (ThermoFisher, catalog #268200).
  • Vero E6 or a TMPRSS2-Vero E6 recombinant cells were seeded into 384-well tissue culture plates at a density of 3,500 cells per well in 20 ⁇ l of stimulation medium and incubated at 37C, 5% CO2 for 2 - 4 hours.
  • antibodies were serially diluted and incubated with diluted pseudovirus listed above at a desired multiplicity of infection.
  • Antibody neutralization was assessed with 12-point titration curves in technical quadruplicate (1:4 serial dilutions prepared in PBS with 0.2% BSA and 1X Pen-Strep solution starting at 18 ⁇ g/ml).
  • Antibodies were serially diluted starting at 72 ⁇ g/ml (4-fold of the final top concentration [18 ⁇ g/ml] in the tissue culture plates). After 30 - 60 minutes of incubation at 37C, 5% CO2, 20 ⁇ l pseudovirus/antibody mixture was added to the tissue culture plates pre-seeded with cells, achieving final antibody concentrations in a total volume of 40 ⁇ l. After 24 hours at 37C, 5% CO2, an equal volume of luciferase substrate was added directly to culture plates and luminescence was quantified on the PerkinElmer EnVision plate reader.
  • Example 7 A novel half-life extended monoclonal antibody against SARS-CoV-2 and related sarbecovirus.
  • This Example demonstrates that all binding residues in the S2 stem helix epitope that AB-1 binds are > 99% conserved.
  • Material and methods for the following results displayed Relative frequencies at 1 month, 3 months, and earliest for polymorphisms in the S2 stem helix region; G1167V, P1162L, P1162S, and V1176F. Page 84 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Table 6. Summary of polymorphisms identified in the S2 stem helix region.
  • the relative frequencies are for the period ending March 1st, 2023, across three different time intervals (earliest [January 6th, 2020 to March 1st, 2023], 3 months [December 1st, 2022 to March 1st, 2023], 1 month [February 1st, 2023 to March 1st, 2023]).
  • Relative frequency is determined by dividing the number of sequences with a mutation of interest observed during a given time interval by the total number of sequences observed during the same time interval.
  • pseudoviruses with spike bearing P1162L or P1162S exhibited reduced susceptibility to AB-1; other polymorphisms did not impact activity. In some embodiments, none of these polymorphisms have exceeded a relative frequency of 0.01 and/or shown significant upward trends in the past 3 months. These data herein suggest little to no immune pressure on this epitope (FIG.8). In some embodiments, none of these polymorphisms have been detected at high relative frequencies in highly prevalent SARS- CoV-2 variants.
  • Example 8 Neutralization activity of a monoclonal antibody described herein, alone or in combination with remdesivir against SARS-CoV-2 Omicron JN.1
  • the aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., remdesivir).
  • the combination was tested following a method of administration where both AB-1 and remdesivir were titrated simultaneously.
  • AB-1 and Remdesivir was also each tested alone.
  • EC50 values, calculated from experiments depicted in FIG.10, are shown in Table 7.
  • Results are expressed as EC50 values for each tested article as single agents or in combination, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates).
  • the EC values are displayed both in function of the AB-1 dilution or in function of the remdesivir dilution. Remdesivir concentration is represented in M and AB-1 concentration is represented in g/ml.
  • Table 7 EC50 values of AB-1 and remdesivir as single agents or in combination against SARS-CoV-2 Omicron JN.1 EC50 Page 87 of 120 12756399v1 Attorney Docket No.: 2017408-0046 AB-1 (titrated) + Remdesivir (titrated) EC values expressed in function of Remdesivir. 0.046 ⁇ M an th agents increased remdesivir (EC500.046 ⁇ M) and AB-1 (0.042 ⁇ g/mL) potency. [0227] Taken together these data demonstrate that the antiviral activity of remdesivir is increased by co-administration of AB-1.
  • Virus SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID 50 /ml.
  • Cell line VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586), passage 12 (from thawing).
  • Antiviral Remdesivir (Selleck Chemicals, catalog #S8932).
  • Antibody AB-1.
  • MTT Assay Reagents MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Merck, catalog #475989 – 1 G, lot #4158001) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Merck, catalog #41639-500ML, lot #102666276).
  • Methods [0235] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom).
  • Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture Page 88 of 120 12756399v1 Attorney Docket No.: 2017408-0046 media and incubated at 37C, 5% CO2, until the following day.
  • Antibody and antiviral neutralization were assessed using 12-point titration curves in technical triplicate with three- fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 and 20 M (final concentration) for Remdesivir alone and the AB-1-Remdesivir combination.
  • a predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells.
  • Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed from the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect.
  • the percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition.
  • Example 9 Neutralization activity of a monoclonal antibody described herein, alone or in combination with nirmatrelvir against SARS-CoV-2 Omicron JN.1
  • the aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., nirmatrelvir).
  • Nirmatrelvir concentration is represented in M and AB-1 concentration is represented in g/ml.
  • Table 8 The EC50 values of AB-1 and nirmatrelvir as single agents or in combination against SARS-CoV-2 Omicron JN.1 EC50 Nirm tr lvir 2693 M an EC50 of 0.089 ⁇ g/mL, compared to 2.693 ⁇ M for nirmatrelvir. Simultaneous titration of both agents increased nirmatrelvir (EC500.080 ⁇ M) and AB-1 (0.072 ⁇ g/mL) potency.
  • Virus SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml.
  • Cell line VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586), passage 13 (from thawing).
  • Antiviral Nirmatrelvir (Insight Biotechnology, catalog # HY-138687) Page 90 of 120 12756399v1 Attorney Docket No.: 2017408-0046
  • Antibody AB-1.
  • Culture Media M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • Infection Media M199 (Gibco, catalog #31150022, lot 2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • BSA Bovine Serum Albumin
  • Penicillin/Streptomycin Gibco, catalog #15070063, lot #2588019
  • MTT Assay Reagents MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Merck, catalog #475989 – 1 G, lot #4158001) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Merck, catalog #41639-500ML, lot #102666276).
  • Methods [0248] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom).
  • Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture media and incubated at 37C, 5% CO2, until the following day.
  • Antibody and antiviral neutralization were assessed using 12-point titration curves in technical triplicate with three- fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 and 20 M (final concentration) for Nirmatrelvir alone and the AB-1-Nirmatrelvir combination.
  • a predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells.
  • Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO 2 , the media was removed from the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO 2 and monitored for cytopathic effect. After 72 hours, 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2.
  • the supernatants were removed from each well, and the MTT precipitates solubilized by adding 50 l of a 1:1 mixture of DMSO and Page 91 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader. The sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells.
  • the percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: [0249]
  • the EC50 values were extrapolated using GraphPad Prism software (v10) from the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition.
  • Example 10 Neutralization activity of a monoclonal antibody described herein, alone or in combination with nirmatrelvir + P-glycoprotein (P-gp) inhibitor against SARS- CoV-2 Omicron JN.1
  • the aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., nirmatrelvir + P-gp inhibitor).
  • the combination was tested following a method of administration where both AB-1 and nirmatrelvir were titrated simultaneously in the presence of a constant concentration (0.25 ⁇ M) of P-gp inhibitor.
  • AB-1 and nirmatrelvir in the presence of a constant concentration (0.25 ⁇ M) of P-gp inhibitor were also each tested alone.
  • EC50 values calculated from experiments depicted in FIG.12, are shown in Table 9. Results are expressed as EC50 values for each tested article as single agents or in combination, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). When the compounds were titrated in combination, the EC values are displayed both in function of the AB-1 dilution or in function of the nirmatrelvir dilution. Nirmatrelvir concentration is represented in M and AB-1 concentration is represented in g/ml. Table 9.
  • Virus SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml.
  • Cell line VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586), passage 13 (from thawing).
  • Antiviral Nirmatrelvir (Insight Biotechnology, catalog #HY-138687); P- glycoprotein (P-gp) inhibitor CP 100356 hydrochloride (Bio-Techne, catalog #4193/10).
  • Antibody AB-1. Page 93 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0258] Culture Media: M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • FBS Fetal Bovine Serum
  • Penicillin/Streptomycin Gibco, catalog #15070063, lot #2588019.
  • Infection Media M199 (Gibco, catalog #31150022, lot #2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • BSA Bovine Serum Albumin
  • Penicillin/Streptomycin Gabco, catalog #15070063, lot #2588019
  • MTT Assay Reagents MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Merck, catalog #475989 – 1 G, lot #4158001) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Merck, catalog #41639-500ML, lot #102666276).
  • Methods [0261] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom).
  • Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture media and incubated at 37C, 5% CO2, until the following day.
  • Antibody and antiviral neutralization were assessed using 12-point titration curves in technical triplicate with three- fold dilutions in infection media at 18 g/mL (final concentration) for AB-1 and 1 M (final concentration) for Nirmatrelvir alone and the AB-1-Nirmatrelvir combination. All antibody and antiviral conditions were tested in the presence of a constant concentration of 0.25 ⁇ M (final concentration) P-gp inhibitor, except for AB-1, which was prepared in the absence of the inhibitor.
  • a predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells.
  • Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed from the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect.
  • the sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells.
  • the percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: [0262]
  • the EC50 values were extrapolated using GraphPad Prism software (v10) from the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition.
  • Example 11 Neutralization activity of a monoclonal antibody described herein, alone or in combination with P-glycoprotein (P-gp) inhibitor against SARS-CoV-2 Omicron JN.1
  • P-gp P-glycoprotein
  • the aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., P-gp).
  • P-gp additional therapeutic agent
  • EC50 values calculated from experiments depicted in FIG.13, are shown in Table 10. Results are expressed as EC50 values for AB-1 as a single agent or in combination with P-gp inhibitor, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). The EC values are displayed in function of the AB-1 dilution in g/ml. Table 10. The EC50 values of AB-1 as a single agent or in combination with P-gp inhibitor against SARS-CoV-2 Omicron JN.1 EC50 Page 95 of 120 12756399v1 Attorney Docket No.: 2017408-0046 AB-1 (titrated) + 0.25 ⁇ M P-gp inhibitor.
  • Virus SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml.
  • Cell line VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586).
  • Antiviral P-glycoprotein (P-gp) inhibitor CP 100356 hydrochloride (Bio- Techne, catalog #4193/10).
  • Antibody AB-1.
  • Culture Media M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • Infection Media M199 (Gibco, catalog #31150022, lot #2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • BSA Bovine Serum Albumin
  • Penicillin/Streptomycin Gabco, catalog #15070063, lot #2588019
  • TT Assay Reagents MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Invitrogen, catalog #M6494, lot #2139890); Isopropanol (Fisher, catalog #P/7500/17, lot#1852201); DMSO (Sigma, catalog #41639-500ML, lot #102666276).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Invitrogen, catalog #M6494, lot #2139890
  • Isopropanol Fisher, catalog #P/7500/17, lot#1852201
  • DMSO Sigma, catalog #41639-500ML, lot #102666276.
  • SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom).
  • Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture Page 96 of 120 12756399v1 Attorney Docket No.: 2017408-0046 media and incubated at 37C, 5% CO2, until the following day.
  • Antibody neutralization was assessed using 12-point titration curve in technical triplicate with three-fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 with or without a constant concentration of 0.25 ⁇ M (final concentration) P-gp inhibitor.
  • a predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells.
  • Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed for the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect every 24 hours.
  • the percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition.
  • Example 12 Neutralization activity of a monoclonal antibody described herein, alone or in combination with Molnupiravir against SARS-CoV-2 Omicron JN.1
  • the aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., molnupiravir).
  • Molnupiravir concentration is represented in M and AB-1 concentration is represented in g/ml.
  • Table 11 The EC50 values of AB-1 and molnupiravir as single agents and in combination against SARS-CoV-2 Omicron JN.1 EC50 M ln ir vir (NHC EIDD-1931) 1319 M an EC50 of 0.689 ⁇ g/mL, compared to 1.319 ⁇ M for molnupiravir. Simultaneous titration of both agents increased molnupiravir (EC500.486 ⁇ M) and AB-1 (0.437 ⁇ g/mL) potency.
  • Virus SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml.
  • Cell line VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586).
  • Infection Media M199 (Gibco, catalog #31150022, lot #2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019).
  • BSA Bovine Serum Albumin
  • Penicillin/Streptomycin Gabco, catalog #15070063, lot #2588019
  • MTT Assay Reagents MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), (Invitrogen, catalog #M6494, lot #2139890) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Sigma, catalog #41639-500ML, lot #102666276).
  • Methods [0287] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom).
  • Molnupiravir is the prodrug that is metabolized into its active form, NHC (EIDD-1931). Accordingly, these studies were conducted using NHC. Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture media and incubated at 37C, 5% CO2, until the following day. Antibody and antiviral neutralization were assessed using 12- point titration curves in technical triplicate with three-fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 and 20 M (final concentration) for NHC alone and the AB-1-NHC combination.
  • a predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells.
  • Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO 2 , the media was removed for the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO 2 and monitored for cytopathic effect.
  • Page 99 of 120 12756399v1 Attorney Docket No.: 2017408-0046
  • 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2.
  • the supernatants were removed from each well, and the MTT precipitates solubilized by adding 50 l of a 1:1 mixture of DMSO and Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader.
  • the sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells.
  • the percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition.
  • Example 13 Neutralization activity of a monoclonal antibody described herein, alone or in combination with Remdesivir against early isolate SARS-CoV-2 (England/02/2020).
  • the aim of this study was to assess the antiviral activity against SARS-CoV-2 (early isolate, England/02/2020) of AB-1, when administered on its own or in combination with remdesivir.
  • the combination was tested following two modes of administration: one where both AB-1 and remdesivir were titrated simultaneously, and one where only remdesivir was titrated while AB-1 was kept at a constant concentration (18 ⁇ g/ml).
  • AB-1 and Remdesivir was also each tested alone.
  • AB-1 was diluted to 36 ⁇ g/ml (twice the final concentration) in 1,150 ⁇ l of infection media, by adding 2 ⁇ l of the 20.4 mg/ml stock into 1,148 ⁇ l of infection media.
  • Remdesivir was diluted to 40 ⁇ g/ml (twice the final concentration) in 450 ⁇ l of infection media by adding 1.8 ⁇ l of 10 mM stock into 448.2 ⁇ l of infection media. When diluted at the same time, 1.6 ⁇ l of AB-1 stock and 3.6 ⁇ l of Remdesivir stock were added into 894.8 ⁇ l of infection media.
  • Virus addition [0301] A predetermined MOI of 0.002 of SARS-CoV-2 (England/02/2020) in 75 ⁇ l was added to each well of the dilutions and in the infected untreated control wells, thereby halving the concentration of the antibodies.
  • Infection media only (without virus) was added to the uninfected untreated control wells. Next, virus and antibodies were incubated for 1 hour at 37oC, 5%CO2.
  • Cell infection [0302] After 1 hour, media was removed from the cells and replaced with 150 ⁇ l of the virus + test dilution mixtures. Plates were incubated for 72 h in a humidified incubator at 37 oC and 5% CO2. Plates were checked at 24 h, 48 h, and 72 h to monitor CPE.
  • MTT assay [0303] 72 h later, CPE was complete and clear, and an MTT assay was performed to quantify the extent of the CPE.
  • MTT reagent 20 ⁇ l were added to all wells, before incubation in a humidified incubator at 37 °C, 5% CO2 for 2 h.
  • the supernatants were removed and the MTT precipitates solubilized by adding 50 ⁇ l of a 1:1 mix of DMSO and Isopropanol. After a further 20 minutes incubation, the supernatants were transferred to clean 96 well plates, and immediately acquired at 560 nm on a Promega GloMax Explorer System plate reader.
  • SPR was used to measure AB-1 binding to partially overlapping peptides spanning the reference molecule target epitope (aa 1133 – 1162), a peptide representing the C-terminal end of the stem helix (aa 1149 – 1167), a control 15mer peptide derived from HIV-1 Env protein, and a peptide designed to encompass the SARS-CoV-2 spike S2 stem helix (aa 1143 – 1162).As shown in FIG.15, SPR data demonstrates that AB-1 and the reference molecule bind to the SARS-CoV-2 spike S2 stem helix peptide.
  • DELFIA and SPR were employed to assess binding of AB-1 and its reference molecule to a panel of spike trimers representative of: 1) SARS-CoV-2 pre-Omicron variants (D614G [ancestral strain with D614G polymorphism], Delta [B.1.617.2]); 2) major SARS-CoV-2 Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4, BA.5, BA.4.6, BF.7, BN.1, BQ.1, BQ.1.1, XBB, XBB.1, XBB.1.5); 3) non-SARS-CoV-2 sarbecoviruses (WIV1, SARS-CoV-1); 4) SARS-CoV-2 Omicron variants with polymorphisms in the AB-1 epitope (P1162S and P1162L).
  • SARS-CoV-2 pre-Omicron variants D614G [ancestral strain with
  • DELFIA data demonstrate that AB-1 binds to all the spike trimers tested in the experiment, showing overall lower EC50 values compared to the reference molecule (FIGS. 16A-16B).
  • SPR data confirms that AB-1 Fab binds to SARS-CoV-2 D614G, Delta, BA.4, Page 105 of 120 12756399v1 Attorney Docket No.: 2017408-0046 BA.5, BQ.1.1, and XBB.1.5 spike trimers with comparable affinities and overall higher affinities than the reference molecule Fab (Table 14).
  • AB-1 Fab binding affinities to SARS- CoV-2 Delta, BA.4, BA.5, BQ.1.1, XBB.1.5 spike trimers are within 2-fold of SARS-CoV-2 D614G spike trimer. These differences are considered within the range of variability of the method, demonstrating that AB-1 Fab has comparable binding affinities across the tested spike trimers. In addition, AB-1 Fab binds to these spike trimers with an approximate 5-fold higher affinity than the reference molecule Fab.
  • AB-1 Fab binding affinities to SARS-CoV-2 spike trimers of BA.2 variants containing polymorphisms in the AB-1 epitope are within 2-fold of the BA.2 parent and AB-1 Fab binds to these spike trimers with an approximate 5-fold higher affinity than the reference molecule Fab.
  • the specificity of these results is confirmed by lack of binding of the isotype control in the DELFIA experiment, and lack of binding of AB-1 and the reference molecule Fabs to the MERS spike trimers used as negative control in the SPR experiment.
  • Example 16 In-vivo (human) study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.
  • This Example demonstrates that an anti-S2 antibody (AB-1) achieves prophylactic efficacy against circulating viral variants of SARS-CoV-2 and related sarbecovirus.
  • the present Example provides a randomized, single-blind, placebo-controlled, sequential group, single ascending dose study to evaluate the safety, tolerability and pharmacokinetics of AB-1 in healthy subjects.
  • Eligible participants were screened and randomized to receive either AB-1 or placebo in each dosing cohort. Five cohorts were enrolled in this study.
  • the first two single ascending dose (SAD) cohorts included 3 healthy volunteers (HV) participants receiving AB-1 and 3 healthy volunteers participants receiving placebo.
  • the last three SAD cohorts planned for this study included 10 HV participants receiving AB-1 and 3 HV participants receiving placebo.
  • An overview of the dosing study design is provided in Table 15.
  • Table 15 Overview of Study Design Study Target Sample Size (n) Proposed Number of Study Objectives Phase Population Dose Subjects d 1 d Page 107 of 120 12756399v1 Attorney Docket No.: 2017408-0046 1200 mg 13
  • Treatment-Emergent Adverse Events TEAEs: [0318] Of the 51 subjects who received AB-1/placebo, 26 (51%) have experienced at least one treatment-emergent adverse events (TEAEs) (Table 16).
  • TEAEs occurring in >2 subjects were: alanine aminotransferase increased (5; 9.8%), blood creatine phosphokinase increased (4; 7.8%); headache (4; 7.8%), and upper respiratory tract infection (3; 5.9%).
  • Grade 3 blood creatine phosphokinase increased was reported in two subjects: 1 in cohort 3 and 1 in cohort 5.
  • Grade 4 blood creatine phosphokinase increased was reported in 2 subjects: 1 in cohort 1 and 1 in cohort 5.
  • Serious Adverse Events No serious adverse events have occurred in the study.
  • Adverse Events Leading to Discontinuation of AB-1/placebo [0322] Of the 51 subjects who received AB-1/placebo, one (2%) experienced a TEAE leading to discontinuation of AB-1/placebo, which was a Grade 2 infusion-related reaction.
  • Infusion-Related Reactions [0323] Infusion-related reactions (IRR) were identified based on clinical assessment by the investigator of the reported AE as an IRR. One subject in the 1200 mg cohort experienced a Grade 2 IRR. Symptoms included pruritus and bilateral periorbital edema. No gastrointestinal, respiratory or cardiovascular symptoms were reported. Treatment included systemic steroids, and the IRR fully resolved. [0324] The infusion duration for the remaining subjects in AB-1 was subsequently increased from 30 minutes to 45 minutes, and the remainder of subjects in the 1200 mg cohort and all subjects in the 2400 mg cohort completed dosing with no other infusion- related reactions reported.
  • Dose-limiting Toxicities [0325] AB-1, dose-limiting toxicities (DLT) were defined as any Grade 3 or greater adverse event or abnormal laboratory value assessed by the investigator to be related to study drug that occurred up through study Day 8. No DLT events were reported. [0326] No deaths occurred in this study. Page 110 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Immunogenicity [0327] As of the data cutoff-date, all randomized subjects were included in the immunogenicity analysis. At baseline, 4 of the 36 (11.1%) subjects randomized to AB-1 and 1 of the 15 (6.7%) subjects randomized to placebo had anti-drug antibodies (ADA).
  • ADA anti-drug antibodies
  • FIG.17 shows the fold increase from baseline of live virus 50% mean neutralization titer (MN50) for the live virus for the respective Omicron variants in the study.
  • MN50 mean neutralization titer
  • the live virus neutralization shows a clear dose response over time and despite significant pre-dose titers in subjects (likely due to prior infections) we observed close to a 10-fold increase from baseline in post dose mean titers (e.g., Omicron XBB1.5) at a dose of 1200 mg and clear separation from placebo for both Omicron variants.
  • Pharmacokinetic Properties [0330] The clinical pharmacokinetic data for AB-1 following IV infusion was characterized using a population pharmacokinetic model (FIG.3).
  • AB-1 PK shows two compartmental behavior following IV infusion, with rapid distribution phase and long terminal elimination phase of approximately 55 days.
  • the inter-subject variability in this phase I study was low, with a CV of approximately 20% in plasma clearance.
