Antigen binding molecules targeting sars-cov-2

Abstract

The disclosure provides, in various embodiments, polypeptides (e.g, antibodies and antigen binding fragments thereof) that specifically bind to receptor binding domains (RBDs) of betacoronavirus Spike glycoproteins, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoproteins. The disclosure also provides, in various embodiments, fusion proteins comprising one or more of polypeptides, polynucleotides encoding polypeptides, vectors and host cells suitable for expressing polypeptides, and methods for treating viral infections (e.g., COVID-19).

Description

5708.1076005 ANTIGEN BINDING MOLECULES TARGETING SARS-COV-2 RELATED APPLICATION(S)

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 424,947, filed on November 13, 2022, U.S. Provisional Application No.63 / 383,699, filed on November 14, 2022, U.S. Provisional Application No.63 / 480,919, filed on January 20, 2023, U.S. Provisional Application No.63 / 492,211, filed on March 24, 2023, and U.S. Provisional Application No 63 / 520,549, filed on August 18, 2023. The entire teachings of the above applications are incorporated herein by reference. INCORPORATION BY REFERENCE OF MATERIAL IN XML

[0002] This application incorporates by reference the Sequence Listing contained in the following eXtensible Markup Language (XML) file being submitted concurrently herewith: a) File name: 5708_1076-005_SL.xml; created November 1, 2023, 584,835 Bytes in size. BACKGROUND

[0003] 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 3.6% (95% CI 3.5-3.7) (Baud et al. Real estimates of mortality following COVID-19 infection, 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.).

[0004] 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, Covid-19 - The Search for Effective Therapy, N Engl J Med.382(19):1851-52 (2020)).

[0005] 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. Accordingly, a need exists for additional therapeutics that can be rapidly deployed, - 1 - 3839034.v15708.1076005 preferably therapeutics that counter escape mutants and retain therapeutic efficacy, e.g., through broadly neutralizing activity. SUMMARY

[0006] There is a critical need to develop specific antiviral therapeutic agents for preventing transmission of COVID-19 as well as treating COVID-19 patients, preferably where such therapeutic agents retain activity against new and emerging variants, with broadly neutralizing activity. The disclosure provides such therapeutics.

[0007] The disclosure provided herein is based, in part, on the discovery that polypeptides disclosed herein specifically bind to the spike receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2-Spike). Accordingly, the disclosure generally relates to compositions (e.g., polypeptides, pharmaceutical compositions) and methods that are useful for reducing Spike (e.g., SARS-CoV-2-Spike) mediated viral entry into a cell.

[0008] Provided herein, among other things, are polypeptides (e.g., antibodies and antigen binding fragments thereof) that specifically bind an RBD of a betacoronavirus Spike glycoprotein (e.g., an RBD of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein). In some embodiments, the polypeptides have one or more properties selected from: a broadly neutralizing activity against a plurality of known and predicted betacoronaviruses (e.g., past, present, emergent, and future betacoronaviruses), and a binding affinity for an RBD epitope (e.g., RBD class 4 epitope) that is highly conserved across a plurality of betacoronaviruses. In some embodiments, a polypeptide has a broadly neutralizing activity against a plurality of known and predicted betacoronaviruses, and a binding affinity for an RBD domain epitope (e.g., RBD class 4 epitope) that is highly conserved across a plurality of betacoronaviruses.

[0009] The disclosure provides, among other things, polypeptides that specifically bind SARS-CoV-2-Spike, wherein the polypeptide comprises a paratope that is substantially similar to a paratope of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); - 2 - 3839034.v15708.1076005 SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); or any combination of the foregoing.

[0010] The disclosure provides, among other things, polypeptides that specifically bind SARS-CoV-2-Spike, wherein the polypeptide comprises a paratope that is substantially similar to a paratope of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); SEQ ID NO:89 and SEQ ID NO:91 (AB-4a); SEQ ID NO:90 and SEQ ID NO:92 (AB-7a); or any combination of the foregoing.

[0011] The disclosure also provides, among other things, a polypeptide that specifically binds SARS-CoV-2-Spike, wherein the polypeptide comprises: an immunoglobulin heavy chain variable domain (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar to an HCDR1, an HCDR2 and an HCDR3, respectively, of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; and an immunoglobulin light chain variable domain (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity - 3 - 3839034.v15708.1076005 determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar to an LCDR1, an LCDR2 and an LCDR3, respectively, of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19 or SEQ ID NO:20.

[0012] The disclosure also provides, among other things, a polypeptide that specifically binds SARS-CoV-2-Spike, wherein the polypeptide comprises: an immunoglobulin heavy chain variable domain (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar to an HCDR1, an HCDR2 and an HCDR3, respectively, of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89 or SEQ ID NO:90; and an immunoglobulin light chain variable domain (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar to an LCDR1, an LCDR2 and an LCDR3, respectively, of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91 or SEQ ID NO:92.

[0013] In some embodiments, a polypeptide disclosed herein comprises an HCDR1, HCDR2 and HCDR3, and an LCDR1, LCDR2 and LCDR3, of an antibody comprising an amino acid sequence selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); or - 4 - 3839034.v15708.1076005 SEQ ID NO:6 and SEQ ID NO:20 (AB-3d).

[0014] In some embodiments, a polypeptide disclosed herein comprises an HCDR1, HCDR2 and HCDR3, and an LCDR1, LCDR2 and LCDR3, of an antibody comprising an amino acid sequence selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); SEQ ID NO:89 and SEQ ID NO:91 (AB-4a); or SEQ ID NO:90 and SEQ ID NO:92 (AB-7a).

[0015] In some embodiments, a polypeptide disclosed herein comprises a paratope that is identical to a paratope of an antibody comprising an amino acid sequence selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); or SEQ ID NO:6 and SEQ ID NO:20 (AB-3d). - 5 - 3839034.v15708.1076005

[0016] In some embodiments, a polypeptide disclosed herein comprises a paratope that is identical to a paratope of an antibody comprising an amino acid sequence selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); SEQ ID NO:89 and SEQ ID NO:91 (AB-4a); or SEQ ID NO:90 and SEQ ID NO:92 (AB-7a).

[0017] The disclosure further provides, among other things, a polypeptide that comprises a VHcomprising SEQ ID NO:2, wherein: X1is not G; X2is not I; X3is not F; X4is not N; X5is not M; X6is not S; X7is not M; X8is not N; X9is not G; X10is not N; X11is not I; or any combination of the foregoing.

[0018] In some embodiments, a polypeptide disclosed herein comprises a VLcomprising SEQ ID NO:7, wherein: X12is not N; - 6 - 3839034.v15708.1076005 X13is not D; X14is not C; X15is not N; X16is not S; X17is not L; X18is not S; X19is not G; X20is not N; or any combination of the foregoing.

[0019] In some embodiments, the disclosure provides a polypeptide that specifically binds SARS-CoV-2-Spike, comprising: a VHsequence that has at least 70% sequence identity to SEQ ID NO:3; or a VLsequence that has at least 70% sequence identity to SEQ ID NO:8; or a combination thereof, wherein the VHsequence does not comprise SEQ ID NO:3, the VLsequence does not comprise SEQ ID NO:8, or both.

[0020] In some embodiments, a polypeptide disclosed herein is a fusion protein.

[0021] In some embodiments, the disclosure provides a polynucleotide encoding a polypeptide disclosed herein, a vector comprising such polynucleotide, and a host cell comprising such polynucleotide and / or vector.

[0022] In some embodiments, the disclosure provides methods of treating a patient and / or subject in need thereof (e.g., a subject having a SARS-CoV infection, such as COVID-19), comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of one or more polypeptides disclosed herein and / or a composition (e.g., pharmaceutical composition) comprising one or more polypeptides disclosed herein.

[0023] In some embodiments, the disclosure provides uses of one or more polypeptides disclosed herein in the manufacture of a medicament for treating a patient and / or subject in need thereof (e.g., a subject having a SARS-CoV infection, such as COVID-19).

[0024] In some embodiments, the disclosure provides pharmaceutical compositions for use in a method of treating an infection (e.g., a SARS-CoV infection, such as a COVID-19 infection) in a subject, comprising one or more polypeptides disclosed herein and / or a composition (e.g., pharmaceutical composition) comprising one or more polypeptides disclosed herein, the method comprising administering an effective amount (e.g., a therapeutically effective amount) of one or - 7 - 3839034.v15708.1076005 more polypeptides disclosed herein and / or a composition (e.g., pharmaceutical composition) comprising one or more polypeptides disclosed herein (e.g., for a time sufficient to treat the infection).

[0025] In some embodiments, the disclosure provides methods of neutralizing SARS-CoV-2 variants in a cell (e.g., a cell in a subject), comprising contacting the cell with an effective amount of a composition comprising a polypeptide disclosed herein or a composition (e.g., pharmaceutical composition) comprising a polypeptide disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0027] The foregoing will be apparent from the following more particular description of example embodiments, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments.

[0028] FIG.1 depicts an alignment of non-limiting examples of heavy chain variable domain (VH) amino acid sequences that are useful in polypeptides as disclosed herein. The heavy chain complementarity determining region (HCDR) amino acid sequences (indicated using boxes) are determined by ImMunoGeneTics (IMGT) numbering (www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html, also accessible at www.imgt.org / ). Identical residues are represented by dots, and variable residues are represented by letters (designated throughout this disclosure by “Xn”) in the depicted sequences. Also see VHconsensus sequence (SEQ ID NO:2) in Table 1. The antibody sequences were computationally generated using information from the sequence and structure of a reference polypeptide (Reference).

[0029] FIG.2 depicts an alignment of non-limiting examples of light chain variable domain (VL) amino acid sequences that are useful in polypeptides as disclosed herein. The light chain complementarity determining region (LCDR) amino acid sequences (indicated using boxes) are determined by IMGT numbering. Identical residues are represented by dots, and variable residues are represented by letters (designated throughout this disclosure by “Xn”) in the depicted sequences. Also see VLconsensus sequence (SEQ ID NO:7) in Table 2. The antibody sequences were computationally generated using information from the sequence and structure of a reference polypeptide (Reference). - 8 - 3839034.v15708.1076005

[0030] FIGs.3A-3B show pseudovirus neutralization data of each antibody (represented as dot) expressed as the Log fold change (FC) of IC50values (i.e., log10(FC of IC50) over a reference polypeptide (Reference) (FIG.3A) or percentage neutralization versus concentration (FIG.3B) for the indicated viruses.

[0031] FIGs.4A-4B show pseudovirus neutralization data expressed as normalized signal versus concentration of antibody. The term “Seeds” refers to test antibodies that have been selected for project learning. Sotrovimab is a clinical-stage antibody.

[0032] FIG.5A shows binding (expressed as Log EC50fold change over Sotrovimab) and pseudovirus neutralization data (expressed as percentage neutralization at 0.28 µg / ml) for BA.4 / 5, where each dot represents an antibody. FIG.5B shows neutralization data for BA.4 / 5 (expressed as percentage neutralization at 0.28 µg / ml) as a function of Hamming distance from Reference.

[0033] FIG.6 shows developability of the top VS-341 hits (i.e., antibodies selected from Project Learning results). Benchmark comparison ranges:1(Tm1>60 ℃ acceptable, Tm150-60 ℃ may be acceptable, Tm1<50℃ outside acceptable range);2(SEC monomer level >95% acceptable, SEC monomer level 95%~90% not applicable; SEC monomer level <90% outside acceptable range);3(relative to PRO-18404, Z-score <1 acceptable, Z-score 1~1.5 not applicable, Z-score >2 outside acceptable range; c.f.9.5 ± 0.3 and 7.5 ± 1.0 for PSR-DNA and PSR-Insulin of Bococizumab ctrl);4( ^^ shift <10nm acceptable, ^^ shift 10~15 nm not applicable, ^^ shift >15 nm outside acceptable range); and5(∆% >-5% acceptable, ∆% -5~ -10% not applicable, ∆% <- 10% outside acceptable range). Ranges, based on TSLP developability studies where appropriate, are arbitrary and separated at least by averaged std errors or SDs. Additional notes are as follows:a(Method optimization ongoing), *(Melting curve suggestive of the compromised Fab thermal stability),†(acceptable), (may be acceptable), **(outside acceptable range), andN / A(not applicable). Value + / - ranges are standard deviations for at least duplicates where available.

[0034] FIGs.7A-7B show pseudovirus neutralization profiles of selected class 4 anti-RBD screening hits (AB-1a, AB-2a, AB-3a, AB-4a, AB-7) and Reference antibody for BA.4 / 5.

[0035] FIGs.8A-8B show binding profiles of selected class 4 anti-RBD screening hits (AB- 3a, AB-4a) and clinical-stage antibodies (Sotrovimab, Bebtelovimab, AZD1061) to RBDs representative of Sarbecovirus clades expressed on yeasts. FIG.8C shows neutralization of a VSV-dG pseudovirus representative of SARS-CoV-2 BQ.1.1 by the class 4 anti-RBD screening hits AB-3a and clinical-stage antibodies (Sotrovimab, Bebtelovimab, AZD1061). SYNAGIS® was used as isotype control. - 9 - 3839034.v15708.1076005

[0036] FIGs.9A-9C shows pseudovirus neutralization profiles of AB-4a, a class 4 anti-RBD antibody identified in the variant set VS-341, and an anti-S2 monoclonal antibody alone and in combination, as well as clinical-stage antibodies Sotrovimab, Bebtelovimab, Cilgavimab + Tixagevimab (EVUSHELD®) for BA.4 / 5 (FIG.9A) and BA.4 / 5 + K444T (FIG.9B). SYNAGIS® was used as isotype control. FIG.9C reports respective EC50and EC90values as ng / ml.

[0037] FIG.10A shows pseudovirus neutralization profiles of the class 4 anti-RBD hits AB- 3a, Sotrovimab and Bebtelovimab alone or combined with an anti-S2 monoclonal antibody (also tested alone) for BA.4 / 5 and BA.4 / 5 + K444T. SYNAGIS® was used as isotype control. FIG. 10B shows results of the neutralization profiles shown in FIG.10A reported as Area Under the Curve (AUC) and efficacy (% max neutralization).

