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

Abstract

Methods are provided herein that can be used to treat or prevent sarbecovirus infection using an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein of sarbecovirus.

Description

Attorney Docket No.: 2017408-0045 METHODS OF TREATING OR PREVENTING SARBECOVIRUS WITH ANTIBODIES OR ANTIGEN-BINDING FRAGMENTS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US Provisional Application No.63 / 643293, filed May 06, 2024, US Provisional Application No.63 / 705484, filed October 9, 2024, and US Provisional Application No.63 / 725372, 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 75 12756300v1Attorney Docket No.: 2017408-0045 SUMMARY

[0005] In one aspect, the disclosure provides a method of treating or preventing a sarbecovirus infection in a subject, comprising: administering a dose of about 100 mg to about 2400 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of a 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 the 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 dose is about 600 mg to about 1800 mg. In some embodiments, a dose is about 1200 mg, about 1300 mg, or about 1400 mg. In some embodiments, a dose is administered about every 6 months.

[0007] In some embodiments, a subject is a human.

[0008] In some embodiments, a dose is administered parenterally. In some embodiments, a dose is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally. In some embodiments, a dose is administered intravenously. In some embodiments, doses are administered intramuscularly.

[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, 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. In some embodiments, an antibody or antigen- binding fragment thereof that binds specifically to an S2 binds specifically to a stem helix region.

[0010] In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to an 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 Page 2 of 75 12756300v1Attorney Docket No.: 2017408-0045 antigen-binding fragment thereof. In some embodiments, an antigen-binding fragment thereof that binds specifically to an S2 is 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 an S2 is an IgG1 isotype.

[0011] In some embodiments, an antibody or antigen-binding fragment that binds specifically to an 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 an 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 an 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. In some embodiments, an antibody or antigen-binding fragment thereof that binds specifically to an 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 an 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. Page 3 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0012] 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

[0013] The Figures described below, which together make up the Drawing, are for illustration purposes only, not for limitation.

[0014] 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 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.

[0015] FIG.2 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.

[0016] FIG.3 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.

[0017] FIG.4 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.

[0018] FIG.5 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 Figure 5.

[0019] FIG.6 is a series graphs showing percent neutralization of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses. Results are representative of at least 12 Page 4 of 75 12756300v1Attorney Docket No.: 2017408-0045 technical replicates across at least 3 biological replicates and shown as mean ± SD. Neutralization curves were fitted with a 4-parameter logistic regression.

[0020] FIG.7 is a schematic depicting relative frequency of mutations of interest (AB-1 epitope region) in prevalent sarbecovirus lineages.

[0021] FIG.8 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.

[0022] FIGS.9A-9B 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. 9A depicts AB-1 and reference molecule binding to major SARS-CoV-2 variants (SARS- CoV-2). FIG.9B 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.9A and FIG.9B left graph, SARS-CoV-2 BA.2 [parent] for FIG.9B right graph. The lowest depicted 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.

[0023] FIG.10 is a series of graphs showing fold changes in live virus 50% mean neutralization titer (e.g., 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. Page 5 of 75 12756300v1Attorney Docket No.: 2017408-0045 DEFINITIONS

[0024] 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.

[0025] 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.

[0026] 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).

[0027] 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 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).

[0028] 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 Page 6 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0029] 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. 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 Page 7 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0030] 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, 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.).

[0031] 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.

[0032] 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. Page 8 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0033] 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.

[0034] 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 Page 9 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0035] 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).

[0036] 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 Page 10 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0037] 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.4thedition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 46, the contents of which is incorporated by 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.

[0038] 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.

[0039] 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 Page 11 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0040] 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 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).

[0041] 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 Page 12 of 75 12756300v1Attorney Docket No.: 2017408-0045 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%, 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.

[0042] 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. Page 13 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0043] 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.

[0044] 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 complete when onset of a sarbecovirus infection has been delayed for a predefined period of time.

[0045] 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.

[0046] 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.

[0047] 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 Page 14 of 75 12756300v1Attorney Docket No.: 2017408-0045 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 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).

[0048] 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).

[0049] 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.

[0050] 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 Page 15 of 75 12756300v1Attorney Docket No.: 2017408-0045 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 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.