  • the pharmacokinetics were linear and showed clear dose proportionality across a wide dose range from 100 mg to 2400 mg.
  • the therapeutic dose for treatment was established as 1200 mg AB-1.
  • the predicted Cmax at this dose was 368875 ng/mL.
  • AB-1 Cmax concentration can be compared to the omicron XBB1.5 EC50 of 8.8 ng/ml. This is 42,000-fold coverage in Page 111 of 120 12756399v1 Attorney Docket No.: 2017408-0046 plasma at Cmax.
  • a neutralizing index (shown below, based on (Stadler et al. Nat Commun.2023;14(1):4545, incorporated by reference in its entirety), associated with efficacy of a mAb of protection from patients with symptomatic covid progressing to hospitalization) was calculated based on the predicted plasma concentration over a course of 60 days at 1200 mg. Based on these calculations the neutralizing index was estimated to range from over 100 to above 30 over the course of the 60 days post-infusion and likely to provide maximal efficacy. Based on the Stadler et al.2023 publication a neutralizing index of 1 provides maximal protection.

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Abstract

Methods are provided herein that can be used to treat or prevent sarbecovirus infection using one or more antibodies or antigen-binding fragments thereof that binds specifically to a Spike protein of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is administered in combination with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus.

Description

Attorney Docket No.: 2017408-0046 METHODS OF TREATING OR PREVENTING SARBECOVIRUS WITH ANTIBODIES OR ANTIGEN-BINDING FRAGMENTS THEREOF CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority to US Provisional Application No.63/643299, filed May 06, 2024, US Provisional Application No.63/705480, filed October 9, 2024, and US Provisional Application No.63/725383, filed November 26, 2024, the entirety of each of which is incorporated herein by reference. BACKGROUND [0002] The SARS-Coronavirus-2 (SARS-CoV-2), a novel coronavirus, first caused a cluster of pneumonia cases (COVID-19) in Wuhan, China. As of March 1, 2020, 79,968 patients in China had tested positive for COVID-19, 2,873 deaths had occurred, equivalent to a mortality rate of about 3.6% (Baud et al. Lancet Infect Dis.20(7):773 (2020)). This figure, however, may be an underestimate of the potential threat of COVID-19 in symptomatic patients (Id.). [0003] COVID-19 has been spreading rapidly throughout the world, resulting in a pandemic. The Coronavirus disease (COVID-2019) situation report released from the World Health Organization on April 21, 2020, reported 2,397,216 confirmed infections and 162,956 deaths. Among them, 83,006 new cases and 5,109 deaths were added within the previous 24 hours. Quarantine, isolation, and infection-control measures have been relied on to prevent disease spread, and supportive care for those who become ill (Baden & Rubin, N Engl J Med.382(19):1851-52 (2020)). [0004] Despite development and use of vaccines and therapeutics, SARS-CoV-2 outbreaks continue, and mutants of SARS-CoV-2 continue to develop and evade these prophylactics and treatments. Notably, numerous attempts have failed to identify potent binders to the highly conserved spike S2 stem helix of SARS-CoV-2. Accordingly, a need exists for additional therapeutics that can be rapidly deployed for SARS-CoV-2 as well as related sarbecovirus. Page 1 of 120 12756399v1 Attorney Docket No.: 2017408-0046 SUMMARY [0005] In one aspect, the disclosure provides a method of treating or preventing a sarbecovirus infection in a subject, comprising: (a) administering a first dose of about 100 mg to about 2400 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of the sarbecovirus about every 3 months to about every 12 months to the subject and (b) administering a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of the sarbecovirus about every 3 months to about every 12 months to the subject. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a HCDR1, a HCDR2 and a HCDR3 of an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a heavy chain variable region of SEQ ID NO: 10, and (ii) a LCDR1, a LCDR2 and a LCDR3 of an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a light chain variable region of SEQ ID NO: 20. [0006] In some embodiments, a first dose is about 300 mg to about 900 mg. In some embodiments, a first dose is about 600 mg or about 650 mg. In some embodiments, a second dose is about 100 mg to about 1400 mg. In some embodiments, a second dose is about 300 mg to about 900 mg. In some embodiments, a second dose is about 300 mg, about 600 mg, or about 650 mg. [0007] In some embodiments, a first dose is administered about every 6 months. In some embodiments, a second dose is administered about every 6 months. In some embodiments, one or both of a first dose and a second dose are administered parenterally. In some embodiments, one or both of a first dose and a second dose are administered intravenously, subcutaneously, intramuscularly, or intraperitoneally. [0008] In some embodiments, one or both of a first dose and a second dose are administered intravenously. In some embodiments, one or both of a first dose and a second dose are administered intramuscularly. In some embodiments, a first dose is administered prior to, substantially simultaneously, or after a second dose. In some embodiments, a first dose and a second dose are co-formulated in a pharmaceutical composition. Page 2 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0009] In some embodiments, a sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV1. In some embodiments, a SARS-CoV-2 is one or more SARS-CoV-2 variants. In some embodiments, one or more SARS-CoV-2 variants is one or more of: Delta, Omicron, BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, BA.2.75, BA.2.75.2, BA.2.86, BA.4.6, BA.5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, D614G, EG.5.1, JN.1, XBB.1.5, and XBB.1.16. In some embodiments, an S2 is a stem helix region. [0010] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 is one or more of: (i) a chimeric antibody, a human antibody, or a humanized antibody, or antigen-binding fragment thereof; (ii) a monospecific antibody or a bispecific antibody, or antigen-binding fragment thereof; and (iii) a monoclonal antibody, or antigen-binding fragment thereof. In some embodiments, an antigen-binding fragment thereof that binds specifically to S2 is or comprises an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody. In some embodiments, an antibody or antigen-binding fragment that binds specifically to S2 is or comprises an IgG1 isotype. [0011] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 11, a LCDR2 of SEQ ID NO: 12, and a LCDR3 of SEQ ID NO: 13; (ii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, and a HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 14, a LCDR2 of SEQ ID NO: 15, and a LCDR3 of SEQ ID NO: 16; or (iii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, and a HCDR3 of SEQ ID NO: 9, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 17, a LCDR2 of SEQ ID NO: 18, and a LCDR3 of SEQ ID NO: 19. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 10, and (ii) a light chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 20. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a Page 3 of 120 12756399v1 Attorney Docket No.: 2017408-0046 heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10, and (ii) a light chain variable region comprising an amino acid sequence of SEQ ID NO: 20. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 21, and (ii) a light chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 22. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain comprising an amino acid sequence of SEQ ID NO: 21, and (ii) a light chain comprising an amino acid sequence of SEQ ID NO: 22. [0012] In some embodiments, an antibody that binds specifically to a Spike protein is bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, cilgavimab, pemivibart, rixagevimab, AZD7442 (tixagevimab-cilgavimab), regdanvimab, sotrovimab, or an antigen- binding fragment thereof of any of the foregoing or a combination thereof. [0013] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein binds specifically to receptor binding domain (RBD) of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD binds specifically to a class 4 region. [0014] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD is one or more of: (i) a chimeric antibody, a human antibody, or a humanized antibody, or antigen-binding fragment thereof; (ii) a monospecific antibody or a bispecific antibody, or antigen-binding fragment thereof; and (iii) a monoclonal antibody, or antigen-binding fragment thereof. In some embodiments, an antigen-binding fragment thereof that binds specifically to RBD is or comprises an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody. In some embodiments, an antibody or antigen-binding fragment that binds specifically to RBD is or comprises an IgG1 isotype. [0015] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 34, a LCDR2 of SEQ ID NO: 35, and a LCDR3 of SEQ ID NO: 36; (ii) a heavy chain variable region comprising a Page 4 of 120 12756399v1 Attorney Docket No.: 2017408-0046 HCDR1 of SEQ ID NO: 26, a HCDR2 of SEQ ID NO: 27, and a HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 37, a LCDR2 of SEQ ID NO: 38, and a LCDR3 of SEQ ID NO: 39; or (iii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 29, a HCDR2 of SEQ ID NO: 30, and a HCDR3 of SEQ ID NO: 31, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 40, a LCDR2 of SEQ ID NO: 41, and a LCDR3 of SEQ ID NO: 42. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a light chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 32, and (ii) a heavy chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO:43. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a light chain variable region comprising an amino acid sequence of SEQ ID NO: 32, and (ii) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 43. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 33, and (ii) a light chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 44. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain comprising an amino acid sequence that is SEQ ID NO: 33, and (ii) a light chain comprising an amino acid sequence that is at SEQ ID NO: 44. [0016] In some embodiments, a subject is not immune compromised. In some embodiments, a subject is immune compromised. In some embodiments, a subject has long COVID-19. BRIEF DESCRIPTION OF THE DRAWING [0017] The Figures described below, which together make up the Drawing, are for illustration purposes only, not for limitation. [0018] FIG.1 is a graph showing a simulated pharmacokinetic profile following a single dose of 1200 mg of an anti-S2 antibody described herein (AB-1) over 43 weeks. The shown Page 5 of 120 12756399v1 Attorney Docket No.: 2017408-0046 areas cover the 90% prediction intervals of plasma (upper curve) and lung (lower curve). Solid lines represent a median profile. Lung concentrations were set at 10% of those in plasma. [0019] FIGS.2A-2F are graphs showing neutralization activity of an antibody that binds specifically to S2 of a sarbecovirus (referred to herein as “AB-1”) and an antibody that binds specifically to a receptor binding domain (RBD; referred to herein as “AB-2”), alone and combination, in VERO-TMPRSS2 cells against SARS-CoV-2 Omicron BQ.1.1 Spike (FIGS.2A-C) and XBB.1.5 Spike (FIGS.2D-F) pseudotyped VSVdG particles when titrated in a checkboard approach to generate two-variable titration curves starting at 18 μg/ml in a fourfold dilution series. FIG.2A and FIG.2D depict neutralization of BQ1.1 and XBB.1.5, respectively, at about a .0703 μg/ml concentration of each antibody tested. FIG.2B and FIG.2E depict neutralization of BQ1.1 and XBB.1.5, respectively, at about a .0175 μg/ml concentration of each antibody tested. FIG.2C and FIG.2F depict neutralization of BQ1.1 and XBB.1.5, respectively, at about a .004 μg/ml concentration of each antibody tested. [0020] FIG.3 is a series of graphs showing a pharmacokinetic profile following a single intravenous dose of 100 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg of an anti-S2 antibody described herein (AB-1) over 43 weeks. The shown areas cover the 95% prediction intervals of 1,000 simulated profiles. Solid lines represent a median profile. Solid circles show observed concentrations. N=3 for the 100 mg and 300 mg doses, N=8 for the 600 mg dose, and N=10 for the 1200 mg and 2400 mg doses. [0021] FIG.4 is a series of graphs showing fold changes in live virus 50% (top panels) and 80% (bottom panels) mean neutralization titer (e.g., MN50 and MN80) following a single dose of 100 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg anti-S2 antibody described herein (AB-1) for the three different variants of interest. [0022] FIG.5 is a series of graphs showing fold changes in live virus 50% (left panel) and 80% (right panel) mean neutralization titer (e.g., MN50 and MN80) following a single intravenous dose of 1200 mg anti-S2 antibody described herein (AB-1) in subjects with low titers. Page 6 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0023] FIG.6 is a series of graphs showing a neutralizing index following a 1200 mg dose of anti-S2 antibody described herein (AB-1). The equation used to calculate a neutralizing index is also indicated in FIG.6. [0024] FIG.7 is a series of graphs showing percent neutralization of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses. Results are representative of at least 12 technical replicates across at least 3 biological replicates and shown as mean ± SD. Neutralization curves were fitted with a 4-parameter logistic regression. [0025] FIG.8 is a schematic depicting relative frequency of mutations of interest (AB-1 epitope region) in prevalent sarbecovirus lineages. [0026] FIG.9 depicts neutralization profiles of AB-1 and remdesivir either alone or in combination against live SARS-CoV-2 (England/02/2020) using a cytopathic effect (CPE)- based assay. The x-axis indicates the concentration of test articles as single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates). [0027] FIG.10 depicts neutralization profiles of AB-1 and remdesivir either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)-based assay. The x-axis indicates the concentration of test articles as single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates). [0028] FIG.11 depicts neutralization profiles of AB-1 and nirmatrelvir either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)- based assay. The x-axis indicates the concentration of test articles as single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates). [0029] FIG.12 depicts neutralization profiles of AB-1 and nirmatrelvir (+ P-gp inhibitor) either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)-based assay. The x-axis indicates the concentration of test articles as Page 7 of 120 12756399v1 Attorney Docket No.: 2017408-0046 single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates). [0030] FIG.13 depicts neutralization profiles of AB-1 either alone or in combination with P-gp inhibitor against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)-based assay. The x-axis indicates the concentration of AB-1 as a single agent or in combination with P-gp inhibitor. Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates). [0031] FIG.14 depicts neutralization profiles of AB-1 and molnupiravir either alone or in combination against live SARS-CoV-2 Omicron JN.1 using a cytopathic effect (CPE)- based assay. The x-axis indicates the concentration of test articles as single agents and in combination (or of the test article with the highest concentration if the concentrations differ). Results are reported as percent (%) neutralization and shown as mean SD (representative of one independent experiment, 3 technical replicates). [0032] FIG.15 is a bar graph depicting the binding of AB-1 and reference molecule to SARS-CoV-2 spike S2 peptides (indicated as “S:” followed by amino acid positions) and HIV-1 Env negative control peptide were assessed by SPR. The bars which represent AB-1 binding have an upside-down triangle above them. [0033] FIGS.16A-16B are bar graphs depicting binding of AB-1 and the reference molecule to spike trimers (indicated as “S:” followed by the respective virus name). FIG. 16A depicts AB-1 and reference molecule binding to major SARS-CoV-2 variants (SARS- CoV-2). FIG.16B depicts AB-1 and reference molecule binding to non-SARS-CoV-2 Sarbecoviruses (“Sarbecov.” labeled graph) and SARS-CoV-2 variants with polymorphisms in the AB-1 binding epitope (SARS-CoV-2 BA.2+P1162L and BA.2+P1162S) and their parent strain (SARS-CoV-2 BA.2 [parent]) (“AB-1 epitope” labeled graph). Results are expressed as EC50 values (μg/mL), shown as mean and 95% confidence interval (CI) and representative of two independent experiments, four technical replicates each. Color-coded dotted lines represent upper 95% confidence internal limits for AB-1 and the reference molecule binding to reference trimers (SARS-CoV-2 D614G for FIG.16A and FIG.16B left graph, SARS-CoV-2 BA.2 [parent] for FIG.16B right graph). The lowest depicted Page 8 of 120 12756399v1 Attorney Docket No.: 2017408-0046 dotted line represents the confidence internal limits for AB-1, and the highest depicted dotted line depicts the confidence internal limits for the reference molecule. In each graph, bars that represent reference molecule binding are always to the left of bars that represent AB-1 binding. [0034] FIG.17 is a series of graphs showing fold changes in live virus 50% mean neutralization titer (MN50) following a single dose of 100 mg, 300 mg, 600 mg, 1200 mg, or 2400 mg anti-S2 antibody described herein (AB-1) for two different variants of interest. DEFINITIONS [0035] In order for various aspects described herein to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein describe the background of various aspects described herein and provide additional detail regarding its practice are hereby incorporated by reference. [0036] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an agent” means one agent or more than one agent. [0037] About: As used herein, the term “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, the term “about” refers to a range of values that fall within about 25%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed about 100% of a possible value). [0038] Acute infection: As used herein, the term “acute infection” refers to an infection that is characterized by relatively sudden or rapid onset of disease (see e.g., Rai et al. “Acute Page 9 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Infection of Viral Pathogens and Their Innate Immune Escape.” Front. Microbiol. 12:672026 (2021), the contents of which is incorporated by reference in its entirety). [0039] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. In some embodiments, an antibody refers to an anti-Spike protein antibody or antigen-binding fragment thereof. Intact antibodies as produced in nature are approximately 150 kD tetrameric agents comprising two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure. Each heavy chain comprises at least four domains (each about 110 amino acids long) – an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CH1, CH2, and the carboxy-terminal CH3 (located at the base of the Y’s stem). A short region, known as the “switch,” connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody. Each light chain comprises two domains – an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. Intact antibody tetramers comprise two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another so that the dimers are connected to one another and a tetramer is formed. Naturally-produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., about 3-, about 4-, or about 5- stranded sheets) packed against each other in a compressed antiparallel beta barrel. [0040] In some embodiments, an antibody or antigen-binding fragment thereof is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, an antibody or antigen-binding fragment thereof is a polypeptide protein having a binding domain that is homologous or largely homologous to an immunoglobulin-binding domain. Page 10 of 120 12756399v1 Attorney Docket No.: 2017408-0046 When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. The Fc region of naturally- occurring antibodies binds to elements of the complement system, and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. Affinity and/or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and/or utilized in accordance with various aspects described herein include glycosylated Fc domains, such as Fc domains with modified or engineered glycosylation. In some embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and/or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology. In some embodiments, an antibody is polyclonal. In some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are humanized, primatized, or chimeric. [0041] Moreover, the term “antibody,” as used herein, can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, an antibody provided herein is utilized in accordance with a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bispecific or multi-specific antibodies (e.g., Zybodies®, etc.); and/or antibody fragments (preferably antibody fragments that exhibit desired antigen-binding activity). An antibody described herein can be an immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold with antibody-like properties, as well as any other known immunological binding moiety, e.g., a Fab, Fab', Fab'2, Fab2, Fab3, F(ab’)2 , Fd, Fv, Feb, scFv, SMIP, antibody, diabody, triabody, Page 11 of 120 12756399v1 Attorney Docket No.: 2017408-0046 tetrabody, minibody, maxibody, tandab, DVD, BiTe, TandAb, or any combination thereof. The subunit structures and three-dimensional configurations of different classes of antibodies are known. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., poly-ethylene glycol, etc.). [0042] Antibody heavy chain: As used herein, the term “antibody heavy chain” refers to the larger of the two types of polypeptide chains present in all antibodies in their naturally occurring conformations. [0043] Antibody light chain: As used herein, the term “antibody light chain” refers to the smaller of the two types of polypeptide chains present in all antibodies in their naturally occurring conformations. [0044] Antigen: As used herein, the term “antigen” or “Ag” refers to a molecule that is capable of provoking an immune response. This immune response may involve either antibody production, the activation of specific immunologically-competent cells, or both. A skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA that comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the various aspects of innovations described herein includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell, or a biological fluid. Page 12 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0045] Antigen-binding fragment: As used herein, the term “antigen-binding fragment” refers to a portion of an intact antibody that binds the antigen to which the intact antibody binds. An antigen-binding fragment of an antibody includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Exemplary antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, VHH, camelid, or VH or VL domains only); or multispecific antibodies formed from antibody fragments. In some embodiments, the antigen-binding fragments of the antibodies described herein are scFvs. In some embodiments, the antigen-binding fragments of the antibodies described herein are VHH domains only. As with full antibody molecules, antigen-binding fragments may be mono- specific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody may comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope of the same antigen. An antigen-binding fragment may be produced by any means. For example, in some embodiments, an antigen-binding fragment is enzymatically or chemically produced by fragmentation of an intact antibody. Alternatively, in some embodiments, an antigen- binding fragment is recombinantly produced. In some embodiments, an antigen-binding fragment is wholly or partially synthetically produced. In some embodiments, an antigen- binding fragment has a length of at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, or at least about 200 amino acids or more. [0046] Binding: As used herein, the term “binding” refers to a non-covalent association between or among two or more entities. “Direct” binding involves physical contact between entities or moieties. Indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts – including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and/or in a biological system or cell). Page 13 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0047] CDR: As used herein, “CDR” refers to a complementarity determining region within an antibody variable region. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. A “set of CDRs” or “CDR set” refers to a group of three or six CDRs that occur in either a single variable region capable of binding the antigen or the CDRs of cognate heavy and light chain variable regions capable of binding the antigen. In general, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, LCDR3). The exact definitional CDR boundaries and lengths are subject to different classification and numbering systems. Certain systems have been established for defining CDR boundaries (e.g., Kabat, IMGT, Chothia, or a combination thereof). CDRs may therefore be referred to by Kabat, Chothia, IMGT, or any other known boundary definitions. Despite differing boundaries, each of these systems has some degree of overlap in what constitutes the “hypervariable regions” within the variable sequences. CDR definitions according to these systems may therefore differ in length and boundary areas with respect to the adjacent framework region (see, e.g., Kabat et al., in “Sequences of Proteins of Immunological Interest,” 5th Edition, U.S. Department of Health and Human Services, 1992; Chothia et al. (1987) J. Mol. Biol.196, 901; and MacCallum et al., J. Mol. Biol. (1996) 262, 732, each of which is incorporated by reference in its entirety). Those skilled in the art appreciate the differences between and among these systems and are capable of understanding CDR boundaries to the extent required to understand and to practice the claims and various aspects of innovations described herein. [0048] Chronic infection: As used herein, the term “chronic infection” refers to a type of persistent infection in which a virus is not cleared but remains in specific cells of infected individuals. Persistent infections may involve stages of both silent and productive infection without rapidly killing or even producing excessive damage of host cells. In some embodiments, a persistent infection is a chronic infection. In some embodiments, a persistent infection is a latent infection (See, e.g., Boldogh et al., Persistent Viral Infection. In: Baron S, editor. Medical Microbiology.4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 46, the contents of which is incorporated by Page 14 of 120 12756399v1 Attorney Docket No.: 2017408-0046 reference in its entirety). While acute infections are typically resolved within a few days or weeks (e.g., influenza), chronic infections can persist at a relatively low level for months, years, decades, or a lifetime. In some embodiments, a chronic infection is long COVID-19. In contrast, a latent infection is characterized by a relatively long period of asymptomatic activity punctuated by a period of rapidly increasing high grade infection and elevated pathogen levels. [0049] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form – e.g., gas, gel, liquid, or solid. [0050] Comprising: A composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as “comprising” (or which “comprises”) one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of” (or which “consists essentially of”) the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as “comprising” or “consisting essentially of” one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of” (or “consists of”) the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method described herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step. [0051] Dosage unit or dose: As used herein, a “dosage unit” or “dose” refers to physically discrete units suited as unitary dosages for the particular subject to be treated, e.g., a human subject. Each unit can contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with a Page 15 of 120 12756399v1 Attorney Docket No.: 2017408-0046 pharmaceutical carrier. The specification for the dosage unit forms can be dictated by: (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s). [0052] Fragment: As used herein, the term “fragment” refers to a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole structure. In some embodiments, a fragment consists of such a discrete portion. In some embodiments, a fragment consists of or comprises a characteristic structural element or moiety found in the whole. In some embodiments, an antigen-binding fragment comprises or consists of at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 210, at least about 220, at least about 230, at least about 240, at least about 250, at least about 275, at least about 300, at least about 325, at least about 350, at least about 375, at least about 400, at least about 425, at least about 450, at least about 475, at least about 500, or more monomeric units (e.g., amino acids) as found in a whole antibody. In some embodiments, an antigen-binding fragment comprises or consists of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 25%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more of the monomeric units (e.g., residues) found in a whole antibody. In some embodiments, a nucleotide fragment comprises or consists of at least about 5%, at least about 10%, at least about 15%, Page 16 of 120 12756399v1 Attorney Docket No.: 2017408-0046 at least about 20%, at least about 25%, at least about 30%, at least about 25%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more of the monomeric units (e.g., residues) found in the whole nucleotide. [0053] Identity: As used herein, the term “identity” refers to the subunit sequence identity between two polymeric molecules, particularly between two amino acid molecules, such as between two polypeptide molecules. When two amino acid sequences have the same residues at the same positions; e.g., if a position in each of two polypeptide molecules is occupied by an Arginine, then they are identical at that position. The identity or extent to which two amino acid sequences have the same residues at the same positions in an alignment is often expressed as a percentage. The identity between two amino acid sequences is a direct function of the number of matching or identical positions; e.g., if half of the positions (e.g., five positions in a polymer of 10 amino acids in length) in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., nine positions in a polymer of 10 amino acids in length) are identical, the two amino acids sequences are 90% identical. [0054] Pharmaceutically acceptable: As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0055] Prevent: As used herein, the term “prevent” when used in connection with the occurrence of sarbecovirus infection, refers to reducing the risk of developing a sarbecovirus infection and/or to delaying onset of one or more characteristics or symptoms of a sarbecovirus infection. Non-limiting examples of characteristics or symptoms of a sarbecovirus infection include fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle, body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, diarrhea, or any combination thereof. Prevention may be considered Page 17 of 120 12756399v1 Attorney Docket No.: 2017408-0046 complete when onset of a sarbecovirus infection has been delayed for a predefined period of time. [0056] RBD: As used herein, the term “RBD” or “receptor binding domain” refers to a receptor binding domain within S1 of a Spike protein of a sarbecovirus (e.g., SARS-CoV-2). RBD plays a role in viral entry and infection. RBD binds to angiotensin converting enzyme type-II (ACE2) receptor on a human cell surface to form a fusion complex. RBD can exhibit some variability among different SARS-CoV-2 variants and mutations in RBD can impair viral replication, facilitate immune escape, and impact vaccine efficacy. The terms “RBD” and “RBD domain” can be used interchangeably herein. [0057] SARS-CoV-2: As used herein, the term “SARS-CoV-2” refers to Severe Acute Respiratory Syndrome Coronavirus 2, a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. SARS-CoV-2 is a positive- sense single-stranded RNA virus that is contagious in humans. SARS-CoV-2 belongs to a group of genetically related viruses that includes SARS-CoV and other coronaviruses. [0058] Spike Protein: As used herein, the term “Spike protein” refers to a class I fusion protein that mediates fusion of a viral envelope with a host cell membrane through a series of conformational changes. In some embodiments, the term “Spike protein” refers to a Spike protein of a sarbecovirus (e.g., SARS-CoV-1, SARS-CoV-2, or WIV1). The Spike protein of sarbecovirus is composed of two main regions or domains known as S1 and S2. S1 contains a receptor-binding domain (RBD) that is responsible for recognition and binding to a host cell receptor. S2 is responsible for membrane fusion. The terms “RBD” and “RBD domain” may be used interchangeably. In some embodiments, a spike protein determines host range and cell tropism of a virus. [0059] S2: As used herein, the term “S2” refers to a S2 subunit of a Spike protein of a sarbecovirus (e.g., SARS-CoV-2). S2 is responsible for fusion to a viral envelope and contains a putative fusion peptide and other fusion infrastructure necessary for membrane fusion with the host cell. S2 can form a flexible “stalk” containing most protein-protein interactions that hold an assembled spike protein trimer in place. S2 contains a stem helix region that is highly conserved among sarbecovirus (e.g., SARS-CoV-1, SARS-CoV-2, or WIV1). Antibodies which bind this stem helix may inhibit membrane fusion, preventing the Page 18 of 120 12756399v1 Attorney Docket No.: 2017408-0046 virus from entering the host cell. In some embodiments, an anti-Spike protein antibody or antigen-binding fragment thereof disclosed herein binds to S2 of a Spike protein of sarbecovirus. As used herein, S2 includes full-length S2 (e.g., having an amino acid sequence of SEQ ID NO: 46 or a variant thereof) and truncated versions thereof as well as mutant, engineered, and modified (e.g., post-translationally) variants thereof of full-length or truncated S2 (e.g., an epitope within S2). [0060] Subject: As used herein, the term “subject” and “patient” refer to an animal (e.g., a mammal, such as a human) who is to be administered an antibody or antigen-binding fragment disclosed herein. A subject to be treated according to methods described herein may be one who has been diagnosed with a condition (e.g., a sarbecovirus infection such as a SARS-CoV-2 infection) or one at risk of developing such conditions. Diagnosis may be performed by any method or technique. One skilled in the art will understand that a subject may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with a condition (e.g., a sarbecovirus infection such as a SARS-CoV-2 infection). [0061] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. [0062] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to partial or complete alleviation, amelioration, delay of onset of, inhibition, prevention, relief, and/or reduction in incidence and/or severity of one or more symptoms or features of a disease, disorder, and/or condition described herein (e.g., a sarbecovirus infection). In some embodiments, treatment is administered to a subject who does not exhibit signs or features of a disease, disorder, and/or condition (e.g., may be prophylactic). In some embodiments, treatment is administered to a subject who exhibits only early or mild signs or features of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of Page 19 of 120 12756399v1 Attorney Docket No.: 2017408-0046 developing pathology associated with the disease, disorder, and/or condition. In some embodiments, treatment is administered to a subject who exhibits established, severe, and/or late-stage signs of the disease, disorder, or condition (e.g., sarbecovirus). In some embodiments, one or more symptoms of a sarbecovirus infection include fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle, body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, diarrhea, or any combination thereof. In some embodiments, one or more symptoms of a severe sarbecovirus infection include trouble breathing, constant chest pain or pressure, bluish lips or face, sudden confusion, altered mental status, or any combination thereof. In some embodiments, one or more symptoms of a late stage sarbecovirus infection include fatigue, energy crashes, brain fog, chronic cough, organ damage, or any combination thereof. In some embodiments, treating comprises administering at least one antibody or antigen- binding fragment thereof described herein to a subject. [0063] Various aspects of the innovations described herein can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of various aspects of innovations described herein. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from about 1 to about 6 should be considered to have specifically disclosed subranges such as from about 1 to about 3, from about 1 to about 4, from about 1 to about 5, from about 2 to about 4, from about 2 to about 6, from about 3 to about 6 etc., as well as individual numbers within that range, for example, about 1, about 2, about 2.7, about 3, about 4, about 5, about 5.3, and about 6. This applies regardless of the breadth of the range. DETAILED DESCRIPTION [0064] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection (e.g., SARS-CoV-1, SARS-CoV-2, or WIV1) in a subject by administering an antibody or antigen-binding fragment thereof that binds specifically to S2 Page 20 of 120 12756399v1 Attorney Docket No.: 2017408-0046 of a sarbecovirus in combination with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus allows for a reduced dose to be administered of an antibody or antigen- binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus relative to administration of the antibody or antigen-binding fragment thereof that binds specifically to a Spike protein alone. [0065] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD) of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus. SARS-CoV-2 [0066] SARS-CoV-2 is the causative agent of COVID-19. In some embodiments, SARS-CoV-2 is the causative agent of acute COVID-19. In some embodiments, SARS- CoV-2 is a causative agent of chronic COVID-19 (e.g., long COVID-19). In some embodiments, different SARS-CoV-2 strains can cause acute COVID-19. In some embodiments, different SARS-CoV-2 strains can cause long COVID-19 (see e.g., Du et al. Int J Environ Res Public Health.19(23):16010 (2022), the contents of which are incorporated herein by reference). The genome of SARS-CoV-2 encodes the nucleoprotein (N), the membrane glycoprotein (M), the small envelope glycoprotein (E), and the Spike protein, in addition to 16 non-structural proteins (Song et al. Clin Chim Acta.509:280-7 (2020)). The Spike protein of SARS-CoV-2 facilitates entry of into a host cell, such as a human host cell. The Spike protein is a trimer with protomers composed of S1 and S2 Page 21 of 120 12756399v1 Attorney Docket No.: 2017408-0046 subunits. S1 contains a receptor-binding domain (RBD) that binds ACE2 receptors, and S2 mediates fusion of viral and host membranes. [0067] A non-limiting example of a wildtype Spike protein sequence of SARS-CoV-2 is NCBI RefSeq YP_009724390: [0068] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHS TQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGT TLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSAN NCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFS ALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLK YNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCP FGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFT NVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGN YNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGY QPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLP FQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTE VPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQT QTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTS VDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKT PPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLI CAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRF NGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTL VKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRAS ANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFT TAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIV NNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVA KNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGC CSCGSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO: 45). [0069] As used herein, Spike protein of SARS-CoV-2 includes wild-type SARS-CoV-2 Spike proteins (e.g., SEQ ID NO: 45 (RefSeq YP_009724390) or homologs thereof) and truncated forms thereof, mutant, and engineered versions of full-length and truncated SARS- Page 22 of 120 12756399v1 Attorney Docket No.: 2017408-0046 CoV-2 Spike proteins, and modified forms (e.g., post-translationally modified forms) of full- length and truncated SARS-CoV-2 Spike proteins. [0070] In some embodiments, an antibody or antigen-binding fragment thereof disclosed herein binds to a Spike protein comprising an amino acid sequence of SEQ ID NO: 45. [0071] In some embodiments, an antibody or antigen-binding fragment thereof described herein binds to a mutant, engineered, and/or modified form of a Spike protein. In some embodiments, a mutant, engineered, or modified form of a Spike protein comprises an amino acid sequence that has at least about 90% sequence identity to wildtype Spike protein sequence (e.g., SEQ ID NO: 45) of SARS-CoV-2, for example, having at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about or at least about 99.9% sequence identity to wildtype Spike protein sequence. [0072] In some embodiments, a mutant, engineered, and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: L5F, S13I, T19R, A67V, del69, del70, del69-70, D80G, T95I, G142D, del142-144, del144, Y145D, W152C, E154K, F157S, del211, L212I, ins214EPE, A222V, D253G, G261D, G339D, V367F, S371L, S371L, S373P, S375F, K417N, N439K, N440K, G446S, L452R, Y453F, S477N, T478K, E484A, E484K, E484Q, F486L, S494P, Q493R, G496S, Q498R, N501T, N501Y, Y505H, T547K, F565L, A570D, H655Y, D614G, Q677H, N679K, P681H, P681R, A701V, T716I, N764K, D796Y, T859N, N856K, F888L, D950N, Q954H, Q957R, N969K, L981F, S982A, Q1071H, V1176F, D1118H, K1191N, or a combination thereof, e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45 or more of the mutations. Page 23 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0073] In some embodiments, a mutant, engineered, and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: L5F, S13I, T19R, A67V, del69, del70, del69-70, D80G, T95I, G142D, del142-144, del144, Y145D, W152C, E154K, F157S, del211, L212I, ins214EPE, A222V, D253G, G261D, G339D, V367F, S371L, S371L, S373P, S375F, K417N, N439K, N440K, G446S, L452R, Y453F, S477N, T478K, E484A, E484K, E484Q, F486L, S494P, Q493R, G496S, Q498R, N501T, N501Y, Y505H, T547K, F565L, A570D, H655Y, D614G, Q677H, N679K, P681H, P681R, A701V, T716I, N764K, D796Y, T859N, N856K, F888L, D950N, Q954H, Q957R, N969K, L981F, S982A, Q1071H, V1176F, D1118H, K1191N, or a combination thereof, e.g., at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45 or more of the mutations. [0074] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:45, one or more mutations selected from: 69del, 70del, 144del, E484K, S494P, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H or K1191N, or a combination thereof. In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises 69del, 70del, 144del, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H. In some embodiments, a mutant, engineered and/or modified form of a Spike protein further comprises E484K, S494P or K1191N, or a combination thereof. [0075] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:45, one or more mutations selected from: D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G or A701V, or a Page 24 of 120 12756399v1 Attorney Docket No.: 2017408-0046 combination thereof. In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, and A701V. [0076] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:45, one or more mutations selected from: T19R, G142D, 156del, 157del, R158G, L452R, T478K, D614G, P681R or D950N, or a combination thereof. In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises T19R, 156del, 157del, R158G, L452R, T478K, D614G, P681R, and D950N. In some embodiments, a mutant, engineered and/or modified form of a Spike protein further comprises G142D. [0077] In some embodiments, a modified Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: A67V, del69-70, T95I, del142-144, Y145D, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K or L981F, or a combination thereof. [0078] In some embodiments, a modified Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof. [0079] In some embodiments, a modified Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, L452R, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof. [0080] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: 69del, 70del, 144del, A222V, G261D, V367F, K417N, N439K, Y453F, S477N, E484K, F486L, N501T, N501Y, A570D or D614G, or a combination thereof. Page 25 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0081] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: E484K, N501Y or D614G, or a combination thereof. [0082] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: F817P, A892P, A899P, A942P, K986P or V987P, or a combination thereof. In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO:1, one or more mutations selected from: L452R, F486V or R493Q, or a combination thereof. [0083] In some embodiments, a mutant, engineered and/or modified form of a Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: A67V, del69-70, T95I, del142-144, Y145D, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K or L981F, or a combination thereof. [0084] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof. [0085] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, L452R, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof. [0086] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, K444T, L452R, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof. Page 26 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0087] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO: 45, one or more mutations selected from: T19I, del24-26, A27S, del69-70, G142D, V213G, G339D, R346T, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, K444T, L452R, N460K, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof. [0088] Additional modified Spike proteins of SARS-CoV-2 can be found at https://covariants.org/shared-mutations, the contents of which are incorporated herein by reference. Non-limiting examples include Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and/or Omicron, for example, AY.3, AY.4, AY.41, AY.44, AY.64, AY.103, B.1, B.1.1, B.1.1.1, B.1.1.529, B.1.1.7, B.1.177, B.1.2, B.1.351, B.1.427/429, B.1.525, B.1.526, B.1.533, B.1.617.1, B.1.617.2, B.1.621, BA.1, BA.1.1, BA.1.15, BA.1.17.2, BA.2, BA.2+P1162L, and BA.2+P1162S, BA.2.3.20, BA.2.10, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA.4, BA.4/5, BA.4/5+K444T, BA.4.6, BA.5, BA.5.2.6, BA.5.8, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, CH.1.1, CH.1.1.1, D.2, GA.5, GR/484A, JN.1, JN.1.7, JN.1.13.1, JN.1.16, KP.1.1, KP.2, KP.3.1.1, KP.3.3, P.1, P.1.17, P.1.10, P.2, P.3, Q.3, Q.4, Q.7, XBB, XBB.1.1, XBB.1.16, XBB.1.5, and/or XBB.1.9.1. [0089] In some embodiments, an antibody or antigen-binding fragment thereof disclosed herein binds to S2 of a Spike protein of SARS-CoV-2. As used herein, S2 includes full- length S2 (e.g., having the amino acid sequence of SEQ ID NO: 46 (PLQPELDSFKEELDKYFKNHTSPDVDL) or homologs thereof) and truncated forms thereof, mutant, and engineered versions of full-length and truncated S2 (e.g., an epitope within S2), and modified forms (e.g., post-translationally modified forms) of full-length and truncated S2. [0090] In some embodiments, an antibody or antigen-binding fragment thereof disclosed herein binds to a mutant, engineered and/or modified form of S2. In some embodiments, the mutant, engineered and/or modified form of S2 comprises an amino acid sequence that has at least about 90% sequence identity to a wild-type full length S2 domain (e.g., SEQ ID NO: 46), for example, having at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at Page 27 of 120 12756399v1 Attorney Docket No.: 2017408-0046 least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% sequence identity. Antibodies and antigen-binding fragments thereof [0091] Provided herein, among other things, are antibodies or antigen-binding fragments thereof that bind a Spike protein of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD) of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus. In some embodiments, an antibody or antigen- binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus. In some embodiments, an antibody that binds specifically to a Spike protein is bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, cilgavimab, pemivibart, rixagevimab, AZD7442 (tixagevimab- cilgavimab), regdanvimab, sotrovimab, or an antigen-binding fragment of any of the foregoing or a combination thereof. [0092] In some embodiments, an antibody or antigen-binding fragment thereof described herein can be or comprise an immunoglobulin, heavy chain antibody, light chain antibody, or other protein scaffold with antibody-like properties, as well as other immunological binding moiety, including a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a disulfide-bonded Fv fragment, a scFv fragment, a diabody, a triabody, a tetrabody, a minibody, a maxibody, a tandab, BiTe, or any combination thereof. [0093] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises or is a monoclonal antibody. In some embodiments, antibody or antigen-binding fragment thereof described herein comprises or is a full-length antibody, e.g., comprising an immunoglobulin Fc region. In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises or is a multispecific antibody, Page 28 of 120 12756399v1 Attorney Docket No.: 2017408-0046 e.g., comprising a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises or is a bispecific antibody molecule. In some embodiments, an antibody or antigen-binding fragment thereof described herein is or has been affinity matured. [0094] An antibody or antigen-binding fragment thereof can include a heavy chain variable domain sequence (VH), and a light chain variable domain sequence (VL). In some embodiments, an antibody or antigen-binding fragment thereof comprises an immunoglobulin molecule of four polypeptide chains, e.g., two heavy chains and two light chains. A heavy chain can include a VH and a heavy chain constant domain. A heavy chain constant domain can include CH1, hinge, CH2, CH3, and optionally, a CH4 region. A light chain can include a VL and a light chain constant domain. A light chain constant domain can include a CL domain. [0095] A VH and/or a VL can be further subdivided into regions of variability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Such VH and/or VL domains can each include three CDRs and four framework regions, arranged from amino-terminus to carboxyl- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, one or more of which can be engineered as described herein. In general, there are three CDRs in each VH (HCDR1, HCDR2, and HCDR3) and three CDRs in each VL (LCDR1, LCDR2, and LCDR3). The extent of the framework region and CDRs can be defined using a number of well-known schemes (see, e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242; Chothia, C. et al. (1987) J. Mol. Biol.196:901-917; and the AbM definition used by Oxford Molecular’s AbM antibody modeling software, each of which is hereby incorporated by reference in its entirety). [0096] An antibody or antigen-binding fragment thereof described herein can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from Page 29 of 120 12756399v1 Attorney Docket No.: 2017408-0046 any subclass (e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. An antibody or antigen- binding fragment thereof described herein can be or comprise a human, humanized, CDR- grafted, or in vitro generated antibody. An antibody or antigen-binding fragment thereof described herein can have or comprise a heavy chain constant region chosen from, e.g., IgG1, IgG2, IgG3, or IgG4. An antibody or antigen-binding fragment thereof can have or comprise a light chain chosen from, e.g., kappa or lambda. In some embodiments, a heavy chain constant region (e.g., IgG1) comprises an LS mutation. In some embodiments, a heavy chain constant region (e.g., IgG1) comprises an LS mutation comprising an M428L mutation, numbering is according to the EU index in Kabat et al. (1991). In some embodiments, a heavy chain constant region (e.g., IgG1) comprises an LS mutation comprising an N434S mutation, numbering is according to the EU index in Kabat et al. (1991). In some embodiments, a heavy chain constant region (e.g., IgG1) comprises an LS mutation comprising a M428L mutation and a N434S mutation, numbering is according to the EU index in Kabat et al. (1991). [0097] In some embodiments, an antibody or antigen-binding fragment thereof described herein is or comprises a monoclonal antibody. Typically, monoclonal antibodies are obtained from a population of substantially homogeneous antibodies, such that the individual antibodies comprising the population are substantially identical, except for possible naturally occurring mutations that may be present in minor amounts. Thus, the modifier “monoclonal” as used herein, indicates the character of the antibody as not being a mixture of discrete antibodies. In some embodiments, monoclonal antibodies directed to a particular epitope are derived from a single cell line (e.g., a B cell line). [0098] In some embodiments, an antibody or antigen-binding fragment thereof described herein is or comprises a polyclonal antibody. In contrast to monoclonal antibodies, polyclonal antibodies are typically obtained from a population of heterogeneous antibodies, such that the antibodies in a particular population include structural variation, for example, affinity for different epitopes on a particular target (e.g., Spike protein of sarbecovirus, such as S2 of a Spike protein). Several methods of producing polyclonal antibodies include use of multiple subcutaneous and/or intraperitoneal injections of the Page 30 of 120 12756399v1 Attorney Docket No.: 2017408-0046 relevant antigen into an animal, optionally including co-administration of one or more adjuvants. [0099] Examples of antibodies or antigen-binding fragments thereof described herein can include: (i) a Fab fragment, a monovalent fragment comprising VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at a hinge