[0038] FIGs.11A is two graphs, and FIG.11B is a chart, showing that AB-3a combined with an anti-S2 antibody (“S2_AB-1”) demonstrates improved neutralization potency and efficacy against Omicron BQ.1.1 pseudovirus. FIGs.11A-11B show neutralization profiles. SYNAGIS® was used as isotype control. Standard deviation (SD) is applied as error bars in FIG.11A. FIG. 11C reports results shown in FIG.11A as EC50(95% confidence interval (CI)) and % median neutralization at 18 µg / ml (95% CI) values. FIG.11D is two graphs showing that an anti-S2 antibody (S2_AB-1) combined with class 4 anti-RBD antibody 3a (“RBD Class 4 mAb-3a” or “AB-3a”) demonstrates improved neutralization potency and efficacy against Omicron BQ.1.1 pseudovirus. The graphs are neutralization profiles. Synagis was used as isotype control. Standard error of the mean (SEM) is applied as error bars.

[0039] FIGs.12A and 12B are graphs, and FIG.12C is a chart, showing that AB-4a combined with an anti-S2 antibody (“S2_AB-1”) demonstrates improved neutralization potency and efficacy against Delta and Omicron BA.5 live viruses. FIGs.12A and 12B show neutralization profiles against SARS-CoV-2 Delta and BA.5 live viruses, respectively. SYNAGIS® was used as isotype control. Standard deviation (SD) is applied as error bars in FIGs.12A and 12B. FIG.12C reports results shown in FIG.12A-12B as EC50(95% CI) and % median neutralization at 18 µg / ml (95% CI) values.

[0040] FIGs.13A-13B show binding profiles of the class 4 anti-RBD molecule AB-2b and a clinical-stage antibody Bebtelovimab to RBDs representative of Sarbecovirus clades expressed on yeast. SYNAGIS® was used as isotype control.

[0041] FIG.14A shows neutralization profiles of the class 4 anti-RBD molecule AB-2b in combination with an anti-S2 monoclonal antibody (S2_AB-1) or an isotype control, for SARS- - 10 - 3839034.v15708.1076005 CoV-2 D614G, Delta, BQ.1.1, or XBB.1.5. Also shown are neutralization profiles of S2_AB-1 or a clinical-stage antibody Bebtelovimab, in combination with the isotype control. SYNAGIS® was used as the isotype control. FIG.14B reports corresponding EC50values, EC90values, and 95% confidence intervals (95% CI) against the indicated pseudoviruses.

[0042] FIG.15A shows neutralization profiles of the class 4 anti-RBD molecule AB-2b in combination with an anti-S2 monoclonal antibody (S2_AB-1) or an isotype control, for SARS- CoV-2 D614G, SARS-CoV-1, or WIV1. Also shown are neutralization profiles of S2_AB-1 or a clinical-stage antibody Bebtelovimab, in combination with the isotype control. SYNAGIS® was used as the isotype control. FIG.15B reports corresponding EC90values and 95% confidenceintervals (95% CI) against the indicated pseudoviruses. FIGs. 15C-15D. Neutralization ofSARS-CoV-2 variants by Anti-S2 in combination with AB-2b. Neutralization profiles of Anti-S2 + AB-2b (tested at two different ratios), Anti-S2, AB-2b, and bebtelovimab as single agents, and isotype control antibody against pseudoviruses representative of the indicated SARS-CoV-2 variants using TMPRSS2-Vero E6 (FIG.15C) or Vero E6 (FIG.15D) cells. The anti-spike antibodies tested as single agents were combined with isotype at the same concentrations to control for overall mass of anti-spike antibodies tested as combinations. The x-axis indicates the concentration of each individual antibody in the combinations, or of the antibody with the highest concentration if the concentrations differ. The results are reported as % neutralization and shown as mean ± standard deviation (representative of three or four independent experiments, four technical replicates each).

[0043] FIG.16 shows that AB-2b has comparable activity to sotrovimab VH / VL- hIgG1-LS in terms of lung viral titer reduction (as measured by TCID50) in a hamster challenge model with SARS-CoV-2 BA.2. However, a combination of AB-2b and S2_AB-1 achieved a much greater reduction in lung viral titer.

[0044] FIGs.17A-17B depict structural analysis of AB-2b Fab binding to SARS-CoV-2 BA.1 RBD and related contact residues. FIG.17C is a low-pass filtered Cryo-EM map of the SARS-CoV-2 BA.1 spike trimer with AB-3a Fab binding RBD and anti-S2 antibody (S2_AB-1) binding S2 stem helix. Map is shown from a side profile and from below. Each of the presumptive Fabs is labeled. FIG.17D is a density-docked atomic model of the SARS-CoV-2 spike assembly with bound Fabs. Spike trimer: a high-resolution structure of the SARS-CoV-2 spike with the S2 stem helix resolved. AB-3a: the designed model for AB-3a Fab. Bottom: three anti-S2 Fabs docked into the propeller shaped density around the S2 stem helix. - 11 - 3839034.v15708.1076005

[0045] FIGs.18A-18B show neutralization of SARS-CoV-2 live virus variants by AB-2b in combination with S2_AB-1. Neutralization profiles of AB-2b + S2_AB-1 combination, as well as AB-2b, S2_AB-1, and bebtelovimab as single agents, and isotype control antibody against SARS-CoV-2 ancestral strain (Eng20 (WT)), Delta, BQ.1.1, XBB.1.1) live viruses are shown. The anti-Spike antibodies tested as single agents were combined with isotype at the same concentrations to control for overall mass of anti-Spike antibodies tested as combinations. The x- axis indicates the concentration of each individual antibody in the combinations, or of the antibody with the highest concentration if the concentrations differ. The results are reported as % neutralization and shown as mean ± standard deviation (representative of one experiment, two to three technical replicates). AB-2b combined with S2_AB-1 demonstrates improved neutralization of SARS-CoV-2 Omicron BQ1.1 and XBB.1.1 live viruses. DETAILED DESCRIPTION

[0046] A description of example embodiments follows.

[0047] Several aspects of the disclosure are described below, with reference to examples for illustrative purposes only. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the disclosure. One having ordinary skill in the relevant art, however, will readily recognize that the disclosure can be practiced without one or more of the specific details or practiced with other methods, protocols, reagents, cell lines and animals. The disclosure is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and / or concurrently with other acts or events. Furthermore, not all illustrated acts, steps or events are required to implement a methodology in accordance with the disclosure. Definitions

[0048] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. It will be further understood that terms, such as those defined in commonly-used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and / or as otherwise defined herein. - 12 - 3839034.v15708.1076005

[0049] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0050] When introducing elements disclosed herein, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. Further, the one or more elements may be the same or different. For example, unless the context clearly indicates otherwise, “a polypeptide” includes a single polypeptide, and two or more polypeptides.

[0051] Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise,” and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of, e.g., a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integer or step. When used herein, the term “comprising” can be substituted with the term “containing” or “including.”

[0052] As used herein, the term “consisting of” excludes any element, step, or ingredient not specified in the claim element. When used herein, the term “consisting essentially of” does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0053] Also provided herein are corresponding embodiments for each and every embodiment featuring the term “comprising,” “containing,” “including,” or “having,” wherein those terms are replaced by the term “consisting of” and / or “consisting essentially of”.

[0054] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and / or.”

[0055] It should be understood that for all numerical bounds describing some parameter in this application, such as “about,” “at least,” “less than,” “fewer than,” and “more than,” the description also necessarily encompasses any range bounded by the recited values. Accordingly, for example, the description “at least 1, 2, 3, 4, or 5” also describes, inter alia, the ranges 1-2, 1- 3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, and 4-5, et cetera. - 13 - 3839034.v15708.1076005

[0056] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0057] As used herein, the term “about” means within an acceptable error range for a particular value, as determined by one of ordinary skill in the art. Typically, an acceptable error range for a particular value depends, at least in part, on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. Alternatively, “about” can mean a range of ± 20%, e.g., ± 10%, ± 5% or ± 1% of a given value. It is to be understood that the term “about” can precede any particular value specified herein, except for particular values used in the Exemplification. When “about” precedes a range, as in “90-99.9%,” the term “about” should be read as applying to both given values of the range, such that “about 90-99.9%” means about 90% repeats to about 99.9%.

[0058] As used herein, the term “polypeptide” refers to a polymer of at least two amino acids covalently linked by an amide bond, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation). A polypeptide can comprise any suitable L-and / or D-amino acid, for example, common ^-amino acids (e.g., alanine, glycine, valine), non- ^-amino acids (e.g., ^-alanine, 4-aminobutyric acid, 6-aminocaproic acid, sarcosine, statine), and unusual amino acids (e.g., citrulline, homocitruline, homoserine, norleucine, norvaline, ornithine). The amino, carboxyl, and / or other functional groups on a polypeptide can be free (e.g., unmodified) or protected with a suitable protecting group. Suitable protecting groups for amino and carboxyl groups, and methods for adding or removing protecting groups are known in the art and are disclosed in, for example, Green and Wuts, “Protecting Groups in Organic Synthesis,” John Wiley and Sons, 1991. The functional groups of a polypeptide can also be derivatized (e.g., alkylated) or labeled (e.g., with a detectable label, such as a fluorogen or a hapten) using methods known in the art. A polypeptide can comprise one or more modifications (e.g., amino acid linkers, acylation, acetylation, amidation, methylation, terminal modifiers (e.g., cyclizing modifications), N-methyl- ^-amino group substitution), if desired. In addition, a polypeptide can be an analog of a known and / or naturally-occurring peptide, for example, a peptide analog having conservative amino acid residue substitution(s).

[0059] As used herein, a “polynucleotide” is defined as a plurality of nucleotides and / or nucleotide analogs linked together in a single molecule. In some embodiments, a polynucleotide - 14 - 3839034.v15708.1076005 disclosed herein comprises deoxyribonucleotides. In some embodiments, the polynucleotide comprises ribonucleotides. Non-limiting examples of polynucleotides include single-, double- or multi-stranded DNA or RNA, DNA-RNA hybrids (e.g., each “T” position may be independently substituted by a “U” or vice versa), or a polymer comprising purine and pyrimidine bases, or other natural, chemically, or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of the polynucleotide can comprise sugars and phosphate groups, modified or substituted sugar or phosphate groups, a polymer of synthetic subunits such as phosphoramidates, or a combination thereof.

[0060] As used herein, the term “sequence identity” refers to the extent to which two nucleotide sequences have the same residues at the same positions when the sequences are aligned to achieve a maximal level of identity, expressed as a percentage. For sequence alignment and comparison, typically one sequence is designated as a reference sequence, to which test sequences are compared. Sequence identity between reference and test sequences is expressed as a percentage of positions across the entire length of the reference sequence where the reference and test sequences share the same nucleotide or amino acid upon alignment of the reference and test sequences to achieve a maximal level of identity. As an example, two sequences are considered to have 70% sequence identity when, upon alignment to achieve a maximal level of identity, the test sequence has the same nucleotide residue at 70% of the same positions over the entire length of the reference sequence.

[0061] Alignment of sequences for comparison to achieve maximal levels of identity can be readily performed by a person of ordinary skill in the art using an appropriate alignment method or algorithm. In some instances, alignment can include introduced gaps to provide for the maximal level of identity. Examples include the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), and visual inspection (see generally Ausubel et al., Current Protocols in Molecular Biology).

[0062] When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequent coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the - 15 - 3839034.v15708.1076005 designated program parameters. A commonly used tool for determining percent sequence identity is Protein Basic Local Alignment Search Tool (BLASTP) available through National Center for Biotechnology Information, National Library of Medicine, of the United States National Institutes of Health. (Altschul et al., 1990).

[0063] As used herein, the term “substantially similar to” refers to a polypeptide disclosed herein that is substantially similar in amino acid sequence (e.g., has at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the amino acid residues amino acid sequence identity) and substantially preserves one or more functional properties of a specified polypeptide disclosed herein (e.g., AB-1). In some embodiments, the one or more functional properties are selected from, without limitation, a substantially similar binding affinity, a substantially similar binding specificity, a substantially similar inhibitory activity, a substantially similar neutralization activity, and a substantially similar self-association property.

[0064] As used herein, a “complementarity determining region (CDR)” encompasses any CDR defined by an art-recognized method for identifying the CDR residues on an antibody. 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 et al., (1989) Nature 342:877; Chothia, C. et al., (1987) J. Mol. Biol.196:901-917; Al-lazikani et al., (1997) J. Molec. Biol.273:927-948; and Almagro, J. Mol. Recognit.17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. Two antibodies are determined to have the same CDR as one another with respect to an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and / or LCDR3, when the identity of that CDR is determined for both antibodies using the same method.

[0065] The extent of the framework region and the CDRs of an antibody can be identified using one of several suitable methodologies that are well known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, and / or the contact definition. Publicly and / or commercially available tools for identifying framework and / or CDR regions include, IgBlast (accessible at www.ncbi.nlm.nih.gov / igblast / ), Scaligner (available from drugdesigntech at www.scaligner.com / ), IMGT rules and / or tools (see, for example, www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html, also accessible at www.imgt.org / ), Chothia Canonical Assignment (accessible at www.bioinf.org.uk / abs / chothia.html), Antigen receptor Numbering And Receptor CalssificatiIon (ANARCI, accessible at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), or the - 16 - 3839034.v15708.1076005 Paratome web server (see Vered Kunik, et al, Nucleic Acids Research, Volume 40, Issue W1, 1 July 2012, Pages W521-W524).

[0066] As used herein, the term “paratope” refers to a set of amino acid residues in an antibody or an antigen-binding fragment thereof that contribute to a binding interaction with an epitope of a target protein. The binding interaction can be a hydrogen bond, a salt bridge, a van der Waal interaction, an ionic bond or a combination thereof. A binding interaction may be direct, or indirect, e.g., via a coordinated intermediate molecule, such as an ion or water. The residues of a paratope, in some embodiments, comprise only residues that are part of a defined CDR. In other embodiments, the residues of a paratope further comprise one or more residues that are not part of a defined CDR.