[0051] 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 Page 16 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0052] Provided herein are methods of treating or preventing a sarbecovirus infection (e.g., SARS-CoV-2 or a variant thereof) in a subject with an antibody or antigen-binding fragment thereof that binds specifically to a Spike protein (e.g., to the S2 subunit of a Spike protein) of sarbecovirus (e.g., SARS-CoV-2). SARS-CoV-2

[0053] 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 subunits. S1 contains a receptor-binding domain (RBD) that binds ACE2 receptors, and S2 mediates fusion of viral and host membranes.

[0054] A non-limiting example of a wildtype Spike protein sequence of SARS-CoV-2 is NCBI RefSeq YP_009724390:

[0055] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHS TQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGT TLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSAN NCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFS ALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLK YNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCP FGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFT NVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGN YNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGY QPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLP Page 17 of 75 12756300v1Attorney Docket No.: 2017408-0045 FQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTE VPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQT QTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTS VDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKT PPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLI CAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRF NGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTL VKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRAS ANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFT TAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIV NNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVA KNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGC CSCGSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO: 45).

[0056] 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- CoV-2 Spike proteins, and modified forms (e.g., post-translationally modified forms) of full- length and truncated SARS-CoV-2 Spike proteins.

[0057] 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.

[0058] 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. Page 18 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0059] 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.

[0060] 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 Page 19 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0061] 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.

[0062] 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 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.

[0063] 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.

[0064] 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.

[0065] 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, Page 20 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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, Page 21 of 75 12756300v1Attorney Docket No.: 2017408-0045 S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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- Page 22 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0077] 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 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

[0078] Provided herein, among other things, are antibodies or antigen-binding fragments thereof that bind specifically to a Spike protein of sarbecovirus. In some embodiments, an antibody or antigen-binding fragment thereof described herein binds specifically to S2 of sarbecovirus (e.g., SARS-CoV-1, SARS-CoV-2, or WIV).

[0079] 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.

[0080] 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 23 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0081] 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.

[0082] 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).

[0083] 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 any subclass (e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. An antibody or antigen- Page 24 of 75 12756300v1Attorney Docket No.: 2017408-0045 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).

[0084] 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).

[0085] 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 relevant antigen into an animal, optionally including co-administration of one or more adjuvants. Page 25 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0086] 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 Fd 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).

[0087] 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).

[0088] 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 Page 26 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0089] 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.

[0090] 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: 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 Page 27 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0091] 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 NOPage 28 of 75 12756300v1Attorney Docket No.: 2017408-0045 VH - Amino acid sequence SEQ ID NO: 10 EVQLVESGAEVKKPGESLKISCKGSGYTFTRYWIGWVRQMPGKPage 29 of 75 12756300v1Attorney Docket No.: 2017408-0045 VL - Amino acid sequence SEQ ID NO: 20 EIVLTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAP

[0092] 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.

[0093] 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. Page 30 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0094] 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 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.

[0095] 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. Sci. USA 86:10029 (1989); U.S. Patent 6,180,370; and Orlandi et al., Proc. Natl. Acad. Sci. 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 Page 31 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0096] 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. Nucleic acids

[0097] Provided herein, among other things, are nucleic acids encoding antibodies or antigen-binding fragments thereof described herein. 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.

[0098] 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) Page 32 of 75 12756300v1Attorney Docket No.: 2017408-0045 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 expression in a mammalian cell (e.g., a CHO cell). Such a sequence may be described as a codon-optimized sequence.

[0099] 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)).

[0100] 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.

[0101] 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. Page 33 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0102] 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.

[0103] 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.

[0104] 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).

[0105] 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. Page 34 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0106] 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 synthetic techniques and in vivo recombination (see, e.g., Ausubel, supra or Sambrook, supra). Methods of use

[0107] 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.

[0108] 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.

[0109] 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 Page 35 of 75 12756300v1Attorney Docket No.: 2017408-0045 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 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.

[0110] 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 Page 36 of 75 12756300v1Attorney Docket No.: 2017408-0045 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. Microbiol. Infect.28(5):657-666 (2022), each of which his hereby incorporated by reference in its entirety).

[0111] 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.

[0112] 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.

[0113] 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 human. In some embodiments, a subject is a primate. In some embodiments, a subject is a human.