region; (iii) a Fab fragment comprising VH and CH1 domains; (iv) a Fv fragment comprising VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment comprising a VH domain; (vi) a camelid or camelized variable domain; (vii) a scFv, a fusion protein of VH and VL regions; or (viii) a single domain antibody. In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises or is a heavy chain and a light chain (e.g., a half antibody). [0100] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising one, two, or three VH CDR sequences in Table 1; and/or (b) a VL comprising one, two, or three VL CDR sequences in Table 1. In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VH in Table 1 (e.g., in areas outside of CDR regions); and/or (a) a VL with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VL in Table 1 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a heavy chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more identity to a heavy chain in Table 1 (e.g., in areas outside of CDR regions); and/or (a) a light chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more identity to a light chain in Table 1 (e.g., in areas outside of CDR regions). Page 31 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0101] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 1, a VH CDR2 amino acid sequence of SEQ ID NO: 2, and a VH CDR3 amino acid sequence of SEQ ID NO: 3; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 11, a VL CDR2 amino acid sequence of SEQ ID NO: 12, and a VL CDR3 amino acid sequence of SEQ ID NO: 13. In some embodiments, an antibody or antigen- binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 4, a VH CDR2 amino acid sequence of SEQ ID NO: 5, and a VH CDR3 amino acid sequence of SEQ ID NO: 6; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 14 a VL CDR2 amino acid sequence of SEQ ID NO: 15, and a VL CDR3 amino acid sequence of SEQ ID NO: 16. In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 7, a VH CDR2 amino acid sequence of SEQ ID NO: 8, and a VH CDR3 amino acid sequence of SEQ ID NO: 9; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 17, a VL CDR2 amino acid sequence of SEQ ID NO: 18, and a VL CDR3 amino acid sequence of SEQ ID NO: 19. [0102] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 10 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a VL comprising an amino acid sequence of SEQ ID NO: 20, or an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 20 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 10 and a VL comprising an amino acid sequence of SEQ ID NO: 20. [0103] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID Page 32 of 120 12756399v1 Attorney Docket No.: 2017408-0046 NO: 21, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 21 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 22, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, at least about 99% identical or higher to SEQ ID NO: 22 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 10 and a light chain comprising an amino acid sequence of SEQ ID NO: 21. [0104] An antibody or antigen-binding fragment thereof described herein can include any amino acid sequences disclosed in WO2023215910A1, which is hereby incorporated by reference in its entirety. Table 1. Amino acid and nucleotide sequences of exemplary antibodies or antigen- binding fragments thereof that specifically bind S2. Sequences SEQ ID NO Page 33 of 120 12756399v1 Attorney Docket No.: 2017408-0046 HCDR1 (CHOTHIA) SEQ ID NO: 7 GYTFTRY Page 34 of 120 12756399v1 Attorney Docket No.: 2017408-0046 LCDR3 (KABAT) SEQ ID NO: 16 QQGHSFPYT so e e o e s, a a o y o a ge - g ag e e eo described herein comprises: (a) a VH comprising one, two, or three VH CDR sequences in Table 1; and/or (b) a VL comprising one, two, or three VL CDR sequences in Table 2. In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VH in Table 2 (e.g., in areas outside of CDR regions); and/or (a) a VL with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, or more identity to a VL in Table 2 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a heavy chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about Page 35 of 120 12756399v1 Attorney Docket No.: 2017408-0046 97%, at least about 98%, at least about 99%, or more identity to a heavy chain in Table 2 (e.g., in areas outside of CDR regions); and/or (a) a light chain with at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more identity to a light chain in Table 2 (e.g., in areas outside of CDR regions). [0106] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 23, a VH CDR2 amino acid sequence of SEQ ID NO: 24, and a VH CDR3 amino acid sequence of SEQ ID NO: 25; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 34, a VL CDR2 amino acid sequence of SEQ ID NO: 35, and a VL CDR3 amino acid sequence of SEQ ID NO: 36. In some embodiments, an anti-Spike protein antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 26, a VH CDR2 amino acid sequence of SEQ ID NO: 27, and a VH CDR3 amino acid sequence of SEQ ID NO: 28; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 37 a VL CDR2 amino acid sequence of SEQ ID NO: 38, and a VL CDR3 amino acid sequence of SEQ ID NO: 39. In some embodiments, an anti-Spike protein antibody or antigen-binding fragment thereof described herein comprises: (a) a VH comprising a VH CDR1 amino acid sequence of SEQ ID NO: 29, a VH CDR2 amino acid sequence of SEQ ID NO: 30, and a VH CDR3 amino acid sequence of SEQ ID NO: 31; and (b) a VL comprising a VL CDR1 amino acid sequence of SEQ ID NO: 40, a VL CDR2 amino acid sequence of SEQ ID NO: 41, and a VL CDR3 amino acid sequence of SEQ ID NO: 42. [0107] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 32, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, at least about or at least about 99% identical or higher to SEQ ID NO: 32 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a VL comprising an amino acid sequence of SEQ ID NO: 43, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, or at Page 36 of 120 12756399v1 Attorney Docket No.: 2017408-0046 least about 99% identical or higher to SEQ ID NO: 43 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 32 and a VL comprising an amino acid sequence of SEQ ID NO: 43. [0108] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 33, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical or higher to SEQ ID NO: 33 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a light chain comprising an amino acid sequence of SEQ ID NO: 44, or an amino acid sequence at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical or higher to SEQ ID NO: 44 (e.g., in areas outside of CDR regions). In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 33 and a light chain comprising an amino acid sequence of SEQ ID NO: 44. Table 2. Amino acid sequences of an exemplary antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus. Sequences SEQ ID NO Page 37 of 120 12756399v1 Attorney Docket No.: 2017408-0046 HCDR2 (KABAT) SEQ ID NO: 27 RIILLSGYANYAQKIQG Page 38 of 120 12756399v1 Attorney Docket No.: 2017408-0046 LCDR1 (KABAT) SEQ ID NO: 37 TGSSSNIGAGYRVH [0109] Provided herein, among other things, are methods of making antibodies or antigen-binding fragments thereof or antigen-binding fragments thereof described herein. In some embodiments, an antibody or antigen-binding fragment thereof described herein is identified using a display technology, such as yeast display, phage display, or ribosome display. In some embodiments, an antibody or antigen-binding fragment thereof described herein is identified using a hybridoma library (e.g., a mammalian hybridoma library, e.g., a mouse hybridoma library), followed by supernatant screening. Page 39 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0110] Combinatorial methods for generating antibodies or antigen-binding fragments thereof are described in, for example, Ladner et al. U.S. Patent No.5,223,409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271; Winter et al. International Publication WO 92/20791; Markland et al. International Publication No. WO 92/15679; Breitling et al. International Publication WO 93/01288; McCafferty et al. International Publication No. WO 92/01047; Garrard et al. International Publication No. WO 92/09690; Ladner et al. International Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum Antibody Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio/Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982, each of which his hereby incorporated by reference in its entirety. [0111] In some embodiments, an antibody or antigen-binding fragment thereof described herein may be derived from other species. In some embodiments, a humanized antibody is an antibody produced by recombinant DNA technology, in which some or all amino acids of a human immunoglobulin light chain or heavy chain that are not required for antigen binding (e.g., constant regions and/or framework regions of variable domains) are used to substitute for the corresponding amino acids from light chain or heavy chain of the cognate, nonhuman antibody. By way of example, a humanized version of a murine antibody to a given antigen has on both heavy and light chains: (1) constant regions of a human antibody; (2) FRs from the variable domains of a human antibody; and (3) CDRs from the murine antibody. Human FRs may be selected based on their highest sequence homology to mouse FR sequence. When necessary, one or more residues in human FRs can be changed to residues at corresponding positions in a murine antibody so as to preserve binding affinity of the humanized antibody to a target. This change is sometimes called “back mutation.” Similarly, forward mutations may be made to revert back to murine sequence for a desired reason, e.g., stability or affinity to a target. Humanized antibodies Page 40 of 120 12756399v1 Attorney Docket No.: 2017408-0046 generally are less likely to elicit an immune response in humans as compared to chimeric human antibodies because the former contain considerably fewer non-human components. [0112] There are various methods for humanizing non-human antibodies. Suitable methods for making humanized antibodies in accordance with various aspects of innovations described herein are described in, e.g., Winter EP 0239400; Jones et al., Nature 321:522- 525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988); Queen et al., Proc. Nat. Acad. ScL USA 86:10029 (1989); U.S. Patent 6,180,370; and Orlandi et al., Proc. Natl. Acad. Sd. USA 86:3833 (1989); each of which are incorporated herein by reference in their entireties. Generally, transplantation of non-human (e.g., murine) CDRs onto a human antibody is achieved as follows. cDNAs encoding VH and VL are isolated from a hybridoma, and nucleic acid sequences encoding VH and VL including CDRs are determined by sequencing. Nucleic acid sequences encoding CDRs are inserted into corresponding regions of a human antibody VH or VL coding sequences and attached to human constant region gene segments of a desired isotype (e.g., γl for CH and for CL). Humanized heavy and light chain genes are co-expressed in mammalian host cells (e.g., CHO or NSO cells) to produce soluble humanized antibody. To facilitate large-scale production of antibodies, it is often desirable to select for a high expressor using, for example, a DHFR gene or GS gene in the producer line. [0113] In some embodiments, an antibody or antigen-binding fragment thereof described herein comprises or is a human antibody. Completely human antibodies may be particularly desirable for therapeutic treatment of human subjects. Human antibodies can be made by a variety of methods including phage display methods described above using antibody libraries derived from human immunoglobulin sequences (see, e.g., U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/60433, WO 98/24893, WO 98/16664, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety). Techniques are also available for the preparation of human monoclonal antibodies in, e.g., Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Riss, (1985); and Boerner et al., J. Immunol., 147(1):86-95, (1991), each of which is incorporated herein by reference in its entirety. Page 41 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Nucleic acids [0114] Provided herein, among other things, are nucleic acids encoding antibodies or antigen-binding fragments thereof that bind a Spike protein of a sarbecovirus. In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to S1 of a sarbecovirus. In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to a receptor binding domain (RBD) of a sarbecovirus. In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus. In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to a stem helix region of a sarbecovirus. [0115] In some embodiments, a nucleic acid encodes an antibody or antigen-binding fragment thereof that binds specifically to S2 of the sarbecovirus. Provided herein are nucleic acids encoding one or more heavy chains, VH domains, heavy chain FRs, heavy chain CDRs, heavy chain constant domains, light chains, VL domains, light chain FRs, light chain CDRs, light chain constant domains, or other immunoglobulin-like sequences, antibodies, or antigen-binding fragments thereof disclosed herein. Such nucleic acids may be present in a vector. Such nucleic acids may be present in the genome of a cell, e.g., a cell of a subject in need of treatment or a cell for production of an antibody, e.g., a mammalian cell for production of an antibody or antigen-binding fragment thereof described herein. [0116] Nucleic acids encoding antibodies or antigen-binding fragments thereof described herein may be modified to include codons that are optimized for expression in a particular cell type or organism. Codon optimized sequences are synthetic sequences, and preferably encode an identical polypeptide (or biologically active fragment of a full-length polypeptide which has substantially the same activity as the full-length polypeptide) encoded by a non-codon optimized parent polynucleotide. In some embodiments, a coding region of a nucleic acid encoding an antibody or antigen-binding fragment thereof described herein, in whole or in part, may include an altered sequence to optimize codon usage for a particular cell type (e.g., a eukaryotic or prokaryotic cell). For example, a coding sequence for a humanized heavy or light chain variable region as described herein may be optimized for expression in a bacterial cell. Alternatively, the coding sequence may be optimized for Page 42 of 120 12756399v1 Attorney Docket No.: 2017408-0046 expression in a mammalian cell (e.g., a CHO cell). Such a sequence may be described as a codon-optimized sequence. [0117] Nucleic acid constructs described herein may be inserted into an expression vector or viral vector by methods known to the art, and nucleic acids may be operably linked to an expression control sequence. A vector comprising any nucleic acids or fragments thereof described herein is further provided herein. Any nucleic acids or fragments thereof described herein can be cloned into any suitable vector and can be used to transform or transfect any suitable host. Selection of vectors and methods to construct them are commonly known to persons of ordinary skill in the art (see, e.g., “Recombinant DNA Part D,” Methods in Enzymology, Vol.153, Wu and Grossman, eds., Academic Press (1987)). [0118] Conventionally used techniques including, for example, electrophoresis, calcium phosphate precipitation, DEAE-dextran transfection, or lipofection, may be used to introduce a foreign nucleic acid (e.g., DNA or RNA) into a prokaryotic or eukaryotic host cell. Desirably, a vector may include regulatory sequences, such as transcription and/or translation initiation and/or termination codons, which are specific to the type of host (e.g., bacterium, fungus, plant, or animal) into which a vector is to be introduced, as appropriate and taking into consideration whether a vector is DNA or RNA. In some embodiments, a vector comprises regulatory sequences that are specific to a genus of a host cell. In some embodiments, a vector comprises regulatory sequences that are specific to a species of a host. [0119] In addition to a replication system and an inserted nucleic acid, a nucleic acid construct can include one or more marker genes, which allow for selection of transformed or transfected hosts. Exemplary marker genes include, e.g., biocide resistance (e.g., resistance to antibiotics or heavy metals) or complementation in an auxotrophic host to provide prototrophy. [0120] An expression vector can comprise a native or nonnative promoter operably linked to an isolated or purified nucleic acid as described above. Selection of promoters, e.g., strong, weak, inducible, tissue-specific, and/or developmental-specific, is within the skill of one in the art. Similarly, combining a nucleic acid as described above with a promoter is also within the skill of one in the art. Page 43 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0121] Suitable vectors include those designed for propagation and expansion and/or for expression. For example, a cloning vector may be selected from the pUC series, the pBluescript series (Stratagene, LaJolla, Calif.), the pET series (Novagen, Madison, Wis.), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), or the pEX series (Clontech, Palo Alto, Calif.). Bacteriophage vectors, such as GT10, GT11, ZapII (Stratagene), EMBL4, and NM1149, may be used. Examples of plant expression vectors that can be used include pBI110, pBI101.2, pBI101.3, pBI121, or pBIN19 (Clontech). Examples of animal expression vectors that can be used include pEUK-C1, pMAM, or pMAMneo (Clontech). The TOPO cloning system (Invitrogen, Carlsbad, Calif.) also can be used in accordance with the manufacturer's recommendations. [0122] Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation of a nucleic acid encoding an antibody or antigen-binding fragment thereof described herein, or to improve introduction of a nucleic acid into a cell. Use of cloning vectors, expression vectors, adapters, and linkers have been described (see, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 2d edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989); and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994), each of which is hereby incorporated by reference in its entirety). [0123] In some embodiments, nucleic acids and vectors described herein are isolated and/or purified. Provided herein, among other things, is a composition comprising an isolated or purified nucleic acid, optionally in the form of a vector. Isolated nucleic acids and vectors may be prepared using standard techniques including, for example, alkali/SDS treatment, CsCl binding, column chromatography, agarose gel electrophoresis, and/or other techniques. The composition can comprise other components as described further herein. [0124] Any method known to one skilled in the art for the insertion of nucleic acids into a vector may be used to construct expression vectors encoding an antibody or antigen- binding fragment thereof described herein under control of transcriptional and/or translational control signals. These methods may include in vitro recombinant DNA and Page 44 of 120 12756399v1 Attorney Docket No.: 2017408-0046 synthetic techniques and in vivo recombination (see, e.g., Ausubel, supra or Sambrook, supra). Methods of use [0125] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection in a subject comprising administering an antibody or antigen-binding fragment thereof described herein. In some embodiments, sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV. In some embodiments, an antibody or antigen-binding fragment thereof described herein binds specifically to S2 of a sarbecovirus. Pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof described herein can be for use in the manufacture of a medicament for treating or preventing sarbecovirus infection in a subject. In some embodiments, various aspects of innovations described herein provide methods of neutralizing a sarbecovirus infection in a subject. [0126] Provided herein, among other things, are methods of treating or preventing a chronic sarbecovirus infection (e.g., long COVID-19) in a subject comprising administering an antibody or antigen-binding fragment thereof described herein. In some embodiments, sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV. In some embodiments, an antibody or antigen-binding fragment thereof described herein binds specifically to S2 of a sarbecovirus. Pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof described herein can be for use in the manufacture of a medicament for treating or preventing a chronic sarbecovirus infection (e.g., long COVID-19) in a subject. In some embodiments, various aspects of innovations described herein provide methods of neutralizing a chronic sarbecovirus infection (e.g., long COVID-19) in a subject. [0127] In some embodiments, a sarbecovirus infection is an acute infection. In some embodiments, a sarbecovirus infection is a chronic infection (e.g., long COVID-19). Long COVID-19 refers to a group of health problems persisting or developing after an initial period of sarbecovirus infection. In some embodiments, long COVID-19 can persist for weeks. In some embodiments, long COVID-19 can persist for months. In some embodiments, long COVID-19 can persist for years. For example, in some embodiments, long COVID-19 begins at one week after initial infection. For example, in some Page 45 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, long COVID-19 begins at two weeks after initial infection. For example, in some embodiments, long COVID-19 begins at three weeks after initial infection. For example, in some embodiments, long COVID-19 begins at four weeks after initial infection. For example, in some embodiments, long COVID-19 begins at five weeks after initial infection. For example, in some embodiments, long COVID-19 begins at six weeks after initial infection. For example, in some embodiments, long COVID-19 begins at seven weeks after initial infection. For example, in some embodiments, long COVID-19 begins at eight weeks after initial infection. For example, in some embodiments, long COVID-19 begins at nine weeks after initial infection. For example, in some embodiments, long COVID-19 begins at ten weeks after initial infection. For example, in some embodiments, long COVID-19 begins at 11 weeks after initial infection. For example, in some embodiments, long COVID-19 begins at 12 weeks after initial infection. [0128] In some embodiments, long COVID-19 is characterized by fatigue. In some embodiments, long COVID-19 is characterized by fatigue and/or memory problems. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, and/or shortness of breath. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, and/or sleep disorders. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, and/or headaches. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, headaches, and/or initial loss of smell and/or taste. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, headaches, initial loss of smell and/or taste, and/or muscle weakness. In some embodiments, long COVID-19 is characterized by fatigue, memory problems, shortness of breath, sleep disorders, headaches, initial loss of smell and/or taste, muscle weakness, and/or fever (See Chen et al. “Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review.” J. Infect. Dis.226(9):1593-1607 (2022); Centers for Disease Control and Prevention, US Department of Health and Human Services, “Long COVID or post-COVID conditions.” (2022); and Alkodaymi et al. “Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systemic review and meta-analysis.” Clin. Page 46 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Microbiol. Infect.28(5):657-666 (2022), each of which his hereby incorporated by reference in its entirety). [0129] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection in a subject comprising administering an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus in combination with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. In some embodiments, a sarbecovirus infection is an acute infection. In some embodiments, a sarbecovirus infection is a chronic infection (e.g., long COVID-19). In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1 of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD) of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus. [0130] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus are co- formulated in a pharmaceutical composition. In some embodiments, an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus are formulated in separate pharmaceutical compositions. [0131] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is administered prior to, substantially simultaneously, or after an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., Page 47 of 120 12756399v1 Attorney Docket No.: 2017408-0046 RBD) of a sarbecovirus is administered prior to, substantially simultaneously, or after an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus. [0132] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection in a subject comprising administering an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to RBD. [0133] In some embodiments, an additional therapeutic agent is administered with an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus in combination with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. Non-limiting examples of additional therapeutic agents include antibiotics (e.g., azithromycin), antibodies or antigen-binding fragments thereof (e.g., other SARS-CoV-2-binding antibodies or antigen-binding fragments), antimalarial agents (e.g., chloroquine or hydroxychloroquine), antiviral agents (e.g., Molnupiravir (LAGEVRIO, Merck), PF-07817883 (Pfizer), STI-1558 (Sorrento Therapeutics), PBI-0451 (Pardes Biosciences), EDP-235 (Enanta Pharmaceuticals), favipiravir, lopinavir and/or ritonavir), cytokines (e.g., type 1 interferons, such as interferon beta-1a), nucleotide analogs (e.g., remdesivir), protease inhibitors (e.g., danoprevir), Renin-Angiotensin-Aldosterone System Inhibitors (e.g., ACE2 inhibitors or angiotensin-receptor blockers (ARBs)), or a combination thereof. [0134] In some embodiments, an additional therapeutic agent is administered with an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus. In some embodiments, an additional therapeutic comprises a nucleotide analog (e.g., remdesivir). In some embodiments, administration of a combination of additional therapeutic agent and antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus reduces the likelihood of a SARS-CoV-2 infection as compared to administration of the additional therapeutic agent alone. In some embodiments, administration of a combination of additional therapeutic agent and antibody or antigen- Page 48 of 120 12756399v1 Attorney Docket No.: 2017408-0046 binding fragment thereof that binds specifically to S2 of a sarbecovirus increases anti-viral activity of the additional therapeutic and/or the antibody or antigen-binding fragment thereof. In some embodiments, an additional therapeutic agent and antibody or antigen- binding fragment thereof are co-administered. In some embodiments, an additional therapeutic agent comprises remdesivir. In some embodiments, an additional therapeutic agent comprises a pro-drug of GS-441524, the parent nucleoside of remdesivir. In some embodiments, an additional therapeutic agent comprises a pro-drug of remdesivir. In some embodiments, an additional therapeutic agent comprises obeldesivir (GS-5245). In some embodiments, an additional therapeutic agent comprises GS-621763. In some embodiments, an additional therapeutic agent comprises molnupiravir. [0135] In some embodiments, an additional therapeutic agent is a protease inhibitor (e.g., nirmatrelvir). In some embodiments, an additional therapeutic agent comprises nirmatrelvir. In some embodiments, an additional therapeutic agent is nirmatrelvir comprising P-glycoprotein (P-gp) inhibitor. In some embodiments, an additional therapeutic agent comprises a P-glycoprotein (P-gp) inhibitor. [0136] In some embodiments, a likelihood of sarbecovirus infection in a subject is reduced by at least about 10%, e.g., by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% at least about or at least about 99% after administration of an antibody or antigen-binding fragment thereof described herein. [0137] In some embodiments, a subject has (e.g., confirmed by testing, such as by PCR or rapid test), or is suspected of having, sarbecovirus. In some embodiments, a subject has sarbecovirus. In some embodiments, the subject has been diagnosed with sarbecovirus. In some embodiments, the subject is at risk of developing sarbecovirus. [0138] In some embodiments, a subject is a mammal. In some embodiments, a subject is a mammal selected from the group consisting of a dog, a cat, a mouse, a rat, a hamster, a guinea pig, a horse, a pig, a sheep, a cow, a chimpanzee, a macaque, a cynomolgus, and a Page 49 of 120 12756399v1 Attorney Docket No.: 2017408-0046 human. In some embodiments, a subject is a primate. In some embodiments, a subject is a human. [0139] In some embodiments, a subject has a heart disease. In some embodiments, a subject has a heart disease selected from the group consisting of a congenital heart disease, a coronary artery disease, a hypertensive heart disease, an inflammatory heart disease, a pulmonary heart disease, a rheumatic heart disease, a valvular heart disease, a cardiomyopathy, heart failure, and combinations thereof. In some embodiments, a subject has a congestive heart failure. In some embodiments, a subject has an inflammatory heart disease selected from the group consisting of endocarditis, cardiomegaly, myocarditis, and combinations thereof. [0140] In some embodiments, a subject has diabetes. [0141] In some embodiments, a subject has a lung disease. Non-limiting examples of lung diseases include acute respiratory distress syndromes, asthma, bronchitis, COPD, emphysema, lung tumors, pleural cavity diseases (e.g., pleural mesothelioma or tension pneumothorax), pulmonary vascular diseases (e.g., embolisms, edema, arterial hypertension or hemorrhage), and respiratory tract infections (e.g., pneumonia or other upper or lower respiratory tract infections). [0142] In some embodiments, a subject is a tobacco smoker. [0143] In some embodiments, a subject is immune compromised (e.g., has an underlying disorder or is on immunosuppressive therapy). In some embodiments, a subject is not immune compromised. In some embodiments, a subject is a recipient of an organ transplant. [0144] In some embodiments, a subject is at least about 40 years or older, e.g., at least about 45 years old, at least about 50 years old, at least about 55 years old, at least about 60 years old, at least about 65 years old, at least about 70 years old, at least about 75 years old, at least about 80 years old, at least about 85 years old, or at least about 90 years old. In some embodiments, the subject is older than about 90 years old. [0145] Administration of an antibody or antigen-binding fragment thereof described herein may be carried out in any convenient manner (e.g., injection, ingestion, transfusion, inhalation, implantation, or transplantation). In some embodiments, an antibody or antigen- binding fragment thereof described herein is administered by injection or infusion. In some Page 50 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, an antibody or antigen-binding fragment thereof described herein is administered transarterially, subcutaneously, intravenously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, or intraperitoneally. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or intramuscularly). In some embodiments, an antibody or antigen-binding fragment thereof described herein described herein is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally by infusion or injection. In some embodiments, an antibody or antigen- binding fragment thereof described herein is administered intramuscularly. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered intravenously. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered subcutaneously. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered by intramuscular injection. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered by intravenous injection. In some embodiments, an antibody or antigen-binding fragment thereof described herein is administered by subcutaneous injection. [0146] In some embodiments, a 100mg, 300 mg, 600 mg, 1200 mg, or 2400 mg dose of an antibody or antigen-binding fragment thereof described herein achieves at least about a 1- fold, at least about a 5-fold, at least about a 10-fold, at least about a 15-fold, at least about a 20-fold, at least about a 25-fold, at least about a 30-fold, at least about a 35-fold, at least about a 40-fold, at least about a 50-fold, at least about a 55-fold, at least about a 60-fold, at least about a 65-fold, at least about a 70-fold, at least about a 75-fold, at least about a 80- fold, at least about a 85-fold, at least about a 90-fold, at least about a 95-fold, or at least about a 100-fold increase from baseline in sarbecovirus neutralizing titer. In some embodiments, a 1200 mg dose of an antibody or antigen-binding fragment thereof described herein achieves at least about a 10-fold increase in sarbecovirus neutralizing titer. [0147] In some embodiments, a 100mg, 300 mg, 600 mg, 1200 mg, or 2400 mg dose of an antibody or antigen-binding fragment thereof described herein achieves a half-life of at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at Page 51 of 120 12756399v1 Attorney Docket No.: 2017408-0046 least about 50 days, at least about 55 days, at least about 60 days, at least about 65 days, at least about 70 days, at least about 75 days, at least about 80 days, at least about 85 days, at least about 90 days, at least about 95 days, or at least about 100 days. In some embodiments, a dose of an antibody or antigen-binding fragment thereof described herein achieves a half- life of at least about 55 days. [0148] In some embodiments, a 1200 mg dose of an antibody or antigen-binding fragment thereof described herein achieves a neutralizing index against SARS-CoV-2 of at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, or at least about 200. In some embodiments, a 1200 mg dose of an antibody or antigen-binding fragment thereof described herein achieves a neutralizing index against SARS-CoV-2 of at least about 30 to greater than 100 against omicron variants of interest. Dosing [0149] Provided herein, among other things, are methods of treating or preventing a sarbecovirus infection in a subject comprising administering a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus in combination with a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus allows for a reduced second dose to be administered of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus relative to the dose administered of the antibody or antigen-binding fragment thereof that binds specifically to a Spike protein as a monotherapy. [0150] Use of the terms “first dose” and second dose” is not indicative of the order of administration of any combination disclosed herein, particularly an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. Page 52 of 120 12756399v1 Attorney Docket No.: 2017408-0046 A first dose and a second dose can be administered in any order or substantially simultaneously. [0151] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is from 25 mg to about 2400 mg, about 25 mg to about 1800mg, about 25 mg to about 900mg, about 25 mg to about 600mg, about 25 mg to about 300mg, about 25 mg to about 200mg, about 50 mg to about 2400 mg, about 50 mg to about 1800 mg, about 50mg to about 1200 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 600 mg, about 100 mg to about 2400 mg, about 100 mg to about 1800 mg, about 100 mg to about 1500 mg, about 100 mg to about 1200 mg, about 100 mg to about 900 mg, about 100mg to about 700 mg, about 300 mg to about 2400 mg, about 300 mg to about 1800 mg, about 300 mg to about 1500 mg, about 300 mg to about 1200 mg, about 300mg to about 1000 mg, about 300mg to about 800 mg, about 300mg to about 700 mg, about 500 mg to about 2400 mg, about 500 mg to about 1800 mg, about 500 mg to about 1600 mg, about 500 mg to about 1200 mg, about 500mg to about 1000 mg, or about 500 mg to about 800 mg. [0152] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 25 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 50 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 75 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 100 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 125 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 150 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 175 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 200 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus Page 53 of 120 12756399v1 Attorney Docket No.: 2017408-0046 is about 225 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 250 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 275 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 300 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 325 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 350 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 375 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 400 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 425 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 450 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 475 mg. [0153] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 500 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 525 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 550 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 575 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 600 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 625 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 650 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that Page 54 of 120 12756399v1 Attorney Docket No.: 2017408-0046 binds specifically to S2 of a sarbecovirus is about 675 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 700 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 725 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 750 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 775 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 800 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 825 mg. [0154] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 850 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 875 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 900 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 925 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 950 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 975 mg. In some embodiments, a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1000 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1025 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1050 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1075 mg. Page 55 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0155] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1100 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1125 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1150 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1175 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1200 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1225 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1250 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1275 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1300 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1325 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1350 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1375 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1400 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1425 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1450 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1475 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1500 mg. In some Page 56 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1525 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1550 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1575 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1600 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1625 mg. [0156] In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1650 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1675 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1700 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1725 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1750 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1775 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1800 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1825 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1850 mg. In some embodiments, a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus is about 1875 mg. [0157] In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus is from about 25 mg to about 2400 mg, 25 mg to about 1800mg, about 25 mg to about 900mg, about 25 Page 57 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg to about 600mg, about 25 mg to about 300 mg, about 25 mg to about 200mg, about 50 mg to about 2400 mg, about 50 mg to about 1800 mg, about 50mg to about 1200 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 100 mg to about 2400 mg, about 100 mg to about 1800 mg, about 100 mg to about 1500 mg, about 100 mg to about 1200 mg, about 100 mg to about 900 mg, about 100 mg to about 700 mg, about 200 mg to about 2400 mg, about 200 mg to about 1800 mg, about 200 mg to about 1200 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, or about 200 mg to about 500 mg. [0158] In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 25 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 50 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 75 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 100 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 125 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 150 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 175 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 200 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 225 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 250 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 275 mg. In some Page 58 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 300 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 325 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 350 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 375 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 400 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 425 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 450 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 475 mg. [0159] In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 500 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 525 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 550 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 575 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 600 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 625 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 650 Page 59 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 675 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 700 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 725 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 750 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 775 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 800 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 825 mg. [0160] In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 850 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 875 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 900 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 925 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 950 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 975 mg. [0161] In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1000 Page 60 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1025 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1050 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1075 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1100 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1125 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1150 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1175 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1200 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1225 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1250 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1275 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1300 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1325 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1350 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1375 Page 61 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1400 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1425 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1450 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1475 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1500 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1525 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1550 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1575 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1600 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1625 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1650 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1675 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1700 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1725 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1750 Page 62 of 120 12756399v1 Attorney Docket No.: 2017408-0046 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1775 mg. In some embodiments, a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus is about 1800 mg. [0162] A combination of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus can be administered on multiple occasions. Administration of doses described herein can be repeated various times. Intervals between a combination of doses can be weekly, monthly, quarterly, or yearly. Administration of doses described herein can be repeated various times. Intervals between doses described herein can be weekly, monthly, quarterly, or yearly. Administration of doses described herein can be repeated various times. In some embodiments, doses described herein are administered at least 2 or more times. In some embodiments, doses described herein are administered at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times or more. In some embodiments, doses and dosing frequencies described herein are repeated indefinitely. In some embodiments, a single dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a single dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., RBD) of a sarbecovirus are administered. [0163] In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 3 months to about every 12 months. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 3 months. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of Page 63 of 120 12756399v1 Attorney Docket No.: 2017408-0046 an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 4 months. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 6 months. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 9 months. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 12 months. [0164] In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 12 weeks to about every 52 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 13 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 14 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 15 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 16 weeks. In some embodiments, administration of a first dose of an Page 64 of 120 12756399v1 Attorney Docket No.: 2017408-0046 antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 17 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 18 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 19 weeks. [0165] In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 20 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 21 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 22 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 23 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 24 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of Page 65 of 120 12756399v1 Attorney Docket No.: 2017408-0046 a sarbecovirus is about every 25 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 26 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 27 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 28 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 29 weeks. [0166] In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 30 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 31 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 32 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 33 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds Page 66 of 120 12756399v1 Attorney Docket No.: 2017408-0046 specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 34 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 35 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 36 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 37 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 38 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 39 weeks. [0167] In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 40 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 41 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus Page 67 of 120 12756399v1 Attorney Docket No.: 2017408-0046 is about every 42 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 43 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 44 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 45 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 46 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 47 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 48 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 49 weeks. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 50 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that Page 68 of 120 12756399v1 Attorney Docket No.: 2017408-0046 binds specifically to a Spike protein of a sarbecovirus is about every 51 weeks. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about every 52 weeks. [0168] In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 4 times to about 1 time annually. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 4 times annually. In some embodiments, administration of a first dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 3 times annually. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about quarterly. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 2 times annually. In some embodiments, administration of a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus is about 1 time annually. [0169] Any dose or combination of doses described herein can be administered at any frequency described herein. Non-limiting examples of doses and frequencies described herein include: a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 300 mg and a second dose of an antibody or Page 69 of 120 12756399v1 Attorney Docket No.: 2017408-0046 antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 300 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 300 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 350 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 400 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 450 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 500 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 550 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 600 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Page 70 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Spike protein (e.g., RBD) of a sarbecovirus of about 600 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 300 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 350 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 400 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 450 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 500 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 550 are administered about every 3 months to about every 12 months (e.g., about every 6 months), a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 600 Page 71 of 120 12756399v1 Attorney Docket No.: 2017408-0046 are administered about every 3 months to about every 12 months (e.g., about every 6 months), or a first dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus of about 650 mg and a second dose of an antibody or antigen-binding fragment thereof that binds specifically to Spike protein (e.g., RBD) of a sarbecovirus of about 650 are administered about every 3 months to about every 12 months (e.g., about every 6 months). [0170] Data obtained from cell culture assays and animal studies can be used in formulating a dose range and frequency that is not toxic for use in humans. A dose of antibody or antigen-binding fragment thereof described herein lies preferably within a range of circulating concentrations that include a dose with little or no toxicity. Dose can vary within this range depending upon the form employed and the route of administration utilized. Kits [0171] Provided herein, among other things, are kits comprising at least one antibody or antigen-binding fragment thereof described herein, and instructions for use and/or administration. In some embodiments, a kit comprises least one antibody or antigen-binding fragment thereof described herein and a pharmaceutically acceptable carrier, and instructions for use and/or administration. [0172] In some embodiments, a kit comprises an antibody or antigen-binding fragment thereof that binds specifically to S2 of a sarbecovirus and an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S1. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a receptor binding domain (RBD). In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to S2 of a sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of a sarbecovirus binds specifically to a stem helix region of a sarbecovirus. Page 72 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0173] Also provided are kits for use in the various methods disclosed herein. In some embodiments, a kit comprises instructions for use in any method described herein. Instructions can comprise a description of administration of a first and second pharmaceutical composition to a subject to achieve an intended activity in a subject. A kit may further comprise a description of selecting a human suitable for treatment based on identifying whether the human is in need of the treatment. In some embodiments, the instructions comprise a description of administering at least one antibody or antigen-binding fragment thereof described herein to a subject. [0174] Instructions relating to administering a dose comprising at least one antibody or antigen-binding fragment thereof described herein generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. Containers may be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses. Instructions supplied in kits as described herein are typically written instructions on a label or package insert. A label or package insert indicates that pharmaceutical compositions are used for treating or preventing sarbecovirus (e.g., SARS-CoV-2) infection in a subject. [0175] Kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Also contemplated are packages for use in combination with a specific device, such as an infusion device. A kit may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierce able by a hypodermic injection needle). A container may also have a sterile access port. [0176] Kits optionally may provide additional components such as buffers and interpretive information. Normally, a kit can include a container and a label or package insert(s) on or associated with the container. In some embodiments, provided herein are articles of manufacture comprising contents of kits described herein. INCORPORATION BY REFERENCE [0177] All publications, patent applications, patents, and other references mentioned herein, including GenBank Accession Numbers, are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not Page 73 of 120 12756399v1 Attorney Docket No.: 2017408-0046 intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which various aspects of innovations described herein belong. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of various aspects of innovations described herein, suitable methods and materials are described herein. [0178] Various aspects of innovations described herein is further illustrated by the following example. An example is provided for illustrative purposes only. It is not to be construed as limiting the scope or content of various aspects of innovations described herein in any way. EXAMPLES [0179] The following examples are provided to describe to the skilled artisan how to make and use methods and compositions described herein and are not intended to limit the scope of various aspects of innovations described herein. Example 1: First-in-human study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus. [0180] This Example demonstrates that an anti-S2 antibody (AB-1) achieves prophylactic efficacy against circulating viral variants of SARS-CoV-2 and related sarbecovirus. AB-1 is a half-life extended monoclonal antibody for prophylaxis of SARS- CoV-2 infection that targets S2 of the SARS-CoV2 spike protein, which contains a stem- helix region, and was selected because S2 is conserved across all SARS-Co-V2 variants to- date. S2 is not immunodominant, and therefore, is not subject to selective pressure due to natural infection or vaccine induced immunity, which suggests that AB-1 will maintain its activity against SARS-Co-V2 and variants. AB-1 is also able to neutralize other sarbecovirus, such as SARS-CoV-1 and WIV1 (Table 3). Page 74 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Table 3: AB-1 EC50 against SARS-CoV2 variants and other sarbecovirus in a pseudoneutralization assay. SARS-CoV-2 variants and other sarbecovirus AB-1 EC50 [ng/ml] [0181] In a single-ascending dose study, healthy volunteers aged 18–55 years were administered either AB-1 or placebo intravenously. There were five sequential dosing cohorts 100 mg, 300 mg, 600 mg, 1200 mg, 2400 mg. Each cohort was randomized to receive either AB-1 or placebo in a ratio of 3:3, 3:3, 10:3, 10:3, 10:3 respectively. Total follow-up will be 43 weeks for each study participant and dosing is now complete. [0182] No dose-limiting toxicity has been observed to date and all treatment-related adverse reactions (e.g., events) observed were mild (grade 1 or 2) at all doses. To date, all Page 75 of 120 12756399v1 Attorney Docket No.: 2017408-0046 treatment-emergent adverse events (AE) were mild (grade 1 or 2) with the exception of four AEs (two grade 3 and two grade 4) of Blood Creatine Phosphokinase Increased that were assessed as not related to study drug and related to physical activity. Preliminary pharmacokinetic data shows dose-proportionality up to 1200 mg of AB-1 (FIG.1) with a Geometric mean half-life of approximately 55 days to 70 days (FIGs.1 and 3). Additional pharmacokinetic studies further confirmed low variability and dose-proportionality up to 2400 mg with a half-life of approximately 55 days (FIG.3). Live virus neutralization against currently circulating strains of SARS-CoV-2 was dose-proportional with clear separation from placebo. Limited anti-drug antibodies were observed in a few participants, but had no impact on PK or viral neutralization titers. Simulated PK of AB-1 confirmed with observed data (assuming 10% lung penetration) are at levels anticipated to protect against COVID-19 infection for at least 150 days (FIG.1). [0183] These preliminary data support that AB-1 will provide at least about a 6 month duration of prophylactic efficacy against currently circulating viral variants when administered. Example 2: First-in-human study of a combination of monoclonal antibodies described herein against SARS-CoV-2 and related sarbecovirus. [0184] The present Example will provide a randomized, dose-escalation trial for evaluation of safety, tolerability, and pharmacokinetics of a combination of an antibody that binds specifically to S2 of a sarbecovirus (referred to herein as “AB-1”) and an antibody that binds specifically to a receptor binding domain (RBD; referred to herein as “AB-2”) of a sarbecovirus. [0185] This study will aim to evaluate AB-1 and AB-2 in combination dose cohorts in 20 healthy volunteers. All subjects will be monitored at periodic clinic visits for 302 days following their dosing. Upon completion of the last subject’s Day 29 clinic visit in the second combination dose cohort, interim analysis will be performed. The interim analysis will evaluate all ongoing safety, PK, immunogenicity, and serum neutralization data for all subjects in the study, at a minimum through Day 29. Page 76 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0186] A total of 20 healthy volunteers will be randomly assigned into two 8:2 ratio cohorts, to receive either AB-1 and AB-2 or placebo, respectively. Table 4 provides an overview of the dose combinations used. A placebo cohort that receives normal saline is also assessed. Table 4: Dosing overview. Combination Cohort 1 650 mg, AB-1 10 (8 active/2 placebo) 650 mg, AB-2 [0187] For the AB-1 and AB-2 combination group, subjects will receive an intramuscular (IM) dose of AB-1 and an IM dose of AB-2 (a “combination dose”). The placebo group will receive a dose of 0.9% sodium chloride given intramuscularly. Interim Analysis Assessments [0188] Primary objectives: Assess safety and tolerability of a combination dose of AB-1 and AB-2 administered IM compared to placebo. [0189] Secondary objectives: Assess pharmacokinetics and immunogenicity of a combination dose of AB-1 and AB-2 administered IM compared to placebo. [0190] Exploratory Objectives: Assess SARS-CoV-2 serum neutralization of a combination dose of AB-1 and AB-2 administered IM compared to placebo. [0191] Safety analysis: Assess adverse events for a combination dose of AB-1 and AB-2 administered IM compared to placebo. [0192] Pharmacokinetic Analyses: Noncompartmental PK parameters will be calculated from serum concentrations of AB-1 and AB-2 and compared between cohorts. Additional PK parameters may be calculated if deemed appropriate. Page 77 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Example 3: Neutralization activity of a combination of monoclonal antibodies described herein against SARS-CoV-2 and related sarbecovirus. [0193] The present Example demonstrates that a combination of an antibody that binds specifically to S2 of a sarbecovirus (referred to herein as “AB-1”) and an antibody that binds specifically to a receptor binding domain (RBD; referred to herein as “AB-2”) achieved strong virus neutralization activity. AB-1 and AB-2 were titrated in a checkboard approach so two-variable titration curves could be generated starting at 18ug/ml in a fourfold dilution series. These dilutions were assayed for neutralization activity in VERO-TMPRSS2 cells against SARS-CoV-2 Omicron BQ.1.1 Spike and XBB.1.5 Spike pseudotyped VSVdG particles. Background and Design: Neutralization of pseudotyped VSVdG with SARS-CoV-2 Omicron BQ.1.1 Spike. [0194] Vero-E6 cells over-expressing TMPRSS2 were seeded in 384 well tissue culture plates. Antibodies were serially diluted and incubated with diluted virus at a desired MOI. After 30 min - 1 hour incubation at 37oC, 5% CO2, pseudovirus/antibody mixture was added to corresponding wells of the culture plates with Vero cells. After 24 hours, luciferase substrate was added directly to culture plates (pseudovirus backbone has a luciferase reporter) and read using the luminescent filter on the Envision. Protocol: [0195] On Day 0, Vero-TMPRSS2 cells were harvested, counted and plated in cell culture plates at 3.5 x 103 cells/well with 20 μl stimulation medium. Plates were spun down for < 5 seconds at 50 g and then incubated at 37 degrees Celsius, 5% CO2 for 2-4 hours while dilution and antibody/pseudovirus incubation plates were prepared. [0196] AB-1 dilution plates (plates 1-4) were prepared as follows: 40 μl of PBS-T +BSA + P/S) was added to rows A-H of columns 1-8 of plates 2 and 4 and rows B-H of column 1-8 of plates 1 and 3. Then, 53.33 μl of AB-1 at 72 μg/ml was added to row A of plate 1 and 3. A total of 13.33 μl was taken from row A of plate 1 and serially diluted through row H and continued through rows A-H of plate 2 to create a (column-wise) 16-pt Page 78 of 120 12756399v1 Attorney Docket No.: 2017408-0046 titration curve at a 1:4 dilution. A total of 13.33 μl was taken from row A of plate 3 and serially diluted through row H and continued through rows A-H of plate 4 to again create a (column-wise) 16-pt titration curve at a 1:4 dilution. [0197] AB-2 dilution plates 5-8 were prepared as follows: 40 μl of PBS-T +BSA + P/S was added to rows A-H of column 8-1 of plates 6 and 8, and rows A-H of column 1-7 of plates 5 and 7. Then, 53.33 μl of PRO-37587-001 at 72 μg/ml was added to column 8 of plate 5 and 7. 13.33 μl was taken from column 8 of plate 5 and serially diluted through column 1 and continued through column 8-1 of plate 6 to create a (row-wise) 16-pt titration curve at a 1:4 dilution. 13.33 μl was taken from column 8 of plate 7 and serially diluted through the column and continued through column 8-1 of plate 8 to create a (row-wise) 16- pt titration curve at a 1:4 dilution. [0198] The following 96 well plates were then combined. All plates had a 40 μl final volume and the combinations below had a final volume of 80 μl. Below stated locations (e.g., top left, bottom right) correlate to the stamp on a 384-well assay plate. Plate 1(20ul) + Plate 6(20ul) (top left)= Plate A Plate 2(20ul) + Plate 8(20ul) (bottom left) = Plate B Plate 3(20ul) + Plate 5(20ul) (top right)= Plate C Plate 4(20ul) + Plate 7(20ul) (bottom right)= Plate D [0199] Dilutions of AB-1, AB-2 (Class-4), PRO-31223-001 (Bebtelovimab), and PRO- 12158-006 (Isotype) alone were made separately. A total of 80 μl of blocking buffer was added to columns 2, 4, 6, and 8 (A-H) and columns, 1, 3, 5, and 7 (B-H) of a 96 well plate. A total of 106.7 μl of antibody at 72 ug/ml was added to well A1 (AB-1), A3 (AB-2), A5 (Bebtelovimab), and A7 (Isotype). A total of 26.7 μl of antibody was transferred to B1, B3, B5, B7, respectively, and 26.7 μl was transferred through columns 1, 3, 5, 7 and through A- H of rows 2, 4, 6, 8 to create a 16-pt curve; 1:4 dilution. [0200] Antibody/pseudovirus plates were prepared as follows: 40 μl of diluted virus was added to each well of the dilution plates. 40 μl of stimulation media was added to column 11-12 of Plate 10 (as a positive control). Plates were incubated at 37oC, 5% CO2 for 30-60 minutes. At the end of the incubation time, 20 μl from each well of the antibody/pseudovirus incubation plates was transferred in quadruplicate to each well of the Page 79 of 120 12756399v1 Attorney Docket No.: 2017408-0046 cell culture plates. Plates were spun down for < 5 seconds at 50 g and then were incubated at 37oC, 5% CO2 for 1 day. On day 1, 40 μl of luciferase detection buffer was added to each well of the cell culture plates. Plates were spun down for < 5 seconds at 50 g, incubated for 15 minutes with gentle rocking and then luminescence signal was recorded. Results [0201] Results depicted in FIGs.2A-F demonstrate strong enhancement of protection, at all concentrations tested and as measured by percent neutralization, of AB-1 combined with AB-2. Example 4: Pharmacodynamic study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus. [0202] As further demonstration of extended live virus neutralization achieved by AB-1 against circulating strains of SARS-CoV-2, pharmacodynamic properties of AB-1 was characterized in subjects with pre-existing SARS -CoV-2 titers (e.g., infection). A subject’s mean neutralization titer of antibodies was measured before and after a 100mg, 300mg, 600mg, 1200mg, or 2400mg dose of AB-1 was administered. As shown in FIG.4, live virus 50% and 80% mean neutralization titer (e.g., MN50 and MN80) was measured using Wild Type D614G, Omicron XBB.1.5, and Omicron BA.5.5 strains of live (e.g., infectious) SARS-CoV-2. All doses tested (i.e., 100mg, 300mg, 600mg, 1200mg, and 2400mg) exhibited a dose dependent, 2 to 100 fold increase in live virus neutralization titer relative to pre-dose. When tested against Omicron variants, an AB-1 dose of 1200mg achieved an approximately 10-fold increase in live virus MN50 titer against XBB.1.5 and BA.5.5 (FIG. 4). Over a 60 day period, subjects that received an AB-1 dose of 1200mg achieved a 20-fold increase in live virus MN50 titer and a 15-fold increase in live virus MN80 titer against XBB.1.5, relative to pre-dose (e.g., baseline) titers (FIG.5). As shown in FIG.1 and FIG. 5, AB-1 achieved a half-life of approximately 55 days. Page 80 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Example 5: Neutralizing capacity of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus. [0203] This Example demonstrates that AB-1 achieves protection against SARS-CoV-2 for over 60 days in subjects with low baseline titer of anti-SARS-Cov2 neutralizing antibodies. In some embodiments, an immunocompromised subject has a low baseline titer of antibodies that can neutralize SARS-CoV-2. A neutralizing index was calculated like described in Stadler et al. “Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis.” The Lancet. Microbe vol.4,11 (2023), the entire contents of which are hereby incorporated by reference. However, the neutralizing index equation was extended to incorporate predicted plasma concentration instead of dose in the numerator of the equation (See FIG.6) as stated in Stadler et al. A neutralizing index against Omicron variants Xbb.1.5 and BA.5.5 following a 1200 mg dose of AB-1 was calculated. A pre-dose (convalescent) MN50 value of 50 and IC50 in vitro values for Xbb.1.5 and BA.5.5 variants of 53 ng/mL and 43 ng/mL, respectively, were obtained by measuring AB-1 neutralization activity against SARS-CoV-2 ancestral strain. As shown in FIG.6, AB-1 in subjects with low baseline titers achieved a neutralizing index of 30 to greater than 100 over a 60-day period. Neutralizing index data demonstrated that AB-1 achieved protection against hospitalization due to Omicron variant Xbb.1.5 or BA.5.5 infection for over 60 days in subjects with low baseline titer levels (e.g., in immunocompromised subjects). Example 6: Neutralizing capacity of a novel half-life extended monoclonal antibody against SARS-CoV-2 and related sarbecovirus. [0204] This Example demonstrates the percent neutralization of various sarbecoviruses (e.g., SARS-CoV-2 variants) achieved by AB-1. A neutralization assay was performed using an isotype control (i.e., negative control) and commercial antibody, bebtelovimab, for comparison. As shown in FIG.7, AB-1 achieved neutralization of SARS CoV-2 variants currently tracked by the CDC as well as non-SARS-CoV-2 sarbecoviruses responsible for previous outbreaks (e.g., SARS-CoV-1) or at risk of zoonotic spillover (e.g., WIV1). AB-1 achieved at least 80% neutralization of all sarbecoviruses tested (FIG.7). AB-1 achieved Page 81 of 120 12756399v1 Attorney Docket No.: 2017408-0046 percent neutralization of non-SARS-CoV-2 sarbecoviruses (e.g., SARS-CoV-1 and WIV1) and SARS-CoV-2 Omicron variants BQ.1, BQ.1.1, and XBBB.1.5 that was superior to bebtelovimab and the isotype control (FIG.7). AB-1 achieved percent neutralization of SARS-CoV-2 D614G, SARS-CoV-2 Delta, and SARS-CoV-2 BA.4/5 that was similar to Bebtelovimab (FIG.7). Table 5 depicts the EC50 (95% CI) value (ng/mL) of AB-1 calculated for each Sarbecovirus tested. Table 5. EC50 values of AB-1 against sarbecoviruses. EC50 (95% SARS- SARS- SARS- SARS- SARS- SARS- CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 SARS- WIV1 [0205] Table 5 depicts EC50 values (μg/mL), shown as mean (95% confidence interval) and representative of three to six independent experiments, four technical replicates each. [0206] As shown in FIG.7, neutralization profiles of AB-1, bebtelovimab and isotype control antibody were measured against pseudoviruses representative of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses. Results were reported as percent neutralization and shown as mean ± standard deviation (representative of three to six independent experiments, four technical replicates each) (FIG.7). Materials: [0207] Pseudoviruses: The SARS-CoV-2 and non-SARS-CoV-2 sarbecoviruses used were deltaG-VSV expressing a spike protein of interest and a reporter system (e.g., luciferase) to quantify infection in permissive cells lines listed below. The pseudovirus panel included the following: spike (WIV-1) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-033-002, BPS Bioscience, catalog # 78696, lot # 221201); spike (SARS- CoV-1) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-032-001, BPS Bioscience, catalog # 78695, lot #221201); spike (SARS-CoV-2, D614G) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-017-001, BPS Bioscience, catalog # 78642, lot # 220512); spike Page 82 of 120 12756399v1 Attorney Docket No.: 2017408-0046 (SARS-CoV-2, B.1.617.2, Delta) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-016- 002, BPS Bioscience, catalog # 78640, lot # 220512); spike (SARS-CoV-2, BA.4/5) pseudotyped deltaG-VSV (Luciferase Reporter)(PV-015-001, BPS Bioscience, catalog # 78644, lot # 220527); spike (SARS-CoV-2, BQ.1) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-026-001, BPS Bioscience, catalog # 78688, lot # 221118); spike (SARSCoV- 2, BQ.1.1) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-027-001, BPS Bioscience, catalog # 78689, lot # 221118); spike (SARS- CoV-2, XBB.1.5) pseudotyped deltaG-VSV (Luciferase Reporter) (PV-041-001, BPS Bioscience, catalog # 78733, lot # 230119). [0208] Cell lines: TMPRSS2-Vero E6 Recombinant Cell Line (CL-030, BPS Biosciences, catalog # 78081, lot # 210522#20); VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586). [0209] Antibodies: AB-1 (Lonza, lot # 1100-130922-01), isotype control (GenScript USA, Inc., lot # U799WHJ270-3, palivizumab variable regions targeting RSV F protein and expressed as human IgG1 with LS mutation in the Fc region), bebtelovimab (GenScript USA, Inc., lot # U3767HH180-46). [0210] Stimulation medium: MEM (catalog # SH30024.02, lot # AH29890509) with 2.5% FBS (catalog # A38403-01, lot # 262908SRP), 0.1 mM nonessential amino acids (catalog #11140-050, lot # 2390759), 1 mM sodium pyruvate (catalog #11360-070, lot #2323639), 1% Penicillin/Streptomycin (catalog # 15140-122, lot # 2441835). [0211] Luciferase detection buffer: ONE-Step™ Luciferase Assay System, components A and B were mixed at 100:1 ratio respectively (BPS Bioscience, catalog # 60690-3, lot # 221221). [0212] Plastics: Tissue culture plates were white 384-Well plates, with lid, cell culture, sterile, polystyrene (ThermoFisher, catalog # 164610). Dilution plates were 96 well plate round bottom, non-treated, polypropylene (Corning, catalog# 3365; Greiner, catalog # 650201). Antibody/pseudovirus incubation plates were Nunc 96-Well polystyrene round bottom microwell plates, with lid, non-tissue culture-treated, sterile (ThermoFisher, catalog #268200). Methods: Page 83 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0213] Vero E6 or a TMPRSS2-Vero E6 recombinant cells were seeded into 384-well tissue culture plates at a density of 3,500 cells per well in 20 μl of stimulation medium and incubated at 37C, 5% CO2 for 2 - 4 hours. In parallel, antibodies were serially diluted and incubated with diluted pseudovirus listed above at a desired multiplicity of infection. Antibody neutralization was assessed with 12-point titration curves in technical quadruplicate (1:4 serial dilutions prepared in PBS with 0.2% BSA and 1X Pen-Strep solution starting at 18 μg/ml). Antibodies were serially diluted starting at 72 μg/ml (4-fold of the final top concentration [18 μg/ml] in the tissue culture plates). After 30 - 60 minutes of incubation at 37C, 5% CO2, 20 μl pseudovirus/antibody mixture was added to the tissue culture plates pre-seeded with cells, achieving final antibody concentrations in a total volume of 40 μl. After 24 hours at 37C, 5% CO2, an equal volume of luciferase substrate was added directly to culture plates and luminescence was quantified on the PerkinElmer EnVision plate reader. Percentage neutralization was calculated with the following formula, where “signalpositiveControl” is defined by the average luminescence signal of wells containing cells without pseudovirus, “signalnegativeControl” is defined as the average luminescence signal of wells containing cells with pseudovirus, “signalwell” is defined as the average luminescence signal of wells containing cells with both antibody and pseudovirus: Percentage neutralization = (1-((signalwell-signalpositiveControl)/(signalnegativeControl – signalpositiveControl))) x 100. Statistical analysis was performed with Prism 9.5.0 software. Half maximal effective concentration (EC50) values and 95% confidence intervals were derived for each Log-transformed antibody titration curve using log(inhibitor) vs. response - - Variable slope (four parameters) equation. Example 7: A novel half-life extended monoclonal antibody against SARS-CoV-2 and related sarbecovirus. [0214] This Example demonstrates that all binding residues in the S2 stem helix epitope that AB-1 binds are > 99% conserved. [0215] Material and methods for the following results displayed: Relative frequencies at 1 month, 3 months, and earliest for polymorphisms in the S2 stem helix region; G1167V, P1162L, P1162S, and V1176F. Page 84 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Table 6. Summary of polymorphisms identified in the S2 stem helix region. Polymorphism Relative Relative Relative Most prevalent frequency frequency (3 frequency lineages 1 . , stem helix region in the most prevalent SARS-CoV-2 lineages was assessed. Methods: [0217] The covSPECTRUM API (Application Programming Interface) was used to query the GenBank database for mutations occurring in the epitope region (Chen C, Nadeau S, Yared M, et al. CoV-Spectrum: analysis of globally shared SARS-CoV-2 data to identify and characterize new variants. Bioinformatics.2022;38(6):1735-1737, which is hereby incorporated by reference in its entirety). For each mutation, the relative frequencies are for the period ending March 1st, 2023, across three different time intervals (earliest [January 6th, 2020 to March 1st, 2023], 3 months [December 1st, 2022 to March 1st, 2023], 1 month [February 1st, 2023 to March 1st, 2023]). Relative frequency is determined by dividing the number of sequences with a mutation of interest observed during a given time interval by the total number of sequences observed during the same time interval. [0218] Mutations were identified that meet the following criteria: (1) Falls within the “Epitope”, “Epitope Adjacent”, “HR1”, or “HR2,” or (2) Satisfies at least one of two criteria: (i) All-time relative frequency: has relative frequency at least 0.001 among all Page 85 of 120 12756399v1 Attorney Docket No.: 2017408-0046 sequences deposited since the start of data availability (January 6th, 2020) through March 1st, 2023, (ii) Recent relative frequency: has relative frequency of at least 0.01 among all sequences deposited from January 1st, 2023, to March 1st, 2023, and has been observed at least 100 times in that period. [0219] The relative frequency data was plotted throughout the course of the pandemic to observe whether the mutation appears to be currently increasing or decreasing in prevalence. [0220] To identify the most prevalent strains amongst sequences harboring each mutation of interest, covSPECTRUM was queried for the set of sequences with each mutation that had been observed from the start of data availability (January 6th, 2020, to March 1st, 2023). SARS-CoV-2 lineages were assigned to sequences harboring the mutation (the nextcladePangoLineage assignment reported by covSPECTRUM) and ranked according to absolute count. For each mutation and lineage, to convert the count to the relative frequency of the strain among all sequences with the mutation, the count of lineage sequences with the mutation was divided by the total number of sequences with the mutation observed from January 6th, 2020, to March 1st, 2023. In this analysis, the four most frequent lineages associated with each mutation were reported. [0221] The five most prevalent lineages were determined for each of three time periods ending on March 1st, 2023 (1 month, 3 months, and since January 6th, 2020) by querying the covSPECTRUM API for the frequency of observed lineages over each of these periods. The overall prevalence of each lineage was determined by converting counts to relative frequency: lineage counts observed in each time interval were divided by the total number of sequences observed in that same time interval. For the five most prevalent lineages over each time period, relative frequency of a mutation within each lineage was determined as follows: the number of sequences belonging to the lineage with the mutation within the time interval was queried, and then divided by the number of all sequences belonging to the lineage in that same time interval. [0222] Software for analysis: Custom python scripts used to retrieve data and complete the analysis are stored in a versioned repository at GitLab. [0223] Four polymorphisms were identified in the S2 stem-helix peptide: G1167V, V1176F, P1162L, P1162S (FIG.8). AB-1 makes contacts with P1162. In some Page 86 of 120 12756399v1 Attorney Docket No.: 2017408-0046 embodiments, pseudoviruses with spike bearing P1162L or P1162S exhibited reduced susceptibility to AB-1; other polymorphisms did not impact activity. In some embodiments, none of these polymorphisms have exceeded a relative frequency of 0.01 and/or shown significant upward trends in the past 3 months. These data herein suggest little to no immune pressure on this epitope (FIG.8). In some embodiments, none of these polymorphisms have been detected at high relative frequencies in highly prevalent SARS- CoV-2 variants. Example 8: Neutralization activity of a monoclonal antibody described herein, alone or in combination with remdesivir against SARS-CoV-2 Omicron JN.1 [0224] The aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., remdesivir). The combination was tested following a method of administration where both AB-1 and remdesivir were titrated simultaneously. AB-1 and Remdesivir was also each tested alone. [0225] EC50 values, calculated from experiments depicted in FIG.10, are shown in Table 7. Results are expressed as EC50 values for each tested article as single agents or in combination, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). When the compounds were titrated in combination, the EC values are displayed both in function of the AB-1 dilution or in function of the remdesivir dilution. Remdesivir concentration is represented in M and AB-1 concentration is represented in g/ml. Table 7: EC50 values of AB-1 and remdesivir as single agents or in combination against SARS-CoV-2 Omicron JN.1 EC50 Page 87 of 120 12756399v1 Attorney Docket No.: 2017408-0046 AB-1 (titrated) + Remdesivir (titrated) EC values expressed in function of Remdesivir. 