[0067] As used herein, the term “antibody mimetic” refers to polypeptides capable of mimicking an antibody’s ability to bind an antigen, but structurally differ from native antibody structures. Examples of antibody mimetics include, but not limited to, Adnectins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Anticalins, Avimers, DARPins, Fynomers, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMPs, and Versabodies.

[0068] As used herein the term “KD,” also referred to as “binding constant,” “equilibrium dissociation constant” or “affinity constant,” is a measure of the extent of a reversible association between two molecular species (e.g., antibody and target protein) and includes both the actual binding affinity as well as the apparent binding affinity. Binding affinity can be determined using methods known in the art including, for example, by measurement of surface plasmon resonance, e.g., using a Biolayer interferometry (Octet, ForteBio) or a surface plasmon resonance (Biacore) system and assay. A reference that compares various surface technologies for measuring binding affinity and kinetics is Yang, D., Singh, A., Wu, H., & Kroe-Barrett, R., Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen binding kinetics, Analytical Biochemistry 508: 78-96 (2016), the contents of which are incorporated by reference herein in their entirety.

[0069] The term “subject” and “patient” are used herein interchangeably to refer to an animal (e.g., a mammal, such as a human) to be treated according to a method disclosed herein. A subject to be treated according to methods described herein may be one who has been diagnosed with a particular condition (e.g., COVID-19), or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been - 17 - 3839034.v15708.1076005 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 the disease or condition.

[0070] The phrase “pharmaceutically acceptable” means that the substance or composition the phrase modifies is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio.

[0071] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the agents / compounds described herein include salts derived from suitable inorganic and organic acids, and suitable inorganic and organic bases.

[0072] Examples of salts derived from suitable acids include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts derived from suitable acids include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethanesulfonate, hydroxymaleate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 2-phenoxybenzoate, phenylacetate, 3-phenylpropionate, phosphate, pivalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0073] Either the mono-, di- or tri-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. - 18 - 3839034.v15708.1076005

[0074] Salts derived from appropriate bases include salts derived from inorganic bases, such as alkali metal, alkaline earth metal, and ammonium bases, and salts derived from aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethylamine and picoline, or N+((C1-C4)alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0075] “Pharmaceutically acceptable carrier” refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the agent with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. Pharmaceutically acceptable carriers that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0076] “Treating” or “treatment,” as used herein, refers to taking steps to deliver a therapy to a subject, such as a mammal, in need thereof (e.g., as by administering to a mammal one or more therapeutic agents). “Treating” or “treatment” includes inhibiting the disease or condition (e.g., as by slowing or stopping its progression or causing regression of the disease or condition) and relieving the symptoms resulting from the disease or condition.

[0077] The term “treating,” or “treatment” refers to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent, or cure a disease, pathological condition, or disorder—such as the particular indications exemplified herein. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and - 19 - 3839034.v15708.1076005 supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable. “Ameliorating” or “palliating” a disease or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0078] A “pharmaceutical composition” refers to a formulation of one or more therapeutic agents and a medium generally accepted in the art for delivery of a biologically active agent to subjects, e.g., humans. In some embodiments, a pharmaceutical composition may include one or more pharmaceutically acceptable excipients, diluents, or carriers. In some embodiments, a pharmaceutical composition suitable for use in methods disclosed herein further comprises one or more pharmaceutically acceptable carriers.

[0079] “Pharmaceutically acceptable carrier, diluent, or excipient” includes any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0080] “Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. In some embodiments, the carrier may be a diluent, adjuvant, excipient, or vehicle with which the agent (e.g., polynucleotide) is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine can be used. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, - 20 - 3839034.v15708.1076005 thickening, lubricating, and coloring agents, etc. The concentration of the agent in such pharmaceutical formulation may vary widely, i.e., from less than about 0.5%, to at least about 1%, or to as much as 15% or 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight. The concentration will be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the mode of administration. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21stEdition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing: 691-1092 (e.g., pages 958-89).

[0081] Non-limiting examples of pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.

[0082] Non-limiting examples of buffers are acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO, and HEPES.

[0083] Non-limiting examples of antioxidants are ascorbic acid, methionine, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0084] Non-limiting examples of amino acids are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, tri-leucine, alanine, glutamic acid, L-threonine, and 2-phenylamine.

[0085] Non-limiting examples of surfactants are polysorbates (e.g., polysorbate-20 or polysorbate-80); polyoxamers (e.g., poloxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUA™ series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., PLURONICS™, PF68, etc.).

[0086] Non-limiting examples of preservatives are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben (methyl, ethyl, propyl, butyl, and the like), - 21 - 3839034.v15708.1076005 benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof.

[0087] Non-limiting examples of saccharides are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, nonreducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, mellibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, or iso-maltulose.

[0088] Non-limiting examples of salts are acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous, and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and the like, as well as from nontoxic organic amines, such as N,N’-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. In some embodiments, the salt is sodium chloride (NaCl).

[0089] Agents (e.g., polynucleotides) described herein may be prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent, or eliminate, or to slow or halt progression of, a condition being treated (see, e.g., Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, and Goodman and Gilman’s The Pharmaceutical Basis of Therapeutics, McGraw-Hill, New York, N.Y., the contents of which are incorporated herein by reference, for a general description of methods for administering various agents for human therapy).

[0090] “Administering” or “administration,” as used herein, refers to providing a compound, composition, or pharmaceutically acceptable salt thereof described herein to a subject in need of treatment or prevention. Administering can be performed, for example, once, a plurality of times, and / or over one or more extended periods. Administration includes both direct administration (including self-administration), and indirect administration (including an act of prescribing a drug or directing a subject to consume an agent). For example, as used herein, one (e.g., a physician) who instructs a subject (e.g., a human patient) to self-administer an agent (e.g., a drug), or to have an agent administered by another and / or who provides a patient with a prescription for a drug is administering an agent to a subject. - 22 - 3839034.v15708.1076005

[0091] “A therapeutically effective amount,” “an effective amount” or “an effective dosage” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., treatment, healing, inhibition or amelioration of physiological response or condition, etc.). A full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of a mammal (e.g., a human patient), mode of administration, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response.

[0092] An effective amount of an agent to be administered can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art. Relevant factors include the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like. For example, suitable dosages can be from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.01 mg / kg to about 1 mg / kg body weight per treatment. Determining the dosage for a particular agent, subject and disease is well within the abilities of one of skill in the art. Preferably, the dosage does not cause or produces minimal adverse side effects.

[0093] Desired response or desired results include effects at the cellular level, tissue level, or clinical results. As such, “a therapeutically effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in some embodiments it is an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. In other embodiments, it is an amount that results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of a composition (e.g., a pharmaceutical composition) disclosed herein may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen and route of administration may be adjusted to provide the optimum therapeutic response.

[0094] Preferred features of each of the aspects or embodiments provided by the invention are applicable to all of the other aspects or embodiments of the invention mutatis mutandis and, without limitation, are exemplified by the dependent claims and also encompass combinations and permutations of individual features (e.g., elements, including numerical ranges and exemplary embodiments) of particular embodiments and aspects of the invention, including the - 23 - 3839034.v15708.1076005 working examples. For example, particular experimental parameters exemplified in the working examples can be adapted for use in the claimed invention piecemeal without departing from the invention. For example, for materials that are disclosed, while specific reference of each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. Thus, if a class of elements A, B, and C are disclosed as well as a class of elements D, E, and F and an example of a combination of elements A-D is disclosed, then, even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-groups of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. This concept applies to all aspects of this application, including elements of a composition of matter and steps of method of making or using the compositions. The forgoing aspects of the invention, as recognized by the person having ordinary skill in the art following the teachings of the specification, can be claimed in any combination or permutation to the extent that they are novel and non-obvious over the prior art—thus, to the extent an element is described in one or more references known to the person having ordinary skill in the art, they may be excluded from the claimed invention by, inter alia, a negative proviso or disclaimer of the feature or combination of features. Polypeptides that Specifically Bind Betacoronavirus Spike Proteins

[0095] Provided herein, among other things, are polypeptides that specifically bind to receptor-binding domain (RBD) of betacoronavirus Spike glycoprotein. In some embodiments, a polypeptide has one or more properties selected from: a broadly neutralizing activity against a plurality of known and predicted betacoronaviruses (e.g., past, present, emergent, and future betacoronaviruses), a binding affinity for an RBD domain epitope (e.g., RBD class 4 epitope) that is highly conserved across a plurality of betacoronaviruses, and an inhibitory activity against potential emerging betacoronavirus escape variants. In some embodiments, a polypeptide specifically binds the RBD of a sarbecovirus (e.g., a SARS-CoV-1 virus, a SARS-CoV-2 virus) Spike protein. In some embodiments, a polypeptide specifically binds the RBD of a SARS-CoV- 1 virus (e.g., a plurality of SARS-CoV-1 variants) Spike protein. In some embodiments, a polypeptide specifically binds the RBD of a SARS-CoV-2 virus (e.g., a plurality of SARS-CoV- - 24 - 3839034.v15708.1076005 2 variants) Spike protein. In some embodiments, a polypeptide specifically binds the RBD of a SARS-CoV-1 virus (e.g., a plurality of SARS-CoV-1 variants) Spike protein and the RBD of a SARS-CoV-2 virus (e.g., a plurality of SARS-CoV-2 variants) spike protein.

[0096] In some embodiments, a polypeptide has a broadly neutralizing activity (e.g., as measured using a neutralization assay described herein or otherwise known to those of ordinary skill the art) against a plurality of betacoronaviruses. In some embodiments, a polypeptide has neutralizing activity against a plurality of sarbecoviruses (e.g., SARS-CoV-1 viruses, SARS- CoV-2 viruses). In some embodiments, a polypeptide has neutralizing activity against a plurality of SARS-CoV-1 viruses (e.g., a plurality of SARS-CoV-1 variants). In some embodiments, a polypeptide has neutralizing activity against a plurality of SARS-CoV-2 viruses (e.g., a plurality of SARS-CoV-2 variants). In some embodiments, a polypeptide has neutralizing activity against a plurality of SARS-CoV-1 viruses (e.g., a plurality of SARS-CoV-1 variants) and a plurality of SARS-CoV-2 viruses (e.g., a plurality of SARS-CoV-2 variants).

[0097] In some embodiments, a polypeptide has a binding affinity for an RBD epitope (e.g., RBD class 4 epitope) that is conserved (e.g., highly conserved) across a plurality of betacoronaviruses. In some embodiments, an RBD epitope is highly conserved across a plurality of sarbecoviruses (e.g., SARS-CoV-1 viruses, SARS-CoV-2 viruses). In some embodiments, an RBD epitope is highly conserved across a plurality of SARS-CoV-1 viruses (e.g., a plurality of SARS-CoV-1 variants). In some embodiments, an RBD epitope is highly conserved across a plurality of SARS-CoV-2 viruses (e.g., a plurality of SARS-CoV-2 variants). In some embodiments, an RBD epitope is highly conserved across a plurality of SARS-CoV-1 viruses (e.g., a plurality of SARS-CoV-1 variants) and a plurality of SARS-CoV-2 viruses (e.g., a plurality of SARS-CoV-2 variants).

[0098] SARS-CoV-2 is the causative agent of COVID-19. The genome of SARS-CoV-2 encodes the nucleoprotein (N), the membrane glycoprotein (M), the small envelope glycoprotein (E), and the spike protein (S), in addition to 16 non-structural proteins (Song et al., Cytokine storm induced by SARS-CoV-2, Clin Chim Acta.509:280-7 (2020)). SARS-CoV-2-Spike, or S of the SARS-CoV-2, facilitates entry of the SARS-CoV-2 virus into a host cell, such as a human host cell. S is a trimer with protomers composed of S1 and S2 subunits. S1 contains an RBD that binds ACE2 receptors, and S2 is necessary for fusion of viral and host membranes.

[0099] A non-limiting example of a wildtype SARS-CoV-2-Spike (S) sequence is NCBI RefSeq YP_009724390 (SEQ ID NO:1). - 25 - 3839034.v15708.1076005

[0100] MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQD LFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKT QSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVS QPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGI NITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCA LDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAW NRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPG QTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEI YQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKST NLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCS FGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGC LIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNN SIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAV EQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGF IKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAA LQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVV NQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQL IRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPA QEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVI GIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVA KNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSC GSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO:1).

[0101] As used herein, SARS-CoV-2-Spike includes wild-type SARS-CoV-2 Spike proteins (e.g., SEQ ID NO:1 (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.

[0102] In some embodiments, a polypeptide binds to a SARS-CoV-2 Spike protein comprising SEQ ID NO:1.

[0103] In some embodiments, a polypeptide binds to a mutant, engineered and / or modified form of SARS-CoV-2-Spike. In some embodiments, a mutant, engineered or modified form of SARS-CoV-2-Spike comprises an amino acid sequence that has at least about 90% sequence identity to a wildtype SARS-CoV-2-Spike sequence (e.g., SEQ ID NO:1), for example, having at - 26 - 3839034.v15708.1076005 least about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to a wildtype SARS-CoV-2-Spike sequence. In some embodiments, a mutant, engineered or modified form of SARS-CoV-2-Spike comprises an amino acid sequence that has about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99% sequence identity to a wildtype SARS-CoV-2-Spike sequence (e.g., SEQ ID NO:1).

[0104] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2- Spike comprises, relative to SEQ ID NO:1, 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., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or more mutations.

[0105] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2- Spike comprises, relative to SEQ ID NO:1, 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, or modified form of SARS-CoV-2-Spike comprises 69del, 70del, 144del, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H. In some embodiments, a mutant, engineered or modified form of SARS- CoV-2-Spike further comprises E484K, S494P, or K1191N, or a combination thereof.

[0106] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2- Spike comprises, relative to SEQ ID NO:1, 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 or modified form of SARS-CoV-2-Spike comprises D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, and A701V.