[0114] 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.

[0115] In some embodiments, a subject has diabetes. Page 37 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0116] 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).

[0117] In some embodiments, a subject is a tobacco smoker.

[0118] 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.

[0119] 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.

[0120] 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 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 Page 38 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0121] 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.

[0122] 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 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.

[0123] 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 Page 39 of 75 12756300v1Attorney Docket No.: 2017408-0045 herein achieves a neutralizing index against SARS-CoV-2 of at least about 30 to greater than 100 against omicron variants of interest. Dosing

[0124] The methods described herein include administering at least one dose of an antibody or antigen-binding fragment thereof described herein. In some embodiments, an antibody or antigen-binding fragment thereof binds specifically to S2 of sarbecovirus.

[0125] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is from about 25 mg to about 2400 mg, 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, about 500 mg to about 800 mg, about 600 mg to about 2400 mg, about 600 mg to about 1800 mg, about 600 mg to about 1600 mg, about 600 mg to about 1400 mg, or about 600mg to about 1200 mg.

[0126] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 25 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 50 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 75 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 100 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 125 mg. In some embodiments, a dose of an antibody or antigen-binding fragment Page 40 of 75 12756300v1Attorney Docket No.: 2017408-0045 thereof that binds specifically to S2 of sarbecovirus is about 150 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 175 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 200 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 225 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 250 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 275 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 300 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 325 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 350 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 375 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 400 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 425 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 450 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 475 mg.

[0127] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 500 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 525 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 550 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 575 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 600 mg. In some embodiments, a dose of an antibody or antigen-binding fragment Page 41 of 75 12756300v1Attorney Docket No.: 2017408-0045 thereof that binds specifically to S2 of sarbecovirus is about 620 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 650 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 675 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 700 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 725 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 750 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 775 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 800 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 825 mg.

[0128] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 850 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 875 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 900 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 925 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 950 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 975 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1000 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1025 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1050 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1075 mg. In some embodiments, a dose of an antibody or antigen-binding fragment Page 42 of 75 12756300v1Attorney Docket No.: 2017408-0045 thereof that binds specifically to S2 of sarbecovirus is about 1100 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1125 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1150 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1175 mg.

[0129] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1200 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1225 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1250 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1275 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1300 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1325 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1350 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1375 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1400 mg.

[0130] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1425 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1450 mg. In some embodiments, a dose of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1475 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1500 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1525 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1550 mg. In some Page 43 of 75 12756300v1Attorney Docket No.: 2017408-0045 embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1575 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1600 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1625 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1650 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1675 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1700 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1725 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1750 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1775 mg. In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1800 mg.

[0131] An antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is typically administered on multiple occasions. Intervals between single doses 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.

[0132] In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 3 months to about every 12 months. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 3 months. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 4 months. In some Page 44 of 75 12756300v1Attorney Docket No.: 2017408-0045 embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 6 months. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 9 months. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 12 months.

[0133] In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus described herein is about every 12 weeks to about every 52 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 12 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 13 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 14 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 15 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 16 weeks. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 17 weeks. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 18 weeks. In some embodiments, administration of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 19 weeks. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 20 weeks.

[0134] In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 21 weeks. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 22 weeks. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 23 weeks. In some embodiments, administration of an Page 45 of 75 12756300v1Attorney Docket No.: 2017408-0045 antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 24 weeks. In some embodiments, administration of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 25 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 26 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 27 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 28 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 29 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 30 weeks.

[0135] In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 31 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 32 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 33 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 34 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 35 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 36 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 37 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 38 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 39 weeks. In some embodiments, Page 46 of 75 12756300v1Attorney Docket No.: 2017408-0045 administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 40 weeks.

[0136] In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 41 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 42 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 43 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 44 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 45 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 46 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 47 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 48 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 49 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 50 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 51 weeks. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about every 52 weeks.

[0137] In some embodiments, administration of a dose described herein is about 4 times to about 1 time annually. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 4 times annually. In some embodiments, administration of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 3 times annually. In Page 47 of 75 12756300v1Attorney Docket No.: 2017408-0045 some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about quarterly in a year. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 2 times annually. In some embodiments, administration of a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is about 1 time annually.