0.046 μM an th agents increased remdesivir (EC500.046 μM) and AB-1 (0.042 μg/mL) potency. [0227] Taken together these data demonstrate that the antiviral activity of remdesivir is increased by co-administration of AB-1. Materials [0228] Virus: SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml. [0229] Cell line: VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586), passage 12 (from thawing). [0230] Antiviral: Remdesivir (Selleck Chemicals, catalog #S8932). [0231] Antibody: AB-1. [0232] Culture Media: M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0233] Infection Media: M199 (Gibco, catalog #31150022, lot 2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0234] MTT Assay Reagents: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Merck, catalog #475989 – 1 G, lot #4158001) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Merck, catalog #41639-500ML, lot #102666276). Methods [0235] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom). Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture Page 88 of 120 12756399v1 Attorney Docket No.: 2017408-0046 media and incubated at 37C, 5% CO2, until the following day. Antibody and antiviral neutralization were assessed using 12-point titration curves in technical triplicate with three- fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 and 20 M (final concentration) for Remdesivir alone and the AB-1-Remdesivir combination. A predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells. Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed from the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect. After 72 hours, 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2. The supernatants were removed from each well, and the MTT precipitates solubilized by adding 50 l of a 1:1 mixture of DMSO and Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader. The sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells. The percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition. Example 9: Neutralization activity of a monoclonal antibody described herein, alone or in combination with nirmatrelvir against SARS-CoV-2 Omicron JN.1 [0237] The aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., nirmatrelvir). The combination was Page 89 of 120 12756399v1 Attorney Docket No.: 2017408-0046 tested following a method of administration where both AB-1 and nirmatrelvir were titrated simultaneously. AB-1 and nirmatrelvir were also each tested alone. [0238] EC50 values, calculated from experiments depicted in FIG.11, are shown in Table 8. Results are expressed as EC50 values for each tested article as single agents or in combination, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). When the compounds were titrated in combination, the EC values are displayed both in function of the AB-1 dilution or in function of the nirmatrelvir dilution. Nirmatrelvir concentration is represented in M and AB-1 concentration is represented in g/ml. Table 8. The EC50 values of AB-1 and nirmatrelvir as single agents or in combination against SARS-CoV-2 Omicron JN.1 EC50 Nirm tr lvir 2693 M an EC50 of 0.089 μg/mL, compared to 2.693 μM for nirmatrelvir. Simultaneous titration of both agents increased nirmatrelvir (EC500.080 μM) and AB-1 (0.072 μg/mL) potency. [0240] Taken together these data demonstrate that the antiviral activity of nirmatrelvir is increased by co-administration of AB-1. Materials [0241] Virus: SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml. [0242] Cell line: VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586), passage 13 (from thawing). [0243] Antiviral: Nirmatrelvir (Insight Biotechnology, catalog # HY-138687) Page 90 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0244] Antibody: AB-1. [0245] Culture Media: M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0246] Infection Media: M199 (Gibco, catalog #31150022, lot 2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0247] MTT Assay Reagents: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Merck, catalog #475989 – 1 G, lot #4158001) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Merck, catalog #41639-500ML, lot #102666276). Methods [0248] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom). Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture media and incubated at 37C, 5% CO2, until the following day. Antibody and antiviral neutralization were assessed using 12-point titration curves in technical triplicate with three- fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 and 20 M (final concentration) for Nirmatrelvir alone and the AB-1-Nirmatrelvir combination. A predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells. Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed from the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect. After 72 hours, 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2. The supernatants were removed from each well, and the MTT precipitates solubilized by adding 50 l of a 1:1 mixture of DMSO and Page 91 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader. The sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells. The percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: [0249] The EC50 values were extrapolated using GraphPad Prism software (v10) from the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition. Example 10: Neutralization activity of a monoclonal antibody described herein, alone or in combination with nirmatrelvir + P-glycoprotein (P-gp) inhibitor against SARS- CoV-2 Omicron JN.1 [0250] The aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., nirmatrelvir + P-gp inhibitor). The combination was tested following a method of administration where both AB-1 and nirmatrelvir were titrated simultaneously in the presence of a constant concentration (0.25 μM) of P-gp inhibitor. AB-1 and nirmatrelvir in the presence of a constant concentration (0.25 μM) of P-gp inhibitor were also each tested alone. [0251] EC50 values, calculated from experiments depicted in FIG.12, are shown in Table 9. Results are expressed as EC50 values for each tested article as single agents or in combination, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). When the compounds were titrated in combination, the EC values are displayed both in function of the AB-1 dilution or in function of the nirmatrelvir dilution. Nirmatrelvir concentration is represented in M and AB-1 concentration is represented in g/ml. Table 9. The EC50 values of AB-1 and nirmatrelvir as single agents or in combination (+ P-gp inhibitor) against SARS-CoV-2 Omicron JN.1 Page 92 of 120 12756399v1 Attorney Docket No.: 2017408-0046 EC50 Nirmatrelvir + 0.25 μM P-gp inhibitor. EC 0.056 μM an . , . t concentration (0.25 μM ) of P-gp inhibitor. Simultaneous titration of both agents increased nirmatrelvir (EC500.0014 μM) and AB-1 (0.027 μg/mL) potency in the presence of a constant concentration (0.25 μM ) of P-gp inhibitor. [0253] Taken together these data demonstrate that the antiviral activity of nirmatrelvir in the presence of a constant concentration (0.25 μM ) of P-gp inhibitor is increased by co- administration of AB-1. Materials [0254] Virus: SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml. [0255] Cell line: VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586), passage 13 (from thawing). [0256] Antiviral: Nirmatrelvir (Insight Biotechnology, catalog #HY-138687); P- glycoprotein (P-gp) inhibitor CP 100356 hydrochloride (Bio-Techne, catalog #4193/10). [0257] Antibody: AB-1. Page 93 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0258] Culture Media: M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0259] Infection Media: M199 (Gibco, catalog #31150022, lot #2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0260] MTT Assay Reagents: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Merck, catalog #475989 – 1 G, lot #4158001) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Merck, catalog #41639-500ML, lot #102666276). Methods [0261] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom). Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture media and incubated at 37C, 5% CO2, until the following day. Antibody and antiviral neutralization were assessed using 12-point titration curves in technical triplicate with three- fold dilutions in infection media at 18 g/mL (final concentration) for AB-1 and 1 M (final concentration) for Nirmatrelvir alone and the AB-1-Nirmatrelvir combination. All antibody and antiviral conditions were tested in the presence of a constant concentration of 0.25 μM (final concentration) P-gp inhibitor, except for AB-1, which was prepared in the absence of the inhibitor. A predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells. Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed from the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect. After 72 hours, 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2. The supernatants were removed from each well, and the MTT precipitates solubilized by adding Page 94 of 120 12756399v1 Attorney Docket No.: 2017408-0046 50 l of a 1:1 mixture of DMSO and Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader. The sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells. The percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: [0262] The EC50 values were extrapolated using GraphPad Prism software (v10) from the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition. Example 11: Neutralization activity of a monoclonal antibody described herein, alone or in combination with P-glycoprotein (P-gp) inhibitor against SARS-CoV-2 Omicron JN.1 [0263] The aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., P-gp). The combination was tested following a method of administration where AB-1 was titrated in the presence of a constant concentration (0.25 μM ) of P-gp inhibitor. AB-1 was also tested alone. [0264] EC50 values, calculated from experiments depicted in FIG.13, are shown in Table 10. Results are expressed as EC50 values for AB-1 as a single agent or in combination with P-gp inhibitor, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). The EC values are displayed in function of the AB-1 dilution in g/ml. Table 10. The EC50 values of AB-1 as a single agent or in combination with P-gp inhibitor against SARS-CoV-2 Omicron JN.1 EC50 Page 95 of 120 12756399v1 Attorney Docket No.: 2017408-0046 AB-1 (titrated) + 0.25 μM P-gp inhibitor. 0.153 μg/mL EC values expressed in function of AB-1 an ) of P-gp inhibitor increased AB-1 (0.153 μg/mL) potency. [0266] Taken together these data demonstrate that the antiviral activity of AB-1 is increased by co-administration of P-gp inhibitor. Materials [0267] Virus: SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml. [0268] Cell line: VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586). [0269] Antiviral: P-glycoprotein (P-gp) inhibitor CP 100356 hydrochloride (Bio- Techne, catalog #4193/10). [0270] Antibody: AB-1. [0271] Culture Media: M199 (Gibco, catalog #31150022, lot 2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0272] Infection Media: M199 (Gibco, catalog #31150022, lot #2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0273] TT Assay Reagents: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), Invitrogen, catalog #M6494, lot #2139890); Isopropanol (Fisher, catalog #P/7500/17, lot#1852201); DMSO (Sigma, catalog #41639-500ML, lot #102666276). Methods [0274] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom). Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture Page 96 of 120 12756399v1 Attorney Docket No.: 2017408-0046 media and incubated at 37C, 5% CO2, until the following day. Antibody neutralization was assessed using 12-point titration curve in technical triplicate with three-fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 with or without a constant concentration of 0.25 μM (final concentration) P-gp inhibitor. A predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells. Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed for the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect every 24 hours. After 72 hours, 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2. The supernatants were removed from each well, and the MTT precipitates solubilized by adding 50 l of a 1:1 mixture of DMSO and Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader. The sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells. The percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition. Example 12: Neutralization activity of a monoclonal antibody described herein, alone or in combination with Molnupiravir against SARS-CoV-2 Omicron JN.1 [0276] The aim of this study was to demonstrate the antiviral activity against SARS- CoV-2 (SARS-CoV-2 Omicron JN.1) that AB-1 achieves, when administered on its own or in combination with an additional therapeutic agent (i.e., molnupiravir). The combination Page 97 of 120 12756399v1 Attorney Docket No.: 2017408-0046 was tested following a method of administration where both AB-1 and molnupiravir were titrated simultaneously. AB-1 and molnupiravir were also each tested alone. [0277] EC50 values, calculated from experiments depicted in FIG.14, are shown in Table 11. Results are expressed as EC50 values for each tested article as single agents and in combination, expressed as the concentration at which 50% of the infection was neutralized (representative of one independent experiment, three technical replicates). When the compounds were titrated in combination, the EC values are displayed both in function of the AB-1 dilution or in function of the molnupiravir dilution. Molnupiravir concentration is represented in M and AB-1 concentration is represented in g/ml. Table 11. The EC50 values of AB-1 and molnupiravir as single agents and in combination against SARS-CoV-2 Omicron JN.1 EC50 M ln ir vir (NHC EIDD-1931) 1319 M an EC50 of 0.689 μg/mL, compared to 1.319 μM for molnupiravir. Simultaneous titration of both agents increased molnupiravir (EC500.486 μM) and AB-1 (0.437 μg/mL) potency. [0279] Taken together these data demonstrate that the antiviral activity of molnupiravir is increased by co-administration of AB-1. Materials [0280] Virus: SARS-CoV-2 hCoV-19/USA/NY/PV96109/2023 (JN.1) (Omicron JN.1); Stock P124092024; Titer 1.58E+07 TCID50/ml. [0281] Cell line: VERO C1008 [Vero 76, clone E6, Vero E6] (CL-004-001, ATCC, catalog # CRL-1586). Page 98 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0282] Antiviral: EIDD-1931 (Beta-d-N4-hydroxycytidine; NHC; the active form of Molnupiravir) (Insight Biotechnology, Catalog # HY-125033) [0283] Antibody: AB-1. [0284] Culture Media: M199 (Gibco, catalog #31150022, lot #2958677) with 5% Fetal Bovine Serum (FBS) (Gibco, catalog #A526801, lot #25633194) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0285] Infection Media: M199 (Gibco, catalog #31150022, lot #2958677) with 0.4% Bovine Serum Albumin (BSA) (Gibco, catalog #15260-037, lot #2904259) and 1X Penicillin/Streptomycin (Gibco, catalog #15070063, lot #2588019). [0286] MTT Assay Reagents: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide), (Invitrogen, catalog #M6494, lot #2139890) dissolved in PBS (Gibco, catalog #10010015, lot #2916970) at 5 mg/ml and filter sterilized; Isopropanol (Fisher, catalog #P/7500/17, lot #1852201); DMSO (Sigma, catalog #41639-500ML, lot #102666276). Methods [0287] SARS-CoV-2 Omicron JN.1 neutralization experiments were performed at Virology Research Services Ltd (Sittingbourne, United Kingdom). Molnupiravir is the prodrug that is metabolized into its active form, NHC (EIDD-1931). Accordingly, these studies were conducted using NHC. Vero E6 cells were detached, counted, and seeded in 96-well plates at 8,000 cells per well in 100 l of culture media and incubated at 37C, 5% CO2, until the following day. Antibody and antiviral neutralization were assessed using 12- point titration curves in technical triplicate with three-fold dilutions in infection media starting at 18 g/mL (final concentration) for AB-1 and 20 M (final concentration) for NHC alone and the AB-1-NHC combination. A predetermined MOI 0.002 of SARS-CoV-2 Omicron JN.1 was added to each well of the antibody, antiviral or antibody-antiviral combination dilutions and the infected, untreated control, wells. Infection media (without virus) was added to the uninfected, untreated, control wells. After 1 hour incubation at 37C, 5% CO2, the media was removed for the seeded cells and replaced with the antibody-virus, antiviral-virus, or antibody-antiviral-virus combination dilution mixtures. Plates were then incubated for 72 hours at 37C, 5% CO2 and monitored for cytopathic effect. After 72 hours, Page 99 of 120 12756399v1 Attorney Docket No.: 2017408-0046 20 l of MTT was added to each well of the plates and incubated for 2 hours at 37C, 5% CO2. The supernatants were removed from each well, and the MTT precipitates solubilized by adding 50 l of a 1:1 mixture of DMSO and Isopropanol. Following 20 minutes of incubation, the supernatants were transferred to a clean 96 well plate and read at 560 nm on the Promega GloMax Explorer System plate reader. The sample values in each plate are normalized to the plate internal controls, where 100% inhibition is derived from the average of the untreated uninfected cells and 0% inhibition is derived from the average of the untreated infected cells. The percent inhibition of SARS-CoV-2 JN.1 infection was calculated using the following formula: the curves representing the best fit (non-linear regression analysis, variable slope) of the logarithm of antibody or antiviral dilutions versus the normalized percentages of inhibition. Example 13: Neutralization activity of a monoclonal antibody described herein, alone or in combination with Remdesivir against early isolate SARS-CoV-2 (England/02/2020). [0289] The aim of this study was to assess the antiviral activity against SARS-CoV-2 (early isolate, England/02/2020) of AB-1, when administered on its own or in combination with remdesivir. The combination was tested following two modes of administration: one where both AB-1 and remdesivir were titrated simultaneously, and one where only remdesivir was titrated while AB-1 was kept at a constant concentration (18 μg/ml). AB-1 and Remdesivir was also each tested alone. [0290] EC50 values are shown in Table 12. Using a CPE-based assay 72 h after infection, remdesivir and AB-1, when tested individually, inhibited SARS- CoV-2 England/02/2020 with an EC50 of 0.96 μg/ml (equal to 1.59 μM) and 0.59 g/ml, respectively. Inhibition of SARS-CoV-2 by both remdesivir and AB-1, when tested individually, did not reach 100% at the highest concentrations and plateaued at approx.80% and 73%, respectively (FIG.9). In contrast, when the two agents were tested in combination, approx.100% inhibition was observed at the highest concentrations (FIG.9). Page 100 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0291] When remdesivir and AB-1 were titrated simultaneously, the EC50, EC80, and EC90 for remdesivir (i.e., when plotting the % inhibition relative to the Remdesivir concentrations) were 0.37 μg/ml, 0.85 μg/ml, and 1.38 μg/ml, respectively. For AB-1, the EC50, EC80, and EC90 values (derived by plotting the % inhibition relative to the AB-1 concentrations) were 0.55 μg/ml, 1.26 μg/ml, and 2.05 μg/ml, respectively. [0292] EC50 values, were extrapolated from the curves representing the best fit (non- linear regression analysis, variable slope) of the logarithm of test articles dilutions vs. the normalized percentages of inhibition, using GraphPad Prism. Negative values were input as 0. For ease of comparison with the articles tested alone, when the compounds were titrated in combination the EC50/80/90 values were calculated by plotting both the log dilutions of remdesivir and of AB-1 in separate graphs. Table 12: EC50, EC80, and EC90 for each antibody tested. EC50 EC80 EC90 R md ivir M 1592 - - inhibition was observed across all the Remdesivir concentration, indicating that this concentration of AB-1 compensates for the decreasing Remdesivir. Page 101 of 120 12756399v1 Attorney Docket No.: 2017408-0046 [0294] Under the conditions tested, AB-1 inhibited SARS-CoV-2 England/02/2020 with an EC50 of 0.588 μg/ml, compared to 0.963 μg/ml for Remdesivir. Inhibition by AB-1 or Remdesivir, when tested individually, did not reach 100% at the highest concentrations and plateaued at approx.80% and 73%, respectively. Simultaneous titration of both articles increased Remdesivir (EC50.369 μg/mL) and AB-1 (0.550 μg/mL) potency and approx. 100% inhibition was observed at the highest concentrations of the combination. When Remdesivir was titrated in the presence of a constant neutralizing concentration of AB-1 (18 μg/ml), similar inhibition was observed across the full dilution series. [0295] Taken together these data demonstrate that the antiviral activity of remdesivir and AB-1 are increased when co-administered (i.e., Remdesivir + AB-1), and close to 100% inhibition is observed at the highest concentrations of the combination. Experimental Procedure [0296] The antiviral activity of twelve dilutions of AB-1, in the presence or absence of Remdesivir, was explored by pre-incubation with SARS-CoV-2 for 1 hour. This mixture was then added to the assay cells. Virus and test article titrations were left on the cells for 72 hours at 37 ºC, 5% CO2 for CPE development, detected with an MTT assay. Cell plating [0297] Cells were detached, counted, diluted in complete media and seeded at 8,000 cells/100 μl into two 96 well plates. After seeding, the plates were incubated in a humidified incubator at 37 °C, 5% CO2 until the following day. Test dilutions [0298] AB-1 was diluted to 36 μg/ml (twice the final concentration) in 1,150 μl of infection media, by adding 2 μl of the 20.4 mg/ml stock into 1,148 μl of infection media. [0299] Remdesivir was diluted to 40 μg/ml (twice the final concentration) in 450 μl of infection media by adding 1.8 μl of 10 mM stock into 448.2 μl of infection media. When diluted at the same time, 1.6 μl of AB-1 stock and 3.6 μl of Remdesivir stock were added into 894.8 μl of infection media. For all samples, a 3-fold dilution series was performed by transferring 37.5 μl into 75 μl of infection media across the dilution series. [0300] When remdesivir was diluted into a constant concentration of AB-1, first 5.2 μl of AB-1 stock were added to 2,994.8 μl of infection media, to make 3 ml of infection media Page 102 of 120 12756399v1 Attorney Docket No.: 2017408-0046 containing 36 μg/ml of AB-1 (AB-1 media). Then, 1.8 μl of remdesivir were added to 448.2 μl of the AB-1 media to make up a solution of 40 μM Remdesivir and 36μg/ml AB-1. Next, a 3-fold serial dilution of this mix was performed directly in the AB-1 media, by transferring 37.5 μl into 75 μl across the dilution series. Virus addition [0301] A predetermined MOI of 0.002 of SARS-CoV-2 (England/02/2020) in 75 μl was added to each well of the dilutions and in the infected untreated control wells, thereby halving the concentration of the antibodies. Infection media only (without virus) was added to the uninfected untreated control wells. Next, virus and antibodies were incubated for 1 hour at 37ºC, 5%CO2. Cell infection [0302] After 1 hour, media was removed from the cells and replaced with 150 μl of the virus + test dilution mixtures. Plates were incubated for 72 h in a humidified incubator at 37 ºC and 5% CO2. Plates were checked at 24 h, 48 h, and 72 h to monitor CPE. MTT assay [0303] 72 h later, CPE was complete and clear, and an MTT assay was performed to quantify the extent of the CPE. To this end, 20 μl of MTT reagent were added to all wells, before incubation in a humidified incubator at 37 °C, 5% CO2 for 2 h. Next, the supernatants were removed and the MTT precipitates solubilized by adding 50 μl of a 1:1 mix of DMSO and Isopropanol. After a further 20 minutes incubation, the supernatants were transferred to clean 96 well plates, and immediately acquired at 560 nm on a Promega GloMax Explorer System plate reader. Determination of EC50 values [0304] Normalized percentages of inhibition were calculated using the following formula: Page 103 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Example 14: Pharmacodynamic study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus. [0305] As further demonstration of extended live virus neutralization achieved by AB-1 against circulating strains of SARS-CoV-2, the binding affinity of AB-1 against SARS- CoV-2 Spike S2 was characterized using surface plasmon resonance (SPR) and Dissociation-Enhanced Lanthanide Fluorescent Immunoassay (DELFIA). [0306] The objective of this study was to assess binding properties of AB-1 to the SARS-CoV-2 spike S2 stem helix peptide (target epitope of the reference antibody). [0307] DELFIA and SPR were employed to assess binding of AB-1 and the reference molecule to biotinylated peptides as reported in Hurlburt et al. Commun Biol.2022; 5(1):342, the contents of which is incorporated by reference in its entirety. Specifically, SPR was used to measure AB-1 binding to partially overlapping peptides spanning the reference molecule target epitope (aa 1133 – 1162), a peptide representing the C-terminal end of the stem helix (aa 1149 – 1167), a control 15mer peptide derived from HIV-1 Env protein, and a peptide designed to encompass the SARS-CoV-2 spike S2 stem helix (aa 1143 – 1162).As shown in FIG.15, SPR data demonstrates that AB-1 and the reference molecule bind to the SARS-CoV-2 spike S2 stem helix peptide. Specificity was confirmed by lack of binding of AB-1 and the reference molecule to the HIV-1 Env peptide used as negative control. Similar results were obtained with DELFIA data which used an isotype control to demonstrate lack of binding to a negative control. Of note, the SPR data demonstrate that AB-1 fragment antigen-binding region (Fab) binds to the SARS-CoV-2 spike S2 peptide representative of the C-terminal end of the stem helix (aa 1149 – 1167) with higher affinity than the reference molecule Fab (KD values: AB-1 Fab, 0.9 nM; reference molecule Fab, 5.4 nM (Table 13). [0308] Kinetics of AB-1 and the reference molecule Fabs binding to SARS-CoV-2 spike S2 (aa 1149 – 1167) peptide (indicated as “S:” followed by amino acid positions) and HIV-1 Env negative control peptide were obtained by SPR at 25 C. Page 104 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Table 13: Kinetics of AB-1 and Reference Molecule Fabs Binding to SARS-CoV-2 Spike S2 [aa 1149 – 1167] Peptide by SPR. Ligand Analyte ka (M-1s-1) kd (s-1) KD (M) Rmax (RU) Chi2 (RU2) S: 1149-1167 AB-1 2.61E+06 2.41E-03 9.25E-10 51.7 4.82 g g equilibrium dissociation constant, Rmax is the maximum analyte binding capacity of the surface and Chi2 is a measure of the closeness of fit calculated as the average squared residual. Results are representative of one experiment without technical replicates. Example 15: Pharmacodynamic study of a novel half-life extended monoclonal antibody AB-1 Binding to SARS-CoV-2 spike trimers. [0310] As further demonstration of extended live virus neutralization achieved by AB-1 against circulating strains of SARS-CoV-2, the binding affinity of AB-1 against spike trimers representative of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses was characterized using SPR and DELFIA. [0311] The objective of this study was to demonstrate binding properties of AB-1 to spike trimers representative of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses. [0312] DELFIA and SPR were employed