[0107] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2- Spike comprises, relative to SEQ ID NO:1, 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, or modified form of SARS-CoV-2-Spike comprises - 27 - 3839034.v15708.1076005 T19R, 156del, 157del, R158G, L452R, T478K, D614G, P681R, and D950N. In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2-Spike further comprises G142D.

[0108] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2- Spike comprises, relative to SEQ ID NO:1, 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.

[0109] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2- Spike comprises, relative to SEQ ID NO:1, one or more mutations selected from: E484K, N501Y, or D614G, or a combination thereof.

[0110] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, one or more mutations selected from: F817P, A892P, A899P, A942P, K986P, or V987P, or a combination thereof.

[0111] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, one or more mutations selected from: L452R, F486V, or R493Q, or a combination thereof.

[0112] In some embodiments, a mutant, engineered, or modified form of SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, 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.

[0113] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, one or more mutations selected from: T19I, del24-26, A27S, G142D, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, or N969K, or a combination thereof.

[0114] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, 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. - 28 - 3839034.v15708.1076005

[0115] In some embodiments, the modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, 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.

[0116] In some embodiments, a modified SARS-CoV-2 Spike protein comprises, relative to SEQ ID NO:1, 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.

[0117] Additional modified SARS-CoV-2 Spike proteins 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, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB.

[0118] In some embodiments, a polypeptide binds to a RBD of a SARS-CoV-2 Spike (S) protein. As used herein, RBD includes full-length RBD (e.g., having the amino acid sequence of SEQ ID NO:46 or homologs thereof) and truncated forms thereof, mutant and engineered versions of full-length and truncated RBD (e.g., an epitope within the RBD (e.g., RBD class 4 epitope)), and modified forms (e.g., post-translationally modified forms) of full-length and truncated RBD.

[0119] In some embodiments, a polypeptide binds SARS-CoV-1-Spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-Spike (e.g., of 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, 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, XBB.1.5, XBB.1.5.10, XBB.1.9.1, and / or EG.5.1) or a fragment thereof (e.g., the S2 domain of SARS-CoV-2-Spike and / or the epitopes in FIG.1) with - 29 - 3839034.v15708.1076005 a KDof about: 5 µM, 2 µM, 1 µM, 500 nM, 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.2 nM or 0.1 nM or less. In some embodiments, a polypeptide binds SARS- CoV-1-Spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-Spike (e.g. of 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, 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, XBB.1.5, XBB.1.5.10, XBB.1.9.1, and / or EG.5.1) or a fragment thereof (e.g., a RBD domain of SARS-CoV-2-Spike).

[0120] RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNS ASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTG CVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYF PLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF (SEQ ID NO:46).

[0121] In some embodiments, a polypeptide binds to a mutant, engineered, or modified form of an RBD. In some embodiments, a mutant, engineered, or modified form of an RBD comprises an amino acid sequence that has at least about 90% sequence identity to a wild-type full length RBD (e.g., SEQ ID NO:46), for example, having at least about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity. In some embodiments, the sequence identity is about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97- 99.2%, or 97-99%. In some embodiments, a mutant, engineered or modified form of SARS- CoV-2-Spike comprises an amino acid sequence that has about: 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97- 99% sequence identity to a wildtype full length RBD (e.g., SEQ ID NO:46). Comparator Polypeptides

[0122] As used herein, the term “comparator” or “comparator polypeptide” refers to a polypeptide (e.g., immunoglobulin molecule) that specifically binds to a SARS-CoV-2-Spike and is not a polypeptide of the disclosure. The sequence of a comparator polypeptide and a polypeptide of the disclosure may be compared to illustrate structural differences between them (e.g., differences at one or more amino acid positions, such as amino acid substitutions). - 30 - 3839034.v15708.1076005 Polypeptides of the disclosure have more than insubstantial differences (e.g., one or more substantial differences) in comparison to a comparator polypeptide, such that, polypeptides disclosed herein will, under controlled conditions, exhibit one or more (i.e., one, two, or all three) of: a different function, in a different way, to achieve a different result, in comparison to a comparator polypeptide. A comparator polypeptide may vary from a polypeptide of the disclosure by one or more amino acids, e.g., in some embodiments, by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids. In some embodiments, a comparator polypeptide diverges from a polypeptide of the disclosure by at least about: 0.4%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or more amino acid percent identity.

[0123] In some embodiments, a comparator polypeptide is an antibody comprising: a) an immunoglobulin heavy chain variable (VH) domain comprising a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 amino acid sequences of SEQ ID NO:22, SEQ ID NO:26, and SEQ ID NO:31, respectively; b) an immunoglobulin light chain variable (VL) domain comprising a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 amino acid sequences of SEQ ID NO:35, SEQ ID NO:38, and SEQ ID NO:42, respectively; or both a) and b).

[0124] In some embodiments, a comparator polypeptide is an antibody comprising: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 sequences of SEQ ID NO:22, SEQ ID NO:26, and SEQ ID NO:31, respectively; and b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 sequences of SEQ ID NO:35, SEQ ID NO:38, and SEQ ID NO:42, respectively.

[0125] See Table 3 and FIGs.1-2 for SEQ ID NOs:22, 26, 31, 35, 38, 42.

[0126] In some embodiments, a comparator polypeptide is an antibody comprising: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:3; b) a VLdomain comprising the amino acid sequence of SEQ ID NO:8, or both a) and b).

[0127] In some embodiments, a comparator polypeptide is an antibody comprising: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:3; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:8. - 31 - 3839034.v15708.1076005

[0128] See Table 1 and FIG.1 for SEQ ID NO:3. See Table 2 and FIG.2 for SEQ ID NO:8.

[0129] In some embodiments, a comparator polypeptide is an antibody referred to herein as the “Reference Antibody”, which comprises a VHdomain comprising the amino acid sequence of SEQ ID NO:3, a VLdomain comprising the amino acid sequence of SEQ ID NO:8, a heavy chain comprising the amino acid sequence of SEQ ID NO:47 and / or SEQ ID NO:48, and a light chain comprising the amino acid sequence of SEQ ID NO:49. The Reference Antibody binds SARS-CoV-2 RBD and neutralizes SARS-CoV-2 variants.

[0130] QVQLVQSGAEVKKPGSSVKVSCKASGGIFNTYTISWVRQAPGQGLEWMGRII LMSGMANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGNYYGWGD DDAFDIWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS C (SEQ ID NO:47).

[0131] QVQLVQSGAEVKKPGSSVKVSCKASGGIFNTYTISWVRQAPGQGLEWMGRII LMSGMANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGNYYGWGD DDAFDIWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:48).

[0132] QTVLTQPPSVSGAPGQRVTISCTGSNSNIGAGYDVHWYQQLPGTAPKLLICG NSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGPNWVFGGGTKLT VLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:49). Complementarity Determining Regions (CDRs)

[0133] A CDR (e.g., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3) can be a CDR defined by any art-recognized method for identifying CDR residues of an antibody, as described further herein (e.g., a CDR as defined by Kabat, a CDR as defined by Chothia, or a CDR as defined by IMGT).

[0134] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) does not comprise all six CDRs of an antibody that comprises a VHamino acid sequence - 32 - 3839034.v15708.1076005 of SEQ ID NO:3 and a VLamino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide does not comprise all six sequences of SEQ ID NO:22, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:35, SEQ ID NO:38, and SEQ ID NO:42. See Table 3 for SEQ ID NO:22, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:35, SEQ ID NO:38, and SEQ ID NO:42.

[0135] In some embodiments, a polypeptide comprises fewer than six (e.g., 1, 2, 3, 4 or 5) CDRs of an antibody that comprises a VHamino acid sequence of SEQ ID NO:3 and a VLamino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide comprises 1, 2, 3, 4 or 5 sequences, but not all 6 sequences, selected from SEQ ID NO:22, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:35, SEQ ID NO:38, and SEQ ID NO:42.

[0136] In some embodiments, a polypeptide comprises all six CDRs of a specific polypeptide disclosed herein. In some embodiments, a polypeptide comprises fewer than six (e.g., 1, 2, 3, 4 or 5) of CDRs of a specific polypeptide disclosed herein.

[0137] In some embodiments, a polypeptide comprises: a) a VHdomain comprising a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in any of SEQ ID NOs:4-6; b) a VLdomain comprising a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in any of SEQ ID NOs:9-20; or both a) and b).

[0138] See Table 3 and FIGs.1-2 for non-limiting examples of corresponding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences.

[0139] In some embodiments, a polypeptide comprises: a) a VHdomain comprising a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in any of SEQ ID NOs:4-6; - 33 - 3839034.v15708.1076005 b) a VLdomain comprising a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in any of SEQ ID NOs:9-20; or both a) and b).

[0140] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4-6; b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9-20; or both a) and b).

[0141] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4-6; and b)a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9-20.

[0142] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of a polypeptide selected from any one of AB-1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d.

[0143] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly - 34 - 3839034.v15708.1076005 conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4- 6; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9- 20, or both a) and b).

[0144] In some embodiments, an amino acid substitution is a conservative substitution. The term “a conservative amino acid substitution” or “a conservative substitution” refers to an amino acid substitution having a value of 0 or greater in BLOSUM62.

[0145] In some embodiments, an amino acid substitution is a highly conservative substitution. The term “a highly conservative amino acid substitution” or “a highly conservative substitution” refers to an amino acid substitution having a value of at least 1 (e.g., at least 2) in BLOSUM62.

[0146] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4- 6; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9- 20.

[0147] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4-6; or - 35 - 3839034.v15708.1076005 b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9-20, or both a) and b).

[0148] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4-6; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9-20.

[0149] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4-6; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9-20, or both a) and b).

[0150] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of any one or more of SEQ ID NOs:4-6; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of any one or more of SEQ ID NOs:9-20.

[0151] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3, of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); - 36 - 3839034.v15708.1076005 SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); or SEQ ID NO:6 and SEQ ID NO:20 (AB-3d).

[0152] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; b) a VLdomain comprising an LCDR1, an LCDR2 and an LCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14, or both a) and b).

[0153] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; and b) a VLdomain comprising an LCDR1, an LCDR2 and an LCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14.

[0154] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that substantially preserve one or more functional properties of an HCDR1, an - 37 - 3839034.v15708.1076005 HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; or b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14, or both a) and b).

[0155] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; and b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14.

[0156] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14, or both a) and b).

[0157] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14. - 38 - 3839034.v15708.1076005

[0158] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14, or both a) and b).

[0159] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence of SEQ ID NO:5; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence of SEQ ID NO:14.

[0160] In some embodiments, a polypeptide comprises: a) an HCDR1 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:22-24 (e.g., at least one amino acid sequence set forth in SEQ ID NO:23 or SEQ ID NO:24); b) an HCDR2 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:26-29 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:27-29); c) an HCDR3 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:31-33 (e.g., at least one amino acid sequence set forth in SEQ ID NO:32 or SEQ ID NO:33); d) an LCDR1 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:35-37 (e.g., at least one amino acid sequence set forth in SEQ ID NO:36 or SEQ ID NO:37); e) an LCDR2 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:38-40 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:39-40); - 39 - 3839034.v15708.1076005 f) an LCDR3 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:42-45 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:43-45); or any combination of the foregoing.

[0161] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of a polypeptide selected from any one of AB- 1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d.

[0162] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of a polypeptide selected from any one of AB- 1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d.

[0163] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of a polypeptide selected from any one of AB-1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d.

[0164] In some embodiments, a polypeptide comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO:24; b) an HCDR2 comprising the amino acid sequence of SEQ ID NO:28; c) an HCDR3 comprising the amino acid sequence of SEQ ID NO:33; d) an LCDR1 comprising the amino acid sequence of SEQ ID NO:37; e) an LCDR2 comprising the amino acid sequence of SEQ ID NO:40; f) an LCDR3 comprising the amino acid sequence of SEQ ID NO:44; or any combination of the foregoing.

[0165] In some embodiments, a polypeptide comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO:24; b) an HCDR2 comprising the amino acid sequence of SEQ ID NO:28; c) an HCDR3 comprising the amino acid sequence of SEQ ID NO:33; d) an LCDR1 comprising the amino acid sequence of SEQ ID NO:37; e) an LCDR2 comprising the amino acid sequence of SEQ ID NO:40; and - 40 - 3839034.v15708.1076005 f) an LCDR3 comprising the amino acid sequence of SEQ ID NO:44.

[0166] In some embodiments, a polypeptide comprises: a) an HCDR1 consisting of the amino acid sequence of SEQ ID NO:24; b) an HCDR2 consisting of the amino acid sequence of SEQ ID NO:28; c) an HCDR3 consisting of the amino acid sequence of SEQ ID NO:33; d) an LCDR1 consisting of the amino acid sequence of SEQ ID NO:37; e) an LCDR2 consisting of the amino acid sequence of SEQ ID NO:40; f) an LCDR3 consisting of the amino acid sequence of SEQ ID NO:44; or any combination of the foregoing.

[0167] In some embodiments, a polypeptide comprises: a) an HCDR1 consisting of the amino acid sequence of SEQ ID NO:24; b) an HCDR2 consisting of the amino acid sequence of SEQ ID NO:28; c) an HCDR3 consisting of the amino acid sequence of SEQ ID NO:33; d) an LCDR1 consisting of the amino acid sequence of SEQ ID NO:37; e) an LCDR2 consisting of the amino acid sequence of SEQ ID NO:40; and f) an LCDR3 consisting of the amino acid sequence of SEQ ID NO:44.

[0168] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein; or both a) and b), optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0169] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; and - 41 - 3839034.v15708.1076005 b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0170] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that are substantially similar (e.g., having at least about 90% sequence identity) in amino acid sequence to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein; or both a) and b), optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0171] In some embodiments, a polypeptide comprises: a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein; or both a) and b), optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0172] In some embodiments, a polypeptide comprises: - 42 - 3839034.v15708.1076005 a) a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; and b) a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0173] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 that substantially preserve one or more functional properties of an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of a polypeptide selected from any antibody set forth in Table 5 herein.