[0138] Any dose described herein can be administered at any frequency described herein. Non-limiting examples of doses and frequencies include: a dose of about 1000 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), a dose of about 1200 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), a dose of about 1250 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), a dose of about 1300 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), a dose of about 1350 mg of an antibody or antigen- binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), a dose of about 1400 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), a dose of about 1450 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months), or a dose of about 1500 mg of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus is administered about every 3 months to about every 12 months (e.g., about every 6 months).

[0139] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 25 mg to about 2400 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds Page 48 of 75 12756300v1Attorney Docket No.: 2017408-0045 specifically to S2 of sarbecovirus from about 25 mg to about 1800mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 25 mg to about 900mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 25 mg to about 300mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 25 mg to about 200mg is administered about every 3 months to about every 12 months (e.g., about every 6 months).

[0140] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 50 mg to about 2400 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 50 mg to about 1800 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 50 mg to about 1200 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 50 mg to about 1000 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 50 mg to about 800 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 50 mg to about 600 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds Page 49 of 75 12756300v1Attorney Docket No.: 2017408-0045 specifically to S2 of sarbecovirus from about 50 mg to about 600 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months).

[0141] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 100 mg to about 2400 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 100 mg to about 1500 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 100 mg to about 1200 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 100 mg to about 900 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months).

[0142] In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 300 mg to about 2400 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 300 mg to about 1800 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 300 mg to about 1200 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 300 mg to about 1000 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 300 mg to about 700 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 500 mg to about 2400 mg is administered Page 50 of 75 12756300v1Attorney Docket No.: 2017408-0045 about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 500 mg to about 1200 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 500 mg to about 1000 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 600 mg to about 2400 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 600 mg to about 1200 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months). In some embodiments, a dose of an antibody or antigen-binding fragment thereof that binds specifically to S2 of sarbecovirus from about 600 mg to about 1000 mg is administered about every 3 months to about every 12 months (e.g., about every 6 months).

[0143] 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

[0144] 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.

[0145] 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. Page 51 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0146] 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.

[0147] 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.

[0148] 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 embodiment, provided herein are articles of manufacture comprising contents of kits described herein. INCORPORATION BY REFERENCE

[0149] 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 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 Page 52 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0150] 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

[0151] The following examples are provided to describe to the skilled artisan how to make and use methods and compositions described herein and is 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.

[0152] 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 2). Table 2: AB-1 EC50 against SARS-CoV2 variants and other sarbecovirus in a pseudoneutralization assay. SARS-CoV-2 variantsandPage 53 of 75 12756300v1Attorney Docket No.: 2017408-0045 SARS-CoV-2 D614G 18.8

[0153] Ina s nge-ascendng dose s udy, ea y voun eers aged 8–55 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.

[0154] 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 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 show low variability and 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 2). Additional pharmacokinetic studies further confirmed low variability and dose- Page 54 of 75 12756300v1Attorney Docket No.: 2017408-0045 proportionality up to 2400 mg with a half-life of approximately 55 days (FIG.2). 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).

[0155] 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: Pharmacodynamic study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.

[0156] 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.3, 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. 3). 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.4). As shown in FIG.1 and FIG. 4, AB-1 achieved a half-life of approximately 55 days. Example 3: Neutralizing capacity of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus. Page 55 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0157] 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.5) 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.5, 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 4: Neutralizing capacity of a novel half-life extended monoclonal antibody against SARS-CoV-2 and related sarbecovirus.

[0158] This Example demonstrates the percent neutralization of various sarbecovriuses (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.6, 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.6). AB-1 achieved 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.6). AB-1 achieved percent neutralization of Page 56 of 75 12756300v1Attorney Docket No.: 2017408-0045 SARS-CoV-2 D614G, SARS-CoV-2 Delta, and SARS-CoV-2 BA.4 / 5 that was similar to Bebtelovimab (FIG.6). Table 3 depicts the EC50 (95% CI) value (ng / mL) of AB-1 calculated for each Sarbecovirus tested. Table 3. 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

[0159] Table 3 depicts EC50 values (μg / mL), shown as mean (95% confidence interval) and representative of three to six independent experiments, four technical replicates each.