to assess binding of AB-1 and its reference molecule to a panel of spike trimers representative of: 1) SARS-CoV-2 pre-Omicron variants (D614G [ancestral strain with D614G polymorphism], Delta [B.1.617.2]); 2) major SARS-CoV-2 Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.3.20, BA.2.75, BA.2.75.2, BA.4, BA.5, BA.4.6, BF.7, BN.1, BQ.1, BQ.1.1, XBB, XBB.1, XBB.1.5); 3) non-SARS-CoV-2 sarbecoviruses (WIV1, SARS-CoV-1); 4) SARS-CoV-2 Omicron variants with polymorphisms in the AB-1 epitope (P1162S and P1162L). [0313] DELFIA data demonstrate that AB-1 binds to all the spike trimers tested in the experiment, showing overall lower EC50 values compared to the reference molecule (FIGS. 16A-16B). SPR data confirms that AB-1 Fab binds to SARS-CoV-2 D614G, Delta, BA.4, Page 105 of 120 12756399v1 Attorney Docket No.: 2017408-0046 BA.5, BQ.1.1, and XBB.1.5 spike trimers with comparable affinities and overall higher affinities than the reference molecule Fab (Table 14). AB-1 Fab binding affinities to SARS- CoV-2 Delta, BA.4, BA.5, BQ.1.1, XBB.1.5 spike trimers are within 2-fold of SARS-CoV-2 D614G spike trimer. These differences are considered within the range of variability of the method, demonstrating that AB-1 Fab has comparable binding affinities across the tested spike trimers. In addition, AB-1 Fab binds to these spike trimers with an approximate 5-fold higher affinity than the reference molecule Fab. Similarly, AB-1 Fab binding affinities to SARS-CoV-2 spike trimers of BA.2 variants containing polymorphisms in the AB-1 epitope (BA.2+P1162L and BA.2+P1162S) are within 2-fold of the BA.2 parent and AB-1 Fab binds to these spike trimers with an approximate 5-fold higher affinity than the reference molecule Fab. The specificity of these results is confirmed by lack of binding of the isotype control in the DELFIA experiment, and lack of binding of AB-1 and the reference molecule Fabs to the MERS spike trimers used as negative control in the SPR experiment. [0314] Affinity comparison of AB-1 and the reference molecule Fabs binding to a panel of SARS-CoV-2 spike trimers and MERS spike trimer (negative control) were obtained by globally fitting the kinetic parameters to a 1:1 binding model at 25°C and 37°C. The parameters displayed in Table 15 represent the equilibrium dissociation constant KD. Results are expressed as average standard deviation (SD) of one independent experiment with technical replicates. Table 14: Affinity Comparison of AB-1 and the Reference Molecule Fabs Binding to a Panel of SARS-CoV-2 Spike Trimers by SPR at 25 C and 37 C. KD (10-9 M), 25 °C KD (10-9 M), 37 °C SARS-CoV-2 spike trimer AB-1 Reference AB-1 Reference Page 106 of 120 12756399v1 Attorney Docket No.: 2017408-0046 KD (10-9 M), 25 °C KD (10-9 M), 37 °C SARS-CoV-2 spike trimer AB-1 Reference Reference molecule AB-1 molecule 76 0 2 [0 ve of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses, and with higher affinities than the reference molecule. Example 16: In-vivo (human) study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus. [0316] This Example demonstrates that an anti-S2 antibody (AB-1) achieves prophylactic efficacy against circulating viral variants of SARS-CoV-2 and related sarbecovirus. The present Example provides a randomized, single-blind, placebo-controlled, sequential group, single ascending dose study to evaluate the safety, tolerability and pharmacokinetics of AB-1 in healthy subjects. [0317] Eligible participants were screened and randomized to receive either AB-1 or placebo in each dosing cohort. Five cohorts were enrolled in this study. The first two single ascending dose (SAD) cohorts included 3 healthy volunteers (HV) participants receiving AB-1 and 3 healthy volunteers participants receiving placebo. The last three SAD cohorts planned for this study included 10 HV participants receiving AB-1 and 3 HV participants receiving placebo. An overview of the dosing study design is provided in Table 15. Table 15: Overview of Study Design Study Target Sample Size (n) Proposed Number of Study Objectives Phase Population Dose Subjects d 1 d Page 107 of 120 12756399v1 Attorney Docket No.: 2017408-0046 1200 mg 13 To assess the (10 active/3 pharmacokinetics of a placebo) single ascending dose of of le 1 Treatment-Emergent Adverse Events (TEAEs): [0318] Of the 51 subjects who received AB-1/placebo, 26 (51%) have experienced at least one treatment-emergent adverse events (TEAEs) (Table 16). TEAEs occurring in >2 subjects (n; %) were: alanine aminotransferase increased (5; 9.8%), blood creatine phosphokinase increased (4; 7.8%); headache (4; 7.8%), and upper respiratory tract infection (3; 5.9%). Page 108 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Table 16: Treatment-Emergent Adverse Events Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Total System Organ Class (N=6) (N=6) (N=13) (N=13) (N=13) (N=51) Preferred Term n(%) n(%) n(%) n(%) n(%) n(%) TEAE 4 (66.7%) 4 (66.7%) 5 (38.5%) 5 (38.5%) 8 (61.5%) 26 (51.0%) [0319] A total of 51 subjects have been exposed to blinded study drug (AB-1 or placebo) at the dose levels described in Table 16. A total of 36 subjects have received AB-1. [0320] Of the 51 subjects who received AB-1/placebo, 3 (5.9%) subjects experienced an adverse event assessed by the investigator to be related to AB-1/placebo. These were Page 109 of 120 12756399v1 Attorney Docket No.: 2017408-0046 (n; %): headache (2; 3.9%), infusion related reaction (1; 2%), nausea (1; 2%) and dizziness (1;2%). Grade 3 or Higher Treatment-Emergent Adverse Events: [0321] Of the 51 subjects who received AB-1/placebo, 4 (7.8%) subjects experienced a Grade 3 or higher TEAE, all of which were ‘blood creatine phosphokinase increased’. Grade 3 blood creatine phosphokinase increased was reported in two subjects: 1 in cohort 3 and 1 in cohort 5. Grade 4 blood creatine phosphokinase increased was reported in 2 subjects: 1 in cohort 1 and 1 in cohort 5. There were no Grade 3 or higher TEAEs assessed by the investigator to be related to AB-1/placebo. Serious Adverse Events: No serious adverse events have occurred in the study. Adverse Events Leading to Discontinuation of AB-1/placebo: [0322] Of the 51 subjects who received AB-1/placebo, one (2%) experienced a TEAE leading to discontinuation of AB-1/placebo, which was a Grade 2 infusion-related reaction. Infusion-Related Reactions: [0323] Infusion-related reactions (IRR) were identified based on clinical assessment by the investigator of the reported AE as an IRR. One subject in the 1200 mg cohort experienced a Grade 2 IRR. Symptoms included pruritus and bilateral periorbital edema. No gastrointestinal, respiratory or cardiovascular symptoms were reported. Treatment included systemic steroids, and the IRR fully resolved. [0324] The infusion duration for the remaining subjects in AB-1 was subsequently increased from 30 minutes to 45 minutes, and the remainder of subjects in the 1200 mg cohort and all subjects in the 2400 mg cohort completed dosing with no other infusion- related reactions reported. Dose-limiting Toxicities: [0325] AB-1, dose-limiting toxicities (DLT) were defined as any Grade 3 or greater adverse event or abnormal laboratory value assessed by the investigator to be related to study drug that occurred up through study Day 8. No DLT events were reported. [0326] No deaths occurred in this study. Page 110 of 120 12756399v1 Attorney Docket No.: 2017408-0046 Immunogenicity [0327] As of the data cutoff-date, all randomized subjects were included in the immunogenicity analysis. At baseline, 4 of the 36 (11.1%) subjects randomized to AB-1 and 1 of the 15 (6.7%) subjects randomized to placebo had anti-drug antibodies (ADA). [0328] Of the 36 subjects who received AB-1, three subjects (8.3%) were defined as post-baseline treatment-emergent ADA positive (subjects pre-dose ADA negative or below cut-off, and post-dose ADA positive above cut-off for 2 or more consecutive assessments). Two subjects (5.6%) were defined as post-baseline treatment-induced ADA positive (subjects pre-dose ADA positive, with pre-dose titer values above the cut-off, and a 4-fold or higher post-dose titer value for at least 1 post-dose assessment). There was no apparent increase in ADA positive status with increasing AB-1 dose. The AB-1 serum concentrations were not affected by ADA status (ADA negative versus ADA positive). Pharmacokinetics: Mechanism of Action and PD Properties [0329] FIG.17 shows the fold increase from baseline of live virus 50% mean neutralization titer (MN50) for the live virus for the respective Omicron variants in the study. The live virus neutralization shows a clear dose response over time and despite significant pre-dose titers in subjects (likely due to prior infections) we observed close to a 10-fold increase from baseline in post dose mean titers (e.g., Omicron XBB1.5) at a dose of 1200 mg and clear separation from placebo for both Omicron variants. Pharmacokinetic Properties [0330] The clinical pharmacokinetic data for AB-1 following IV infusion was characterized using a population pharmacokinetic model (FIG.3). AB-1 PK shows two compartmental behavior following IV infusion, with rapid distribution phase and long terminal elimination phase of approximately 55 days. The inter-subject variability in this phase I study was low, with a CV of approximately 20% in plasma clearance. The pharmacokinetics were linear and showed clear dose proportionality across a wide dose range from 100 mg to 2400 mg. [0331] The therapeutic dose for treatment was established as 1200 mg AB-1. The predicted Cmax at this dose was 368875 ng/mL. At this dose, AB-1 Cmax concentration can be compared to the omicron XBB1.5 EC50 of 8.8 ng/ml. This is 42,000-fold coverage in Page 111 of 120 12756399v1 Attorney Docket No.: 2017408-0046 plasma at Cmax. Assuming a 10% penetration in lung interstitial fluid, the likely effect site provides a target coverage of 4200-fold. A neutralizing index (shown below, based on (Stadler et al. Nat Commun.2023;14(1):4545, incorporated by reference in its entirety), associated with efficacy of a mAb of protection from patients with symptomatic covid progressing to hospitalization) was calculated based on the predicted plasma concentration over a course of 60 days at 1200 mg. Based on these calculations the neutralizing index was estimated to range from over 100 to above 30 over the course of the 60 days post-infusion and likely to provide maximal efficacy. Based on the Stadler et al.2023 publication a neutralizing index of 1 provides maximal protection. [0332] efficacy against currently circulating viral variants when administered. EQUIVALENTS [0333] It is to be appreciated by those skilled in the art that various alterations, modifications, and improvements to various aspects of innovations described herein will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of various aspects of innovations described herein and are intended to be within the spirit and scope of such aspects of innovation. Accordingly, the foregoing description and drawing are by way of example only and any various aspects of innovations described herein if further described in detail by the claims that follow. [0334] Those skilled in the art will appreciate typical standards of deviation or error attributable to values obtained in assays or other processes described herein. The publications, websites and other reference materials referenced herein to describe the background of various aspects of innovations described herein and to provide additional detail regarding its practice are hereby incorporated by reference in their entireties. Page 112 of 120 12756399v1

Claims

Attorney Docket No.: 2017408-0046 CLAIMS 1. A method of treating or preventing a sarbecovirus infection in a subject, comprising: (a) administering a first dose of about 100 mg to about 2400 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of the sarbecovirus about every 3 months to about every 12 months to the subject, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a HCDR1, a HCDR2 and a HCDR3 of an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a heavy chain variable region of SEQ ID NO: 10, and (ii) a LCDR1, a LCDR2 and a LCDR3 of an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a light chain variable region of SEQ ID NO: 20; and (b) administering a second dose of an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of the sarbecovirus about every 3 months to about every 12 months to the subject. 2. The method of claim 1, wherein the first dose is about 300 mg to about 900 mg. 3. The method of claim 2, wherein the first dose is about 600 mg or about 650 mg. 4. The method of any one of claims 1-3, wherein the second dose is about 100 mg to about 1400 mg. 5. The method of claim 4, wherein the second dose is about 300 mg to about 900 mg. 6. The method of claim 5, wherein the second dose is about 300 mg, about 600 mg, or about 650 mg. Page 113 of 120 12756399v1 Attorney Docket No.: 2017408-0046 7. The method of any one of claims 1-6, wherein the first dose is administered about every 6 months. 8. The method of any one of claims 1-7, wherein the second dose is administered about every 6 months. 9. The method of any one of claims 1-8, wherein one or both of the first dose and the second dose are administered parenterally. 10. The method of claim 9, wherein one or both of the first dose and the second dose are administered intravenously, subcutaneously, intramuscularly, or intraperitoneally. 11. The method of claim 10, wherein one or both of the first dose and the second dose are administered intravenously. 12. The method of claim 10, wherein one or both of the first dose and the second dose are administered intramuscularly. 13. The method of any one of claims 1-12, wherein the first dose is administered prior to, substantially simultaneously, or after the second dose. 14. The method of any one of claims 1-12, wherein the first dose and the second dose are co-formulated in a pharmaceutical composition. 15. The method of any one of claims 1-14, wherein the sarbecovirus is SARS-CoV- 1, SARS-CoV-2, or WIV1. 16. The method of any one of claims 1-15, wherein the SARS-CoV-2 is one or more SARS-CoV-2 variants. 17. The method of claim 16, wherein the one or more SARS-CoV-2 variants is one or more of: Delta, Omicron, BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, BA.2.75, BA.2.75.2, Page 114 of 120 12756399v1 Attorney Docket No.: 2017408-0046 BA.2.86, BA.4.6, BA.5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, D614G, EG.5.1, JN.1, JN.1.7, JN.1.13.1, JN.1.16, KP.1.1, KP.2, KP.3.1.1, KP.3.3, XBB.1.5, and XBB.1.16. 18. The method of any one of claims 1-17, wherein the S2 is a stem helix region. 19. The method of any one of claims 1-18, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 is one or more of: (i) a chimeric antibody, a human antibody, or a humanized antibody, or antigen- binding fragment thereof; (ii) a monospecific antibody or a bispecific antibody, or antigen-binding fragment thereof; and (iii) a monoclonal antibody, or antigen-binding fragment thereof. 20. The method of any one of claims 1-19, wherein the antigen-binding fragment thereof that binds specifically to S2 is or comprises an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody. 21. The method of any one of claims 1-20, wherein the antibody or antigen-binding fragment that binds specifically to S2 is or comprises an IgG1 isotype. 22. The method of any one of claims 1-21, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, and a HCDR3 of SEQ ID NO: 3, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 11, a LCDR2 of SEQ ID NO: 12, and a LCDR3 of SEQ ID NO: 13; (ii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 4, a HCDR2 of SEQ ID NO: 5, and a HCDR3 of SEQ ID NO: 6, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 14, a LCDR2 of SEQ ID NO: 15, and a LCDR3 of SEQ ID NO: 16; or (iii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 7, a HCDR2 of SEQ ID NO: 8, and a HCDR3 of SEQ ID NO: 9, and a light chain variable Page 115 of 120 12756399v1 Attorney Docket No.: 2017408-0046 region comprising a LCDR1 of SEQ ID NO: 17, a LCDR2 of SEQ ID NO: 18, and a LCDR3 of SEQ ID NO: 19. 23. The method of claim 22, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 10, and (ii) a light chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 20. 24. The method of claim 23, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 10, and (ii) a light chain variable region comprising an amino acid sequence of SEQ ID NO: 20. 25. The method of claim 24, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 21, and (ii) a light chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 22. 26. The method of claim 25, wherein the antibody or antigen-binding fragment thereof that binds specifically to S2 comprises: (i) a heavy chain comprising an amino acid sequence of SEQ ID NO: 21, and (ii) a light chain comprising an amino acid sequence of SEQ ID NO: 22. 27. The method of any one of claims 1-26, wherein the antibody that binds specifically to a Spike protein is bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, cilgavimab, pemivibart, rixagevimab, AZD7442 (tixagevimab-cilgavimab), Page 116 of 120 12756399v1 Attorney Docket No.: 2017408-0046 regdanvimab, sotrovimab, or an antigen-binding fragment thereof of any of the foregoing or a combination thereof. 28. The method of any one of claims 1-27, wherein the antibody or antigen-binding fragment thereof that binds specifically to a Spike protein binds specifically to receptor binding domain (RBD) of a sarbecovirus. 29. The method of claim 28, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD binds specifically to a class 4 region. 30. The method of claim 28 or 29, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD is one or more of: (i) a chimeric antibody, a human antibody, or a humanized antibody, or antigen- binding fragment thereof; (ii) a monospecific antibody or a bispecific antibody, or antigen-binding fragment thereof; and (iii) a monoclonal antibody, or antigen-binding fragment thereof. 31. The method of any one of claims 28-30, wherein the antigen-binding fragment thereof that binds specifically to RBD is or comprises an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody. 32. The method of any one of claims 28-31, wherein the antibody or antigen-binding fragment that binds specifically to RBD is or comprises an IgG1 isotype. 33. The method of any one of claims 28-32, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 34, a LCDR2 of SEQ ID NO: 35, and a LCDR3 of SEQ ID NO: 36; Page 117 of 120 12756399v1 Attorney Docket No.: 2017408-0046 (ii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 26, a HCDR2 of SEQ ID NO: 27, and a HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 37, a LCDR2 of SEQ ID NO: 38, and a LCDR3 of SEQ ID NO: 39; or (iii) a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 29, a HCDR2 of SEQ ID NO: 30, and a HCDR3 of SEQ ID NO: 31, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 40, a LCDR2 of SEQ ID NO: 41, and a LCDR3 of SEQ ID NO: 42. 34. The method of claim 33, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a light chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 32, and (ii) a heavy chain variable region comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO:43. 35. The method of claim 34, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a light chain variable region comprising an amino acid sequence of SEQ ID NO: 32, and (ii) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 43. 36. The method of claim 35, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: (i) a heavy chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 33, and (ii) a light chain comprising an amino acid sequence that is at least about 90% identical to SEQ ID NO: 44. 37. The method of claim 36, wherein the antibody or antigen-binding fragment thereof that binds specifically to RBD comprises: Page 118 of 120 12756399v1 Attorney Docket No.: 2017408-0046 (i) a heavy chain comprising an amino acid sequence that is SEQ ID NO: 33, and (ii) a light chain comprising an amino acid sequence that is at SEQ ID NO: 44. 38. The method of any one of claims 1-37, wherein the subject is not immune compromised. 39. The method of any one of claims 1-37, wherein the subject is immune compromised. 40. The method of any one of claims 1-39, wherein the subject has long COVID-19. Page 119 of 120 12756399v1
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Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
WO1990002809A1 (en) 1988-09-02 1990-03-22 Protein Engineering Corporation Generation and selection of recombinant varied binding proteins
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
WO1991017271A1 (en) 1990-05-01 1991-11-14 Affymax Technologies N.V. Recombinant library screening methods
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992009690A2 (en) 1990-12-03 1992-06-11 Genentech, Inc. Enrichment method for variant proteins with altered binding properties
WO1992015679A1 (en) 1991-03-01 1992-09-17 Protein Engineering Corporation Improved epitode displaying phage
WO1992018619A1 (en) 1991-04-10 1992-10-29 The Scripps Research Institute Heterodimeric receptor libraries using phagemids
WO1992020791A1 (en) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1993001288A1 (en) 1991-07-08 1993-01-21 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Phagemide for screening antibodies
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1998016664A1 (en) 1996-10-15 1998-04-23 Kennametal Inc. Cutting tool insert
WO1998024893A2 (en) 1996-12-03 1998-06-11 Abgenix, Inc. TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
US6180370B1 (en) 1988-12-28 2001-01-30 Protein Design Labs, Inc. Humanized immunoglobulins and methods of making the same
WO2023021591A1 (en) 2021-08-18 2023-02-23 国立大学法人東北大学 Endometrium model, method for producing endometrium model, and endometrial implantation model
WO2023215910A1 (en) * 2022-05-06 2023-11-09 Generate Biomedicines, Inc. Antigen binding molecules targeting sars-cov-2
WO2023222825A1 (en) * 2022-05-18 2023-11-23 Vib Vzw Sarbecovirus spike s2 subunit binders
WO2024102674A1 (en) * 2022-11-13 2024-05-16 Generate Biomedicines, Inc. Antigen binding molecules targeting sars-cov-2

Patent Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
WO1990002809A1 (en) 1988-09-02 1990-03-22 Protein Engineering Corporation Generation and selection of recombinant varied binding proteins
US6180370B1 (en) 1988-12-28 2001-01-30 Protein Design Labs, Inc. Humanized immunoglobulins and methods of making the same
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
WO1991017271A1 (en) 1990-05-01 1991-11-14 Affymax Technologies N.V. Recombinant library screening methods
WO1992020791A1 (en) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992009690A2 (en) 1990-12-03 1992-06-11 Genentech, Inc. Enrichment method for variant proteins with altered binding properties
WO1992015679A1 (en) 1991-03-01 1992-09-17 Protein Engineering Corporation Improved epitode displaying phage
WO1992018619A1 (en) 1991-04-10 1992-10-29 The Scripps Research Institute Heterodimeric receptor libraries using phagemids
WO1993001288A1 (en) 1991-07-08 1993-01-21 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Phagemide for screening antibodies
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1998016664A1 (en) 1996-10-15 1998-04-23 Kennametal Inc. Cutting tool insert
WO1998024893A2 (en) 1996-12-03 1998-06-11 Abgenix, Inc. TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
WO2023021591A1 (en) 2021-08-18 2023-02-23 国立大学法人東北大学 Endometrium model, method for producing endometrium model, and endometrial implantation model
WO2023215910A1 (en) * 2022-05-06 2023-11-09 Generate Biomedicines, Inc. Antigen binding molecules targeting sars-cov-2
US20230357367A1 (en) * 2022-05-06 2023-11-09 Generate Biomedicines, Inc. Antigen Binding Molecules Targeting SARS-CoV-2
WO2023222825A1 (en) * 2022-05-18 2023-11-23 Vib Vzw Sarbecovirus spike s2 subunit binders
WO2024102674A1 (en) * 2022-11-13 2024-05-16 Generate Biomedicines, Inc. Antigen binding molecules targeting sars-cov-2

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
"Centers for Disease Control and Prevention", 2022, US DEPARTMENT OF HEALTH AND HUMAN SERVICES, article "Long COVID or post-COVID conditions"
"Recombinant DNA Part D.'' Methods in Enzymology", vol. 153, 1987, ACADEMIC PRESS
ALKODAYMI ET AL.: "Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systemic review and meta-analysis", CLIN. MICROBIOL. INFECT., vol. 28, no. 5, 2022, pages 657 - 666
AUSUBEL ET AL.: "Current Protocols in Molecular Hiology", 1994, GREENE PUBLISHING ASSOCIATES AND JOHN WILEY & SONS
BADENRUBIN, N ENGL J MED., vol. 382, no. 19, 2020, pages 1851 - 52
BARBAS ET AL., PNAS, vol. 88, 1991, pages 7978 - 7982
BAUD ET AL., LANCET INFECT DIS., vol. 2, no. 7, 2020, pages 773
BOERNER ET AL., J. IMMUNOL, vol. 147, no. 1, 1991, pages 86 - 95
BOLDOGH ET AL.: "Medical Microbiology", 1996, UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON;, article "Persistent Viral Infection"
CHEN CNADEAU SYARED M ET AL.: "CoV-Spectrum: analysis of globally shared SARS-CoV-2 data to identify and characterize new variants", BIOINFORMATICS, vol. 38, no. 6, 2022, pages 1735 - 1737
CHEN ET AL.: "Global Prevalence of Post COVID- 19 Condition or Long COVID: A Meta-Analysis and Systematic Review", J. INFECT. DIS., vol. 226, no. 9, 2022, pages 1593 - 1607
CHOTHIA. C. ET AL., J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
CLACKSON, NATURE, vol. 352, 1991, pages 624 - 628
COLE ET AL.: "Monoclonal Antibodies and Cancer Therapy.", 1985, ALAN R. RISS
DU ET AL., INT J ENVIRON RES PUBLIC HEALTH., vol. 19, no. 23, 2022, pages 16010
GARRAD ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 1373 - 1377
GRAM ET AL., PNAS, vol. 89, 1992, pages 3576 - 3580
GRIFFTHS, EMBO J, vol. 12, 1993, pages 725 - 734
HAWKINS ET AL., J MOL BIOL, vol. 226, 1992, pages 889 - 896
HAY ET AL., HUM ANTIBODY HYBRIDOMAS, vol. 3, 1992, pages 81 - 85
HOOGENBOOM ET AL., NUC ACID RES, vol. 19, 1991, pages 4133 - 4137
HURLBURT ET AL., COMMUN BIOL., vol. 5, no. 1, 2022, pages 342
HURLBURT NICHOLAS K. ET AL: "Structural definition of a pan-sarbecovirus neutralizing epitope on the spike S2 subunit", vol. 5, no. 1, 11 April 2022 (2022-04-11), XP093080291, Retrieved from the Internet <URL:https://www.nature.com/articles/s42003-022-03262-7> DOI: 10.1038/s42003-022-03262-7 *
HUSE ET AL., SCIENCE, vol. 246, 1989, pages 1275 - 1281
JONES ET AL., NATURE, vol. 321, 1986, pages 22 - 525
MACCALLUM ET AL., J. MOL. BIOL., vol. 262, 1996, pages 732
ORLANDI ET AL., PROC. NATL. ACAD. SD. USA, vol. 86, 1989, pages 3833
PIEPENBRINK MICHAEL S. ET AL: "Potent universal beta-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody", PLOS PATHOGENS, vol. 18, no. 7, 21 July 2022 (2022-07-21), US, pages 1 - 25, XP093221919, ISSN: 1553-7374, DOI: 10.1371/journal.ppat.1010691 *
QUEEN ET AL., PROC. NAT. ACAD. SCL USA, vol. 86, 1989, pages 10029
RAI ET AL.: "Acute Infection of Viral Pathogens and Their Innate Immune Escape", FRONT. MICROBIOL., vol. 12, 2021, pages 672026
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 327
SAMBROOK ET AL.: "Molecular Cloning. a Laboratory Manual", 1989, COLD SPRING HARBOR PRESS
SONG ET AL., CLIN CHIM ACTA., vol. 509, 2020, pages 280 - 7
STADLER ET AL., NAT COMMUN., vol. 14, no. 1, 2023, pages 4545
STADLER ET AL.: "Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis", THE LANCET. MICROBE, vol. 4, 2023, pages 11
TAN CHEE WAH ET AL: "Broad-spectrum pan-genus and pan-family virus vaccines", CELL HOST & MICROBE, ELSEVIER, NL, vol. 31, no. 6, 14 June 2023 (2023-06-14), pages 902 - 916, XP087338783, ISSN: 1931-3128, [retrieved on 20230614], DOI: 10.1016/J.CHOM.2023.05.017 *
VERHOEYEN ET AL., SCIENCE, vol. 239, 1988, pages 1534 - 1536

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