[0174] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, or both a) and b), optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0175] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly - 43 - 3839034.v15708.1076005 conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0176] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, or both a) and b), optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0177] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 comprising up to 1, 2, or 3 conservative substitutions (e.g., up to 1, 2, or 3 highly conservative substitutions), relative to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, - 44 - 3839034.v15708.1076005 optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0178] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; or b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, or both a) and b), optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0179] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2 and an HCDR3, respectively, of a VHamino acid sequence set forth in Table 1 or Table 4 herein; and b) a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2 and an LCDR3, respectively, of a VLamino acid sequence set forth in Table 2 or Table 4 herein, optionally wherein the VHamino acid sequence set forth in Table 1 or Table 4 herein and the VLamino acid sequence set forth in Table 2 or Table 4 herein are a sequence pair set forth in Table 5 herein.

[0180] In some embodiments, a polypeptide comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3, of an antibody comprising a VH / VLpair selected from Table 5 herein.

[0181] In some embodiments, a) an HCDR1 amino acid sequence corresponds to positions 26-33 of a VHamino acid sequence set forth in Table 4; b) an HCDR2 amino acid sequence corresponds to positions 51-58 of a VHamino acid sequence set forth in Table 4; - 45 - 3839034.v15708.1076005 c) an HCDR3 amino acid sequence corresponds to positions 97-115 of a VHamino acid sequence set forth in Table 4; d) an LCDR1 amino acid sequence corresponds to positions 26-34 of a VLamino acid sequence set forth in Table 4; e) an LCDR2 amino acid sequence corresponds to positions 52-54 of a VLamino acid sequence set forth in Table 4; f) an LCDR3 amino acid sequence corresponds to positions 91-103 of a VLamino acid sequence set forth in Table 4.

[0182] In some embodiments, a polypeptide comprises: a) an HCDR1 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:22-24 and (HCDR1 amino acid sequences set forth in) Table 4 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:23-24 and Table 4); b) an HCDR2 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:26-29 and (HCDR2 amino acid sequences set forth in) Table 4 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:27-29 and Table 4); c) an HCDR3 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:31-33 and (HCDR3 amino acid sequences set forth in) Table 4 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:32-33 and Table 4); d) an LCDR1 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:35-37 and (LCDR1 amino acid sequences set forth in) Table 4 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:36-37 and Table 4); e) an LCDR2 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:38-40 and (LCDR2 amino acid sequences set forth in) Table 4 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:39-40 and Table 4); f) an LCDR3 comprising at least one amino acid substitution relative to at least one amino acid sequence set forth in SEQ ID NOs:42-45 and (LCDR3 amino acid sequences set forth in) Table 4 (e.g., at least one amino acid sequence set forth in SEQ ID NOs:43-45 and Table 4); - 46 - 3839034.v15708.1076005 or any combination of the foregoing, optionally wherein a VHamino acid sequence comprising the HCDR1, the HCDR2, and the HCDR3, and a VLamino acid sequence comprising the LCDR1, the LCDR2, and the LCDR3, are a sequence pair set forth in Table 5 herein.

[0183] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLPGYA (SEQ ID NO:604); and iii. an HCDR3 comprising ARGFNRDYYGWGDDDAFDF (SEQ ID NO:605); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYR (SEQ ID NO:37); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0184] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTEDTYT (SEQ ID NO:606); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 comprising ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0185] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYG (SEQ ID NO:607); iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYR (SEQ ID NO:37); ii. an LCDR2 comprising GRS; and - 47 - 3839034.v15708.1076005 iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0186] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDYSDVYT (SEQ ID NO:609); ii. an HCDR2 comprising IILLLGYA (SEQ ID NO:610); and iii. an HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYY (SEQ ID NO:611); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0187] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising LSNIGAGYR (SEQ ID NO:613); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0188] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYS (SEQ ID NO:614); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising ESNIGAGYD (SEQ ID NO:615); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0189] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: - 48 - 3839034.v15708.1076005 i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising LSNIGAGYR (SEQ ID NO:613); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0190] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSDYT (SEQ ID NO:609); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0191] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0192] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and - 49 - 3839034.v15708.1076005 iii. an HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYD (SEQ ID NO:36); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSYFDPHWV (SEQ ID NO:610).

[0193] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 comprising ARGFNEDYYGWGDDDAFDF (SEQ ID NO:614); and b) a VLdomain comprising: i. an LCDR1 comprising VSNIGAGYD (SEQ ID NO:615); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0194] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising PSNIGAGYR (SEQ ID NO:616); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0195] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDIYT (SEQ ID NO:617); ii. an HCDR2 comprising IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: - 50 - 3839034.v15708.1076005 i. an LCDR1 comprising VSNIGAGYD (SEQ ID NO:615); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0196] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising ESNIGAGYD (SEQ ID NO:615); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0197] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising VSNIGAGYR (SEQ ID NO:618); ii. an LCDR2 comprising GSS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0198] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYV (SEQ ID NO:619); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYD (SEQ ID NO:36); ii. an LCDR2 comprising GRS; iii. an LCDR3 comprising QSYDSSSFDPHWV (SEQ ID NO:620). - 51 - 3839034.v15708.1076005

[0199] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYR (SEQ ID NO:37); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSYFDPHWV (SEQ ID NO:610).

[0200] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 comprising ARGFNYDYYGWGDDDAFDF (SEQ ID NO:621); and b) a VLdomain comprising: i. an LCDR1 comprising VSNIGAGYR (SEQ ID NO:618); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0201] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 comprising IILLSGYS (SEQ ID NO:614); and iii. an HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 comprising SSNIGAGYD (SEQ ID NO:36); ii. an LCDR2 comprising GRS; iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0202] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 comprising GDTSDTYT (SEQ ID NO:24); - 52 - 3839034.v15708.1076005 ii. an HCDR2 comprising IILLSGYG (SEQ ID NO:607); and iii. an HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 comprising ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 comprising GRS; and iii. an LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO:44).

[0203] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLPGYA (SEQ ID NO:604); and iii. an HCDR3 consisting of ARGFNRDYYGWGDDDAFDF (SEQ ID NO:605); and b) a VLdomain comprising: i. an LCDR1 consisting of SSNIGAGYR (SEQ ID NO:37); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0204] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTEDTYT (SEQ ID NO:606); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 consisting of ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0205] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYG (SEQ ID NO:607); iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and - 53 - 3839034.v15708.1076005 b) a VLdomain comprising: i. an LCDR1 consisting of SSNIGAGYR (SEQ ID NO:37); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0206] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDYSDVYT (SEQ ID NO:609); ii. an HCDR2 consisting of IILLLGYA (SEQ ID NO:610); and iii. an HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 consisting of SSNIGAGYY (SEQ ID NO:611); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0207] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of LSNIGAGYR (SEQ ID NO:613); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0208] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYS (SEQ ID NO:614); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of ESNIGAGYD (SEQ ID NO:615); ii. an LCDR2 consisting of GRS; and - 54 - 3839034.v15708.1076005 iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0209] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of LSNIGAGYR (SEQ ID NO:613); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0210] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSDYT (SEQ ID NO:609); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0211] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0212] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: - 55 - 3839034.v15708.1076005 i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 consisting of SSNIGAGYD (SEQ ID NO:36); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSYFDPHWV (SEQ ID NO:610).

[0213] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 consisting of ARGFNEDYYGWGDDDAFDF (SEQ ID NO:614); and b) a VLdomain comprising: i. an LCDR1 consisting of VSNIGAGYD (SEQ ID NO:615); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0214] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of PSNIGAGYR (SEQ ID NO:616); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0215] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDIYT (SEQ ID NO:617); ii. an HCDR2 consisting of IILLSGYT (SEQ ID NO:612); and - 56 - 3839034.v15708.1076005 iii. an HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 consisting of VSNIGAGYD (SEQ ID NO:615); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0216] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYT (SEQ ID NO:612); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of ESNIGAGYD (SEQ ID NO:615); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0217] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of VSNIGAGYR (SEQ ID NO:618); ii. an LCDR2 consisting of GSS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0218] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYV (SEQ ID NO:619); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: - 57 - 3839034.v15708.1076005 i. an LCDR1 consisting of SSNIGAGYD (SEQ ID NO:36); ii. an LCDR2 consisting of GRS; iii. an LCDR3 consisting of QSYDSSSFDPHWV (SEQ ID NO:620).

[0219] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of SSNIGAGYR (SEQ ID NO:37); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSYFDPHWV (SEQ ID NO:610).

[0220] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO:28); and iii. an HCDR3 consisting of ARGFNYDYYGWGDDDAFDF (SEQ ID NO:621); and b) a VLdomain comprising: i. an LCDR1 consisting of VSNIGAGYR (SEQ ID NO:618); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44).

[0221] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYS (SEQ ID NO:614); and iii. an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO:608); and b) a VLdomain comprising: i. an LCDR1 consisting of SSNIGAGYD (SEQ ID NO:36); ii. an LCDR2 consisting of GRS; iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44). - 58 - 3839034.v15708.1076005

[0222] In some embodiments, a polypeptide comprises: a) a VHdomain comprising: i. an HCDR1 consisting of GDTSDTYT (SEQ ID NO:24); ii. an HCDR2 consisting of IILLSGYG (SEQ ID NO:607); and iii. an HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO:33); and b) a VLdomain comprising: i. an LCDR1 consisting of ESNIGAGYR (SEQ ID NO:606); ii. an LCDR2 consisting of GRS; and iii. an LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO:44). Variable Domains

[0223] In some embodiments, a polypeptide binds to a SARS-CoV-2 Spike protein (e.g., SEQ ID NO:1 or SEQ ID NO:46) and comprises an immunoglobulin light chain variable domain, an immunoglobulin heavy chain variable domain, or an immunoglobulin light chain variable domain and an immunoglobulin heavy chain variable domain, wherein the polypeptide does not comprise SEQ ID NO:3 or SEQ ID NO:8 or both SEQ ID NO:3 and SEQ ID NO:8.

[0224] In some embodiments, a polypeptide binds to one or more epitope residues of a wildtype SARS-CoV-2 Spike protein (e.g., one or more epitope residues in the SARS-CoV-2 S1 subunit).

[0225] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises a VHdomain, a VLdomain, or both. In some embodiments, a polypeptide comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO:3, a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO:8, or both.

[0226] In some embodiments, a polypeptide comprises a VH(e.g., a mammalian VHsuch as a rodent (e.g., mouse) VH, a primate (e.g., a human) VH) domain. In some embodiments, a polypeptide comprises a VHdomain that is humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% humanized), contains human framework regions, or both.

[0227] In some embodiments, a polypeptide comprises a VHdomain that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:3.

[0228] In some embodiments, a polypeptide comprises a VHdomain that has at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:3. In some embodiments, a - 59 - 3839034.v15708.1076005 polypeptide comprises a VHdomain that has at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:3. In some embodiments, a polypeptide comprises a VHdomain that has at least about 85% sequence identity to the amino acid sequence of SEQ ID NO:3. In some embodiments, a polypeptide comprises a VHdomain that has at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:3.

[0229] In some embodiments, a polypeptide comprises a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative substitution) relative to the amino acid sequence of SEQ ID NO:3. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5- 14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a VHdomain that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:3. In some embodiments, the at least one amino acid substitution replaces only an HCDR1, an HCDR2, and / or an HCDR3 residue, of SEQ ID NO:3. In some embodiments, the at least one amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of SEQ ID NO:3.

[0230] In some embodiments, a polypeptide comprises a VHdomain that has 100% sequence identity to the amino acid sequence of SEQ ID NO:3. In some embodiments, a polypeptide comprises a VHdomain that comprises the amino acid sequence of SEQ ID NO:3.

[0231] In some embodiments, a polypeptide comprises a VHdomain that has at least about 70% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6). The sequences identified as SEQ ID NOs:4-6, 89, and 90 are shown in Table 1, which correspond to human VHdomains. In some embodiments, a polypeptide comprises a VHdomain that has at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6). In some embodiments, a polypeptide comprises a VHdomain that has at least about 85% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6). In some embodiments, a polypeptide comprises a VHdomain that has at least about 90% sequence - 60 - 3839034.v15708.1076005 identity to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6).

[0232] In some embodiments, a polypeptide comprises a VHdomain that comprises at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6). For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7- 12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a VHdomain that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6).

[0233] In some embodiments, an amino acid substitution is a conservative substitution.

[0234] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0235] In some embodiments, a polypeptide comprises a VHdomain that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6). In some embodiments, a polypeptide comprises a VHdomain that comprises the amino acid sequence of any one of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6).

[0236] In some embodiments, a polypeptide comprises a VL(e.g., a mammalian VLsuch as a rodent (e.g., mouse) VL, a primate (e.g., a human) VL) domain. In some embodiments, a polypeptide comprises a VLdomain that is humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% humanized), contains human framework regions, or both.

[0237] In some embodiments, a polypeptide comprises a VLdomain that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:8.

[0238] In some embodiments, a polypeptide comprises a VLdomain that has at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide comprises a VLdomain that has at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide comprises a VLdomain that has at least about 85% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide comprises a VLdomain that has at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:8. - 61 - 3839034.v15708.1076005

[0239] In some embodiments, a polypeptide comprises a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative substitution) relative to the amino acid sequence of SEQ ID NO:8. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5- 14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a VLdomain that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:8. In some embodiments, the at least one amino acid substitution replaces only an LCDR1, an LCDR2, and / or an LCDR3 residue, of SEQ ID NO:8. In some embodiments, the at least one amino acid substitution replaces only a non-CDR residue (e.g., within a framework region), of SEQ ID NO:8.

[0240] In some embodiments, an amino acid substitution is a conservative substitution.

[0241] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0242] In some embodiments, a polypeptide comprises a VLdomain that has 100% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide comprises a VLdomain

[0243] that comprises the amino acid sequence of SEQ ID NO:8.