[0160] As shown in FIG.6, 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.6). Materials:

[0161] 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 (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 # Page 57 of 75 12756300v1Attorney Docket No.: 2017408-0045 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).

[0162] 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).

[0163] 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).

[0164] 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).

[0165] 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).

[0166] 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:

[0167] 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 Page 58 of 75 12756300v1Attorney Docket No.: 2017408-0045 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 5: A novel half-life extended monoclonal antibody against SARS-CoV-2 and related sarbecovirus.

[0168] This Example demonstrates that all binding residues in the S2 stem helix epitope that AB-1 binds are > 99% conserved.

[0169] 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. Table 4. Summary of polymorphisms identified in the S2 stem helix region. Polymorphism Relative Relative Relative Most prevalentPage 59 of 75 12756300v1Attorney Docket No.: 2017408-0045 P1162L 0.002 0.0035 0.0017 BA.5.8, BA.2, AY.4, B.1.1.7 1stem helix region in the most prevalent SARS-CoV-2 lineages was assessed. Methods:

[0171] The covSPECTRUM API (Application Programming Interface) was used to query the GenBank database for mutations occurring in the epitope region (Chen 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.

[0172] 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 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.

[0173] 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.

[0174] To identify the most prevalent strains amongst sequences harboring each mutation of interest, covSPECTRUM was queried for the set of sequences with each Page 60 of 75 12756300v1Attorney Docket No.: 2017408-0045 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.

[0175] 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.

[0176] Software for analysis: Custom python scripts used to retrieve data and complete the analysis are stored in a versioned repository at GitLab.

[0177] Four polymorphisms were identified in the S2 stem-helix peptide: G1167V, V1176F, P1162L, P1162S (FIG.7). AB-1 makes contacts with P1162. In some 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.7). In some embodiments, none of these polymorphisms have been detected at high relative frequencies in highly prevalent SARS- CoV-2 variants. Page 61 of 75 12756300v1Attorney Docket No.: 2017408-0045 Example 6: Pharmacodynamic study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.

[0178] 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).

[0179] 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).

[0180] 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) (FIG.8).

[0181] As shown in FIG.8, 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 5).

[0182] 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-1Env negative control peptide were obtained by SPR at 25 C.Page 62 of 75 12756300v1Attorney Docket No.: 2017408-0045 Table 5: 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 gequilibrium 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 7: Pharmacodynamic study of a novel half-life extended monoclonal antibody AB-1 Binding to SARS-CoV-2 spike trimers.

[0184] 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.

[0185] 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.

[0186] 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).

[0187] 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. 9A-9B). SPR data confirm that AB-1 Fab binds to SARS-CoV-2 D614G, Delta, BA.4, BA.5, BQ.1.1, XBB.1.5 spike trimers with comparable affinities and overall higher affinities Page 63 of 75 12756300v1Attorney Docket No.: 2017408-0045 than the reference molecule Fab (Table 6). AB-1 Fab binding affinities to SARS-CoV-2 Delta, BA.4, BA.5, BQ.1.1, and 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.

[0188] 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 6 represent the equilibrium dissociation constant KD. Results are expressed as average standard deviation (SD) of one independent experiment with technical replicates. Table 6: 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 (10-9M), 25 °C KD (10-9M), 37 °C SARS-CoV-2 spike trimer AB-1ReferenceAB-1ReferenceKD(10-9M), 25 °C KD(10-9M), 37 °C 2Page 64 of 75 12756300v1Attorney Docket No.: 2017408-0045

[0189] In conclusion, AB-1 consistently binds to multiple spike trimers representative of SARS-CoV-2 variants and non-SARS-CoV-2 sarbecoviruses, and with higher affinities than the reference molecule. Example 8: First-in-human study of a novel half-life extended monoclonal antibody against SARS-CoV2 and related sarbecovirus.

[0190] This Example demonstrates that an anti-S2 antibodyprophylactic 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.