[0244] In some embodiments, a polypeptide comprises a VLdomain that has at least about 70% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20). The sequences identified as SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20) are shown in Table 2, which correspond to human VLdomains. In some embodiments, a polypeptide comprises a VLthat has at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20). In some embodiments, a polypeptide comprises a VLdomain that has at least about 85% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:20-30. In some embodiments, a polypeptide comprises a VLdomain that has at least about 90% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0245] In some embodiments, a polypeptide comprises a VLdomain that comprises at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID - 62 - 3839034.v15708.1076005 NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20). For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7- 12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a VLdomain that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0246] In some embodiments, an amino acid substitution is a conservative substitution.

[0247] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0248] In some embodiments, a polypeptide comprises a VLdomain that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20). In some embodiments, a polypeptide comprises a VLdomain that comprises the amino acid sequence of any one of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0249] In some embodiments, a polypeptide comprises a VH(e.g., a mammalian VHsuch as a rodent (e.g., mouse) VH, a primate (e.g., a human) VH) domain and a VL(e.g., a mammalian VLsuch as a rodent (e.g., mouse) VL, a primate (e.g., a human) VL) domain. In some embodiments, a polypeptide comprises a VHdomain and VLdomain that are humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% humanized), contain human framework regions, or both.

[0250] In some embodiments, a polypeptide comprises: a) a VHdomain that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:3; b) a VLdomain that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:8; or both a) and b).

[0251] In some embodiments, a polypeptide comprises: a) a VHdomain that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:3; and b) a VLdomain that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:8.

[0252] In some embodiments, a polypeptide comprises: - 63 - 3839034.v15708.1076005 a) a VHdomain that has at least about 55% (e.g., at least about: 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:3; b) a VLdomain that has at least about 55% (e.g., at least about: 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:8; or both a) and b), wherein the polypeptide does not comprise all 6 CDRs of an antibody comprising a VHamino acid sequence of SEQ ID NO:3 and a VLamino acid sequence of SEQ ID NO:8.

[0253] In some embodiments, a polypeptide comprises: a) a VHdomain that has at least about 55% (e.g., at least about: 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:3; and b) a VLdomain that has at least about 55% (e.g., at least about: 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:8, wherein the polypeptide does not comprise all 6 CDRs of an antibody comprising a VHamino acid sequence of SEQ ID NO:3 and a VLamino acid sequence of SEQ ID NO:8.

[0254] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative substitution) relative to the amino acid sequence of SEQ ID NO:3; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative substitution) relative to the amino acid sequence of SEQ ID NO:8; or both a) and b).

[0255] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:3; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:8. - 64 - 3839034.v15708.1076005

[0256] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of SEQ ID NO:3; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of SEQ ID NO:8; or both a) and b).

[0257] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of SEQ ID NO:3; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of SEQ ID NO:8.

[0258] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:3; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:8; or both a) and b).

[0259] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:3; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:8.

[0260] In some embodiments, a polypeptide comprises: - 65 - 3839034.v15708.1076005 a) a VHdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); b) a VLdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20); or both a) and b).

[0261] In some embodiments, a polypeptide comprises: a) a VHdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); and b) a VLdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0262] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20); or both a) and b).

[0263] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20). - 66 - 3839034.v15708.1076005

[0264] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20); or both a) and b).

[0265] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0266] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20); or both a) and b).

[0267] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a - 67 - 3839034.v15708.1076005 non-CDR residue (e.g., within a framework region), of any one or more of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0268] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); and b) a VLdomain comprising the amino acid sequence of any one of SEQ ID NOs:9- 20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0269] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6); and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:8.

[0270] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:3; and b) a VLdomain comprising the amino acid sequence of any one of SEQ ID NOs:9- 20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0271] In some embodiments, a polypeptide comprises: a) a VHdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:5; b) a VLdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:14; or both a) and b).

[0272] In some embodiments, a polypeptide comprises: a) a VHdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:5; and b) a VLdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:14.

[0273] In some embodiments, a polypeptide comprises: - 68 - 3839034.v15708.1076005 a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:5; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:14; or both a) and b).

[0274] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:5; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:14.

[0275] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of SEQ ID NO:5; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of SEQ ID NO:14; or both a) and b).

[0276] In some embodiments, an amino acid substitution is a conservative substitution.

[0277] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0278] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of SEQ ID NO:5; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of SEQ ID NO:14.

[0279] In some embodiments, a polypeptide comprises: - 69 - 3839034.v15708.1076005 a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:5; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:14; or both a) and b).

[0280] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:5; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of SEQ ID NO:14.

[0281] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:5, and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:14 (AB-2b).

[0282] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:9 (AB-1a).

[0283] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:10 (AB-1b).

[0284] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:11 (AB-1c).

[0285] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:12 (AB-1d).

[0286] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:5; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:13 (AB-2a).

[0287] In some embodiments, a polypeptide comprises: - 70 - 3839034.v15708.1076005 a) a VHdomain comprising the amino acid sequence of SEQ ID NO:5; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:15 (AB-2c).

[0288] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:5; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:16 (AB-2d).

[0289] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:17 (AB-3a).

[0290] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:18 (AB-3b).

[0291] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:19 (AB-3c).

[0292] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:20 (AB-3d).

[0293] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:89; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:91 (AB-4a).

[0294] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:90; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:92 (AB-7a).

[0295] In some embodiments, a polypeptide comprises a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 that are substantially similar in amino acid sequence to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in any of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6).

[0296] In some embodiments, a polypeptide comprises a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 that are substantially similar in amino acid sequence to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in any of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0297] In some embodiments, a polypeptide comprises a VHdomain that comprises an HCDR1, an HCDR2, and an HCDR3 that are identical in amino acid sequence to an HCDR1, an - 71 - 3839034.v15708.1076005 HCDR2, and an HCDR3, respectively, of a VHamino acid sequence set forth in any of SEQ ID NOs:4-6, 89, and 90 (e.g., SEQ ID NOs:4-6).

[0298] In some embodiments, a polypeptide comprises a VLdomain that comprises an LCDR1, an LCDR2, and an LCDR3 that are identical in amino acid sequence to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLamino acid sequence set forth in any of SEQ ID NOs:9-20, 91, and 92 (e.g., SEQ ID NOs:9-20).

[0299] In some embodiments, a polypeptide comprises a VHdomain that has at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90, or any combination of the foregoing. For example, a VHdomain can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90, or any combination of the foregoing. In some embodiments, a VHdomain has at least about 85% or at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90, or any combination of the foregoing.

[0300] In some embodiments, a polypeptide comprises a VLdomain that has at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:8. For example, the VLdomain can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the VLdomain has at least about 85% or at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:8. The sequence identified as SEQ ID NO:8 is shown in Table 2, which corresponds to a human VLdomain.

[0301] In some embodiments, a polypeptide comprises a VLdomain that has at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing. For example, the VLdomain can have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, - 72 - 3839034.v15708.1076005 SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing. In some embodiments, the VLdomain has at least about 85% or at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing.

[0302] In some embodiments, a polypeptide comprises a VHdomain that comprises at least 1 amino acid substitution (e.g., at least 1 conservative substitution such as highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:3. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5- 14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, or 9-11. In some embodiments, a VHdomain comprises about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:3. In some embodiments, the at least 1 amino acid substitution replaces only an HCDR1, an HCDR2, and / or an HCDR3 residue of SEQ ID NO:3. In some embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region) of SEQ ID NO:3.

[0303] In some embodiments, a polypeptide comprises a VHdomain that comprises at least 1 amino acid substitution relative to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90, or any combination of the foregoing. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, or 9-11. In some embodiments, a VHdomain comprises about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90, or any combination of the foregoing.

[0304] In some embodiments, the at least 1 amino acid substitution replaces only an HCDR1, an HCDR2, and / or an HCDR3 residue of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90, or any combination of the foregoing. In particular embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region) of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, SEQ ID NO:90,or any combination of the foregoing. - 73 - 3839034.v15708.1076005

[0305] In some embodiments, a polypeptide comprises a VLdomain that comprises at least 1 amino acid substitution relative to the amino acid sequence of SEQ ID NO:8. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5- 14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, or 9-11. In some embodiments, the VLdomain comprises about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:8. In some embodiments, the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2, and / or an LCDR3 residue of SEQ ID NO:8. In particular embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region) of SEQ ID NO:8.

[0306] In some embodiments, a polypeptide comprises a VLdomain that comprises at least 1 amino acid substitution relative to the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7- 12, 8-12, 8-11, or 9-11. In some embodiments, a VLdomain comprises about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing.

[0307] In some embodiments, the at least 1 amino acid substitution replaces only an LCDR1, an LCDR2, and / or an LCDR3 residue of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing. In particular embodiments, the at least 1 amino acid substitution replaces only a non-CDR residue (e.g., within a framework region) of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing.

[0308] In some embodiments, a polypeptide comprises a VHdomain that comprises the amino acid sequence of SEQ ID NO:3. In some embodiments, a polypeptide comprises a VH- 74 - 3839034.v15708.1076005 domain that comprises the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, or SEQ ID NO:90.

[0309] In some embodiments, a polypeptide comprises a VLdomain that comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, a polypeptide comprises a VLdomain that comprises SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92.

[0310] In some embodiments, a polypeptide comprises a VLdomain that comprises the amino acid sequence of SEQ ID NO:22. In some embodiments, a polypeptide comprises a VLdomain that comprises SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92.

[0311] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:8.

[0312] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:3; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20.

[0313] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:8.

[0314] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, or SEQ ID NO:20. - 75 - 3839034.v15708.1076005

[0315] In some embodiments, VHand VLdomains may be linked together via a linker (e.g., a synthetic linker) to form various types of single-chain antibody designs in which the VH / VLdomains pair intramolecularly, or intermolecularly in those cases when the VHand VLdomains are expressed by separate chains, to form a monovalent antigen binding site.

[0316] In some embodiments, a polypeptide comprises a VHdomain that has at least about 70% sequence identity to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein. In some embodiments, a polypeptide comprises a VHdomain that has at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein. In some embodiments, a polypeptide comprises a VHdomain that has at least about 85% sequence identity to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein. In some embodiments, a polypeptide comprises a VHdomain that has at least about 90% sequence identity to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein.

[0317] In some embodiments, a polypeptide comprises a VHdomain that comprises at least one amino acid substitution relative to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2- 17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a VHdomain that comprises about 1-10 amino acid substitutions, relative to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein.

[0318] In some embodiments, an amino acid substitution is a conservative substitution.

[0319] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0320] In some embodiments, a polypeptide comprises a VHdomain that has 100% sequence identity to any one of VHamino acid sequences set forth in Table 1 and Table 4 herein. In some embodiments, a polypeptide comprises a VHdomain that comprises any one of VHamino acid sequences set forth in Table 1 and Table 4 herein.

[0321] In some embodiments, a polypeptide comprises a VLdomain that has at least about 70% sequence identity to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein. In some embodiments, a polypeptide comprises a VLthat has at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, - 76 - 3839034.v15708.1076005 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein. In some embodiments, a polypeptide comprises a VLdomain that has at least about 85% sequence identity to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein. In some embodiments, a polypeptide comprises a VLdomain that has at least about 90% sequence identity to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0322] In some embodiments, a polypeptide comprises a VLdomain that comprises at least one amino acid substitution relative to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2- 17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a VLdomain that comprises about 1-10 amino acid substitutions, relative to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0323] In some embodiments, an amino acid substitution is a conservative substitution.

[0324] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0325] In some embodiments, a polypeptide comprises a VLdomain that has 100% sequence identity to any one of VLamino acid sequences set forth in Table 2 and Table 4 herein. In some embodiments, a polypeptide comprises a VLdomain that comprises the amino acid sequence of any one of VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0326] In some embodiments, a polypeptide comprises: a) a VHdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; b) a VLdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein; or both a) and b).

[0327] In some embodiments, a polypeptide comprises: a) a VHdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; and - 77 - 3839034.v15708.1076005 b) a VLdomain that has at least about 70% (e.g., at least about: 75, 80, 85, 90, 95, 98, or 99%) sequence identity to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0328] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein; or both a) and b).

[0329] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) relative to one or more VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0330] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of any one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of any one or more VLamino acid sequences set forth in Table 2 and Table 4 herein; or both a) and b).

[0331] In some embodiments, a polypeptide comprises: - 78 - 3839034.v15708.1076005 a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a HCDR1, a HCDR2 and / or a HCDR3 residue, of any one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a LCDR1, a LCDR2 and / or a LCDR3 residue, of any one or more VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0332] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more VLamino acid sequences set forth in Table 2 and Table 4 herein; or both a) and b).

[0333] In some embodiments, a polypeptide comprises: a) a VHdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more VHamino acid sequences set forth in Table 1 and Table 4 herein; and b) a VLdomain that comprises at least one amino acid substitution (e.g., at least one conservative substitution such as highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region), of any one or more VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0334] In some embodiments, a polypeptide comprises: a) a VHdomain comprising any one of VHamino acid sequences set forth in Table 1 and Table 4 herein; and b) a VLdomain comprising any one of VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0335] In some embodiments, a polypeptide comprises: - 79 - 3839034.v15708.1076005 a) a VHdomain comprising any one of VHamino acid sequences set forth in Table 1 and Table 4 herein; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:8.

[0336] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:3; and b) a VLdomain comprising any one of VLamino acid sequences set forth in Table 2 and Table 4 herein.

[0337] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:255; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:14.

[0338] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:292; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:477.

[0339] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:206; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:14.

[0340] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:202; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:434.

[0341] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:140; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:472.

[0342] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:240; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:449.

[0343] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:213; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:472.

[0344] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:258; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:477.

[0345] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:213; and - 80 - 3839034.v15708.1076005 b) a VLdomain comprising the amino acid sequence of SEQ ID NO:477.

[0346] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:5; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:512.

[0347] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:158; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:469.

[0348] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:213; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:452.

[0349] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:232; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:469.

[0350] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:140; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:449.

[0351] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:213; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:484.

[0352] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:204; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:455.

[0353] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:213; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:461.

[0354] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:137; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:426.

[0355] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:240; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:424.

[0356] In some embodiments, a polypeptide comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:130; and - 81 - 3839034.v15708.1076005 b) a VLdomain comprising the amino acid sequence of SEQ ID NO:477. Paratopes

[0357] Amino acid residues of a paratope contribute to an antibody’s interaction with an epitope of its target protein. An interaction can be a hydrogen bond, a salt bridge, a van der Waals interaction, an electrostatic interaction, a hydrophobic interaction, pi-interaction effects, an ionic bond, and / or any combination thereof. An interaction can be direct, or indirect, e.g., via a coordinated intermediate molecule, such as an ion or water. The residues of a paratope, in some embodiments, comprise only residues that are part of a defined CDR. In some embodiments, the residues of a paratope further comprise one or more residues that are not part of a defined CDR (e.g., residues within a defined framework region).

[0358] In some embodiments, a paratope is oriented less than about 5.0 angstroms from an epitope on a target antigen when a polypeptide is bound to the target antigen, e.g., less than about: 4.5, 4.0, 3.5, 3.0, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, or 0.9 angstroms, or about: 0.9-5.0, 0.9-4.8.1.0-5, 1.0-4.5, 1.0-4.0, 1.0-3.5, 1.1-3.5, 1.1-3.0, 1.2-3.0, 1.2-2.5, 1.3-2.5, 1.3-2.4, 1.4-2.4, 1.4-2.3, 1.5-2.3, 1.5-2.2, 1.6-2.2, 1.6-2.1, 1.7-2.1, 1.7-2.0, or 1.8-2.0 angstroms, from the epitope. In some embodiments, less than all of the amino acid residues constituting a paratope (e.g., about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% of the amino acid residues) in the paratope are oriented less than about 5.0 angstroms from an epitope on a target antigen when a polypeptide is bound to the target antigen.

[0359] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprising a paratope comprises a VHdomain and a VLdomain. In some embodiments, paratope residues are contained within a VHand VLof a polypeptide.

[0360] In some embodiments, a polypeptide comprises a paratope that differs from a paratope of an antibody comprising a VH / VLcombination of SEQ ID NO:3 / SEQ ID NO:8.

[0361] In some embodiments, a polypeptide comprises a VHdomain that has at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:3. For example, a VHcan have at least about: 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:3. In some embodiments, a VHhas at least about 85% or at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:3. The sequence identified as SEQ ID NO:3 is shown in Table 1, which corresponds to a human VHdomain. - 82 - 3839034.v15708.1076005

[0362] In some embodiments, a polypeptide comprises a paratope that is substantially similar (e.g., having at least about 90% sequence identity) to a paratope of an antibody comprising a VH / VLcombination of SEQ ID NO:3 / SEQ ID NO:8. In some embodiments, a polypeptide comprises a paratope that is substantially similar (e.g., having at least about 90% sequence identity) to, and substantially preserves one or more functional properties of, a paratope of an antibody comprising a VH / VLcombination of SEQ ID NO:3 / SEQ ID NO:8.

[0363] In some embodiments, a polypeptide comprises a paratope that has 100% sequence identity to a paratope of an antibody comprising a VH / VLcombination of SEQ ID NO:3 / SEQ ID NO:8.

[0364] In some embodiments, a polypeptide comprises a paratope that differs from a paratope of an antibody comprising a VH / VLcombination of SEQ ID NO:3 / SEQ ID NO:8, by substitution (e.g., conservative substitution such as highly conservative substitution) of from 1 to 3 (e.g., 1, 2 or 3) residues.

[0365] In some embodiments, a polypeptide comprises a paratope that differs from a paratope of a VH / VLcombination selected from: SEQ ID NO:4 / SEQ ID NO:9 (AB-1a), SEQ ID NO:4 / SEQ ID NO:10 (AB-1b), SEQ ID NO:4 / SEQ ID NO:11 (AB-1c), SEQ ID NO:4 / SEQ ID NO:12 (AB-1d), SEQ ID NO:5 / SEQ ID NO:13 (AB-2a), SEQ ID NO:5 / SEQ ID NO:14 (AB- 2b), SEQ ID NO:5 / SEQ ID NO:15 (AB-2c), SEQ ID NO:5 / SEQ ID NO:16 (AB-2d), SEQ ID NO:6 / SEQ ID NO:17 (AB-3a), SEQ ID NO:6 / SEQ ID NO:18 (AB-3b), SEQ ID NO:6 / SEQ ID NO:19 (AB-3c), or SEQ ID NO:6 / SEQ ID NO:20 (AB-3d), by substitution (e.g., conservative such as highly conservative substitution) of from 1 to 3 (e.g., 1, 2 or 3) residues. See Table 1 for SEQ ID NOs:4-6 and Table 2 for SEQ ID NOs:9-20.

[0366] In some embodiments, a polypeptide comprises a paratope that is substantially similar (e.g., having at least about 90% sequence identity) to a paratope of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); - 83 - 3839034.v15708.1076005 SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); or any combination thereof.

[0367] In some embodiments, a polypeptide comprises a paratope that is substantially similar (e.g., having at least about 90% sequence identity) to, and substantially preserves one or more functional properties of, a paratope of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); or any combination thereof.

[0368] In some embodiments, a polypeptide comprises a paratope comprising only one or more conservative substitutions (e.g., only one or more highly conservative substitutions) relative a paratope of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); - 84 - 3839034.v15708.1076005 SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); SEQ ID NO:6 and SEQ ID NO:20 (AB-3d); or any combination thereof.

[0369] In some embodiments, the disclosure provides a polypeptide that specifically binds SARS-CoV-2-Spike, wherein the polypeptide comprises a paratope that has 100% sequence identity to a paratope of an antibody comprising a VH / VLpair selected from: SEQ ID NO:4 and SEQ ID NO:9 (AB-1a); SEQ ID NO:4 and SEQ ID NO:10 (AB-1b); SEQ ID NO:4 and SEQ ID NO:11 (AB-1c); SEQ ID NO:4 and SEQ ID NO:12 (AB-1d); SEQ ID NO:5 and SEQ ID NO:13 (AB-2a); SEQ ID NO:5 and SEQ ID NO:14 (AB-2b); SEQ ID NO:5 and SEQ ID NO:15 (AB-2c); SEQ ID NO:5 and SEQ ID NO:16 (AB-2d); SEQ ID NO:6 and SEQ ID NO:17 (AB-3a); SEQ ID NO:6 and SEQ ID NO:18 (AB-3b); SEQ ID NO:6 and SEQ ID NO:19 (AB-3c); or SEQ ID NO:6 and SEQ ID NO:20 (AB-3d).

[0370] In some embodiments, a polypeptide comprises a paratope that is substantially similar to a paratope of a polypeptide selected from any one of AB-1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d. In some embodiments, a polypeptide comprises a paratope comprising only conservative substitutions (e.g., only highly conservative substitutions) relative a paratope of a polypeptide selected from any one of AB-1a, AB-1b, AB- 1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d. In some embodiments, a polypeptide comprises a paratope comprising up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 conservative substitutions (e.g., up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 highly conservative substitutions), relative a paratope of a polypeptide selected from any one of AB-1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB- 3c, and AB-3d. In some embodiments, a polypeptide comprises a paratope having 100% sequence identity to a paratope of a polypeptide selected from any one of AB-1a, AB-1b, AB-1c, AB-1d, AB-2a, AB-2b, AB-2c, AB-2d, AB-3a, AB-3b, AB-3c, and AB-3d. - 85 - 3839034.v15708.1076005

[0371] In some embodiments, a polypeptide comprises a paratope that is substantially similar to a paratope of a VH / VLcombination selected from: SEQ ID NO:4 / SEQ ID NO:9 (AB-1a), SEQ ID NO:4 / SEQ ID NO:10 (AB-1b), SEQ ID NO:4 / SEQ ID NO:11 (AB-1c), SEQ ID NO:4 / SEQ ID NO:12 (AB-1d), SEQ ID NO:5 / SEQ ID NO:13 (AB-2a), SEQ ID NO:5 / SEQ ID NO:14 (AB- 2b), SEQ ID NO:5 / SEQ ID NO:15 (AB-2c), SEQ ID NO:5 / SEQ ID NO:16 (AB-2d), SEQ ID NO:6 / SEQ ID NO:17 (AB-3a), SEQ ID NO:6 / SEQ ID NO:18 (AB-3b), SEQ ID NO:6 / SEQ ID NO:19 (AB-3c), or SEQ ID NO:6 / SEQ ID NO:20 (AB-3d).

[0372] In some embodiments, a polypeptide comprises a paratope that is identical to a paratope of a VH / VLcombination selected from: SEQ ID NO:4 / SEQ ID NO:9 (AB-1a), SEQ ID NO:4 / SEQ ID NO:10 (AB-1b), SEQ ID NO:4 / SEQ ID NO:11 (AB-1c), SEQ ID NO:4 / SEQ ID NO:12 (AB-1d), SEQ ID NO:5 / SEQ ID NO:13 (AB-2a), SEQ ID NO:5 / SEQ ID NO:14 (AB- 2b), SEQ ID NO:5 / SEQ ID NO:15 (AB-2c), SEQ ID NO:5 / SEQ ID NO:16 (AB-2d), SEQ ID NO:6 / SEQ ID NO:17 (AB-3a), SEQ ID NO:6 / SEQ ID NO:18 (AB-3b), SEQ ID NO:6 / SEQ ID NO:19 (AB-3c), or SEQ ID NO:6 / SEQ ID NO:20 (AB-3d). Consensus Sequences

[0373] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises a VHcomprising the amino acid sequence of SEQ ID NO:2, wherein: X1is not G; X2is not I; X3is not F; X4is not N; X5is not M; X6is not S; X7is not M; X8is not N; X9is not G; X10is not N; X11is not I; or any combination of the foregoing.

[0374] The sequence identified as SEQ ID NO:2 is shown in Table 1, which is a consensus VHsequence for SEQ ID Nos:3-6 herein.

[0375] In some embodiments: X1is G or D; - 86 - 3839034.v15708.1076005 X2is I, T or Y; X3is F, S or D; X4is N or D; X5is M or L; X6is S or F; X7is M, Y or A; X8is N or H; X9is G or P; X10is N or D; X11is I or F; or any combination of the foregoing.

[0376] In some embodiments: X1is D; X2is T or Y; X3is S or D; X4is D; X5is L; X6is F; X7is Y or A; X8is H; X9is P; X10is D; X11is F; or any combination of the foregoing.

[0377] In some embodiments, X1is not G. In some embodiments, X1is G or D. In some embodiments, X1is G. In some embodiments, X1is D.

[0378] In some embodiments, X2is not I. In some embodiments, X2is I, T or Y. In some embodiments, X2is T or Y. In some embodiments, X2is I. In some embodiments, X2is T. In some embodiments, X2is Y.

[0379] In some embodiments, X3is not F. In some embodiments, X3is F, S or D. In some embodiments, X3is S or D. In some embodiments, X3is F. In some embodiments, X3is S. In some embodiments, X3is D. - 87 - 3839034.v15708.1076005

[0380] In some embodiments, X4is not N. In some embodiments, X4is N or D. In some embodiments, X4is N. In some embodiments, X4is D.

[0381] In some embodiments, X5is not M. In some embodiments, X5is M or L. In some embodiments, X5is M. In some embodiments, X5is L.

[0382] In some embodiments, X6is not S. In some embodiments, X6is S or F. In some embodiments, X6is S. In some embodiments, X6is F.

[0383] In some embodiments, X7is not M. In some embodiments, X7is M, Y or A. In some embodiments, X7is Y or A. In some embodiments, X7is M. In some embodiments, X7is Y. In some embodiments, X7is A.

[0384] In some embodiments, X8is not N. In some embodiments, X8is N or H. In some embodiments, X8is N. In some embodiments, X8is H.

[0385] In some embodiments, X9is not G. In some embodiments, X9is G or P. In some embodiments, X9is G. In some embodiments, X9is P.

[0386] In some embodiments, X10is not N. In some embodiments, X10is N or D. In some embodiments, X10is N. In some embodiments, X10is D.

[0387] In some embodiments, X11is not I. In some embodiments, X11is I or F. In some embodiments, X11is I. In some embodiments, X11is F.

[0388] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises a VLcomprising the amino acid sequence of SEQ ID NO:7, wherein: X12is not N; X13is not D; X14is not C; X15is not N; X16is not S; X17is not L; X18is not S; X19is not G; X20is not N; or any combination of the foregoing.

[0389] The sequence identified as SEQ ID NO:7 is shown in Table 2, which is a consensus VLsequence for SEQ ID Nos:8-20 herein.

[0390] In some embodiments: X12is N or S; - 88 - 3839034.v15708.1076005 X13is D or R; X14is C, A, S, or Y; X15is N or R; X16is S or D; X17is L or S; X18is S or F; X19is G or D; X20is N or H; or any combination of the foregoing.

[0391] In some embodiments: X12is S; X13is R; X14is A, S, or Y; X15is R; X16is D; X17is S; X18is F; X19is D; X20is H; or any combination of the foregoing.

[0392] In some embodiments, X12is not N. In some embodiments, X12is N or S. In some embodiments, X12is N. In some embodiments, X12is S.

[0393] In some embodiments, X13is not D. In some embodiments, X13is D or R. In some embodiments, X13is D. In some embodiments, X13is R.

[0394] In some embodiments, X14is not C. In some embodiments, X14is C, A, S, or Y. In some embodiments, X14is A, S, or Y. In some embodiments, X14is C. In some embodiments, X14is A. In some embodiments, X14is S. In some embodiments, X14is Y.

[0395] In some embodiments, X15is not N. In some embodiments, X15is N or R. In some embodiments, X15is N. In some embodiments, X15is R.

[0396] In some embodiments, X16is not S. In some embodiments, X16is S or D. In some embodiments, X16is S. In some embodiments, X16is D.

[0397] In some embodiments, X17is not L. In some embodiments, X17is L or S. In some embodiments, X17is L. In some embodiments, X17is S. - 89 - 3839034.v15708.1076005

[0398] In some embodiments, X18is not S. In some embodiments, X18is S or F. In some embodiments, X18is S. In some embodiments, X18is F.