[0191] 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 7. Table 7: Overview of Study Design Study Target Sample Size (n) Proposed Number of Study Objectives Phase Population Dose Subjects d 1 d fPage 65 of 75 12756300v1Attorney Docket No.: 2017408-0045 2400 mg 13 AB-1 administered (10 active / 3 intravenously placebo) T th of le 1t

[0192] Of the 51 subjects who received AB-1 / placebo, 26 (51%) have experienced at least one treatment-emergent adverse events (TEAEs) (Table 8). 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 66 of 75 12756300v1Attorney Docket No.: 2017408-0045 Table 8: 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%)Treatment-Related Adverse Events (TRAEs):

[0193] A total of 51 subjects have been exposed to blinded study drug (AB-1 or placebo) at the dose levels described in Table 8. A total of 36 subjects have received AB-1.

[0194] 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 67 of 75 12756300v1Attorney Docket No.: 2017408-0045 (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:

[0195] 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:

[0196] 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:

[0197] 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.

[0198] 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:

[0199] 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.

[0200] No deaths occurred in this study. Page 68 of 75 12756300v1Attorney Docket No.: 2017408-0045 Immunogenicity

[0201] 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).

[0202] 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 increases 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

[0203]

[0202] FIG.10 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.

[0204] These preliminary data support that AB-1 will provide prophylactic efficacy against currently circulating viral variants when administered. Pharmacokinetic Properties

[0205] The clinical pharmacokinetic data for AB-1 following IV infusion was characterized using a population pharmacokinetic model (FIG.2). 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.

[0206] 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 Page 69 of 75 12756300v1Attorney Docket No.: 2017408-0045 be compared to the omicron XBB1.5 EC50 of 8.8 ng / ml. This is 42,000-fold coverage in 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.

[0207] efficacy against currently circulating viral variants when administered. EQUIVALENTS

[0208] 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.

[0209] 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 70 of 75 12756300v1

Claims

Attorney Docket No.:2017408-0045 CLAIMS 1. A method of treating or preventing a sarbecovirus infection in a subject, comprising: administering a 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 the 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.

2. The method of claim 1, wherein the dose is about 600 mg to about 1800 mg.

3. The method of claim 2, wherein the dose is about 1200 mg, about 1300 mg, or about 1400 mg.

4. The method of any one of claims 1-3, wherein the dose is administered about every 6 months.

5. The method of any one of claims 1-4, wherein the subject is a human.

6. The method of any one of claims 1-5, wherein the dose is administered parenterally.

7. The method of claim 6, wherein the dose is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally.

8. The method of claim 7, wherein the dose is administered intravenously. Page 71 of 75 12756300v1Attorney Docket No.:2017408-0045 9. The method of claim 7, wherein the dose is administered intramuscularly.

10. The method of any one of claims 1-9, wherein the sarbecovirus is SARS-CoV-1, SARS-CoV-2, or WIV1.

11. The method of claim 10, wherein the SARS-CoV-2 is one or more SARS-CoV-2 variants.

12. The method of claim 11, 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, 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.

13. The method of any one of claims 1-12, wherein the antibody or antigen-binding fragment thereof that binds specifically to the S2 binds specifically to a stem helix region.

14. The method of any one of claims 1-13, wherein the antibody or antigen-binding fragment thereof that binds specifically to the 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.

15. The method of any one of claims 1-14, wherein the antigen-binding fragment thereof that binds specifically to the S2 is an scFv, Fab, Fab', F(ab')2, Fc, nanobody, or camelid antibody.

16. The method of any one of claims 1-15, wherein the antibody or antigen-binding fragment that binds specifically to the S2 is an IgG1 isotype. Page 72 of 75 12756300v1Attorney Docket No.:2017408-0045 17. The method of any one of claims 1-16, wherein the antibody or antigen-binding fragment that binds specifically to the 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.

18. The method of claim 17, wherein the antibody or antigen-binding fragment thereof that binds specifically to the 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.

19. The method of claim 18, wherein the antibody or antigen-binding fragment thereof that binds specifically to the 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.

20. The method of claim 19, wherein the antibody or antigen-binding fragment thereof that binds specifically to the S2 comprises: Page 73 of 75 12756300v1Attorney Docket No.:2017408-0045 (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.

21. The method of claim 20, wherein the antibody or antigen-binding fragment thereof that binds specifically to the 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.

22. The method of any one of claims 1-21, wherein the subject is not immune compromised.

23. The method of any one of claims 1-21, wherein the subject is immune compromised.

24. The method of any one of claims 1-23, wherein the subject has long COVID-19. Page 74 of 75 12756300v1

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