[0399] In some embodiments, X19is not G. In some embodiments, X19is G or D. In some embodiments, X19is G. In some embodiments, X19is D.

[0400] In some embodiments, X20is not N. In some embodiments, X20is N or H. In some embodiments, X20is N. In some embodiments, X20is H.

[0401] In some embodiments, a) X1is G, X2is Y, X3is D, X4is N, X5is L, X6is F, X7is A, X8is H, X9is P, X10is D, X11is F, X12is S, X13is D, X14is C, X15is R, X16is D, X17is S, X18is S, X19is G, X20is H, or a combination thereof (AB-1a); b) X1is G, X2is Y, X3is D, X4is N, X5is L, X6is F, X7is A, X8is H, X9is P, X10is D, X11is F, X12is S, X13is D, X14is A, X15is R, X16is D, X17is S, X18is S, X19is G, X20is H, or a combination thereof (AB-1b); c) X1is G, X2is Y, X3is D, X4is N, X5is L, X6is F, X7is A, X8is H, X9is P, X10is D, X11is F, X12is S, X13is D, X14is S, X15is R, X16is D, X17is S, X18is S, X19is G, X20is H, or a combination thereof (AB-1c); d) X1is G, X2is Y, X3is D, X4is N, X5is L, X6is F, X7is A, X8is H, X9is P, X10is D, X11is F, X12is S, X13is D, X14is Y, X15is R, X16is D, X17is S, X18is S, X19is G, X20is H, or a combination thereof (AB-1d); e) X1is D, X2is T, X3is S, X4is D, X5is L, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is R, X14is C, X15is R, X16is S, X17is L, X18is F, X19is D, X20is H, or a combination thereof (AB-2a); f) X1is D, X2is T, X3is S, X4is D, X5is L, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is R, X14is A, X15is R, X16is S, X17is L, X18is F, X19is D, X20is H, or a combination thereof (AB-2b); g) X1is D, X2is T, X3is S, X4is D, X5is L, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is R, X14is S, X15is R, X16is S, X17is L, X18is F, X19is D, X20is H, or a combination thereof (AB-2c); h) X1is D, X2is T, X3is S, X4is D, X5is L, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is R, X14is Y, X15is R, X16is S, X17is L, X18is F, X19is D, X20is H, or a combination thereof (AB-2d); - 90 - 3839034.v15708.1076005 i) X1is D, X2is T, X3is S, X4is D, X5is M, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is D, X14is C, X15is R, X16is S, X17is L, X18is S, X19is D, X20is H, or a combination thereof (AB-3a); j) X1is D, X2is T, X3is S, X4is D, X5is M, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is D, X14is A, X15is R, X16is S, X17is L, X18is S, X19is D, X20is H, or a combination thereof (AB-3b); k) X1is D, X2is T, X3is S, X4is D, X5is M, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is D, X14is S, X15is R, X16is S, X17is L, X18is S, X19is D, X20is H, or a combination thereof (AB-3c); or l) X1is D, X2is T, X3is S, X4is D, X5is M, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is D, X14is Y, X15is R, X16is S, X17is L, X18is S, X19is D, X20is H, or a combination thereof (AB-3d).

[0402] In some embodiments, X1is D, X2is T, X3is S, X4is D, X5is L, X6is S, X7is Y, X8is N, X9is G, X10is D, X11is F, X12is S, X13is R, X14is A, X15is R, X16is S, X17is L, X18is F, X19is D, X20is H, or a combination thereof (AB-2b). Constant Domains

[0403] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises: a) an antibody heavy chain constant domain sequence; b) an antibody light chain constant domain sequence; or c) both an antibody heavy chain constant domain sequence and an antibody light chain constant domain sequence.

[0404] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence. In some embodiments, an antibody heavy chain constant domain is selected from the group consisting of an IgA constant domain, an IgD constant domain, an IgE constant domain, an IgG constant domain, and an IgM constant domain.

[0405] In some embodiments, an IgG constant domain is an IgG1 constant domain (e.g., SEQ ID NO:576 or SEQ ID NO:50), an IgG2 constant domain, an IgG3 constant domain, or an IgG4 constant domain. In some embodiments, the IgG2 constant domain is an IgG2a constant domain, an IgG2b constant domain or an IgG2c constant domain. In some embodiments, the IgA constant domain is an IgA1 constant domain or an IgA2 constant domain. In some embodiments, the antibody heavy chain constant domain is an IgG1 constant domain (e.g., IGHV1-5 or IGHV5-51). - 91 - 3839034.v15708.1076005

[0406] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:576).

[0407] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:576. For example, a polypeptide can comprise an antibody heavy chain constant domain sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:576. In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:576.

[0408] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:576. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:576.

[0409] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:576.

[0410] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:50). - 92 - 3839034.v15708.1076005

[0411] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:50. For example, a polypeptide can comprise an antibody heavy chain constant domain sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:50. In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:50.

[0412] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:50. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:50.

[0413] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:50.

[0414] In some embodiments, a polypeptide comprises an Fc polypeptide, or Fc domain (e.g., an IgG1 domain, an IgG2 domain or an IgG4 domain). In some embodiments, an Fc domain comprises one or more mutations that, for example, decreases (e.g., inhibits, ablates) an effector function of the Fc domain, increases half-life of an antibody or antibody fragment that comprises the Fc domain, or a combination thereof. See, e.g., Dumet et al., Insights into the IgG heavy chain engineering patent landscape as applied to IgG4 antibody development, Mabs. 11(8):1341-50 (2019) (particularly Tables 1 and 2 therein) and WO02060919, the contents of which are incorporated by reference herein in their entirety. In some embodiments, an Fc domain comprises a LS modification (i.e., M428L / N434S substitutions with numbering determined by Kabat) or a YTE modification (i.e., M252Y / S254T / T256E substitutions as determined by Kabat numbering). In some embodiments, an Fc domain comprises a LS modification.

[0415] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises an antibody light chain constant domain sequence. - 93 - 3839034.v15708.1076005

[0416] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that is a λ constant domain (e.g., SEQ ID NO:577 or SEQ ID NO:52).

[0417] GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAG VETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:577).

[0418] GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAG VETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:52).

[0419] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:557 or SEQ ID NO:52. For example, a polypeptide can comprise an antibody light chain constant domain sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:557 or SEQ ID NO:52. In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has at least about 70% or at least about 80% sequence identity to SEQ ID NO:557 or SEQ ID NO:52.

[0420] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:557 or SEQ ID NO:52. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7- 12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:557 or SEQ ID NO:52. In some embodiments, the at least one amino acid substitution is a conservative substitution. In some embodiments, the at least one amino acid substitution is a highly conservative substitution.

[0421] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:557 or SEQ ID NO:52.

[0422] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has at least about 60% sequence identity to the amino acid sequence of - 94 - 3839034.v15708.1076005 SEQ ID NO:557. For example, a polypeptide can comprise an antibody light chain constant domain sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:557. In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has at least about 70% or at least about 80% sequence identity to SEQ ID NO:557.

[0423] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:557. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:557. In some embodiments, the at least one amino acid substitution is a conservative substitution. In some embodiments, the at least one amino acid substitution is a highly conservative substitution.

[0424] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:557.

[0425] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that is a κ constant domain (e.g., SEQ ID NO:51).

[0426] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:51).

[0427] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51. For example, a polypeptide can comprise an antibody light chain constant domain sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51. In some embodiments, a polypeptide comprises an antibody light - 95 - 3839034.v15708.1076005 chain constant domain sequence that has at least about 70% or at least about 80% sequence identity to SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51.

[0428] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6- 13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51. In some embodiments, the at least one amino acid substitution is a conservative substitution. In some embodiments, the at least one amino acid substitution is a highly conservative substitution.

[0429] In some embodiments, a polypeptide comprises an antibody light chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51.

[0430] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain sequence; and b) an antibody light chain constant domain sequence.

[0431] In some embodiments, a polypeptide comprises an antibody heavy chain constant domain that is an IgG1 constant domain (e.g., SEQ ID NO:576 or SEQ ID NO:50), and an antibody light chain constant domain that is a λ constant domain (e.g., SEQ ID NO:577 or SEQ ID NO:52).

[0432] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain comprising SEQ ID NO:576; b) an antibody light chain constant domain comprising SEQ ID NO:577; or both a) and b).

[0433] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain comprising SEQ ID NO:576; and b) an antibody light chain constant domain comprising SEQ ID NO:577.

[0434] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain comprising SEQ ID NO:50; b) an antibody light chain constant domain comprising SEQ ID NO:577; or both a) and b). - 96 - 3839034.v15708.1076005

[0435] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain comprising SEQ ID NO:50; and

[0436] an antibody light chain constant domain comprising SEQ ID NO:577.

[0437] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain comprising SEQ ID NO:576; b) an antibody light chain constant domain comprising SEQ ID NO:52; or both a) and b).

[0438] In some embodiments, a polypeptide comprises: a) an antibody heavy chain constant domain comprising SEQ ID NO:576; and b) an antibody light chain constant domain comprising SEQ ID NO:52. Antibodies and Antigen Binding Fragments

[0439] In some embodiments, a polypeptide specifically binds a spike receptor-binding domain (RBD) class 4 epitope of a betacoronavirus Spike glycoprotein (SARS-CoV-2-Spike).

[0440] In some embodiments, a polypeptide is an immunoglobulin molecule, such as an antibody (e.g., a whole antibody, an intact antibody) or an antigen-binding fragment of an antibody.

[0441] In some embodiments, a polypeptide is an antibody. As used herein, the term “antibody” refers to an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable domain of the immunoglobulin molecule. As used herein, the term “antibody” refers to a full-length antibody.

[0442] In some embodiments, a polypeptide is an antibody comprising two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds or multimers thereof (for example, IgM). Each heavy chain comprises a VH and a heavy chain constant domain (comprising domains CH1, hinge CH2 and CH3). Each light chain comprises a VL and a light chain constant domain (CL). VH and VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed within framework regions (FRs). VH and VL each comprises three CDRs and four FRs, arranged from the amino-terminus to the carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. An antibody can be of any species, such as a murine antibody, a human antibody, or a humanized antibody.

[0443] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of any one or more of - 97 - 3839034.v15708.1076005 SEQ ID NOs:578-591. For example, a polypeptide can comprise a heavy chain amino acid sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:578-591. In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:578-591.

[0444] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:578).

[0445] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLPGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNRDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:579).

[0446] QVQLVQSGAEVKKPGSSVKVSCKASGDTEDTYTISWVRQAPGQGLEWMGRI ILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP - 98 - 3839034.v15708.1076005 VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:580).

[0447] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYGNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:581).

[0448] QVQLVQSGAEVKKPGSSVKVSCKASGDYSDVYTISWVRQAPGQGLEWMGRI ILLLGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:582).

[0449] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:583).

[0450] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYSNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS - 99 - 3839034.v15708.1076005 CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:584).

[0451] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:585).

[0452] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSDYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:586).

[0453] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNEDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:587). - 100 - 3839034.v15708.1076005

[0454] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDIYTISWVRQAPGQGLEWMGRII LLSGYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGDD DAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:588).

[0455] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYVNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:589).

[0456] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNYDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:590).

[0457] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRI ILLSGYGNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGD DDAFDFWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS - 101 - 3839034.v15708.1076005 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:591).

[0458] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that comprises at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:578-591. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:578-591.

[0459] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:578-591.

[0460] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:578. For example, a polypeptide can comprise a heavy chain amino acid sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:578. In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:578.

[0461] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:578. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:578.

[0462] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:578.

[0463] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:579. For - 102 - 3839034.v15708.1076005 example, a polypeptide can comprise a heavy chain amino acid sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:579. In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:579.

[0464] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:579. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:579.

[0465] In some embodiments, a polypeptide comprises a heavy chain amino acid sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:579.

[0466] In some embodiments, a polypeptide comprises a light chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:592-603. For example, a polypeptide can comprise a light chain amino acid sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:592-603. In some embodiments, a polypeptide comprises a light chain amino acid sequence that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:592-603.

[0467] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYRVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:592).

[0468] QTVLTQPPSVSGAPGQRVTISCTGSESNIGAGYRVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV - 103 - 3839034.v15708.1076005 LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:593).

[0469] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYYVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:594).

[0470] QTVLTQPPSVSGAPGQRVTISCTGSESNIGAGYDVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:595).

[0471] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSYFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:596).

[0472] QTVLTQPPSVSGAPGQRVTISCTGSVSNIGAGYDVHWYQQLPGTAPKLLIAG RSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLT VLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:597).

[0473] QTVLTQPPSVSGAPGQRVTISCTGSPSNIGAGYRVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:598).

[0474] QTVLTQPPSVSGAPGQRVTISCTGSVSNIGAGYRVHWYQQLPGTAPKLLIAGS SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:599).

[0475] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSSFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:600).

[0476] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYRVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSYFDPHWVFGGGTKLTV - 104 - 3839034.v15708.1076005 LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:601).

[0477] QTVLTQPPSVSGAPGQRVTISCTGSVSNIGAGYRVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:602).

[0478] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:603).

[0479] QTVLTQPPSVSGAPGQRVTISCTGSESNIGAGYRVHWYQQLPGTAPKLLIAGR SNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTV LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:603).

[0480] In some embodiments, a polypeptide comprises a light chain amino acid sequence that comprises at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:592-603. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a light chain amino acid sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:592-603.

[0481] In some embodiments, a polypeptide comprises a light chain amino acid sequence that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:592-603.

[0482] In some embodiments, a polypeptide comprises a light chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:592. For example, a polypeptide can comprise a light chain amino acid sequence that has at least about: 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:592. In some embodiments, a polypeptide comprises a light chain amino acid sequence - 105 - 3839034.v15708.1076005 that has at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:592.

[0483] In some embodiments, a polypeptide comprises a light chain amino acid sequence that comprises at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:592. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, a polypeptide comprises a light chain amino acid sequence that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:592.

[0484] In some embodiments, a polypeptide comprises a light chain amino acid sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:592.

[0485] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:578-591; or b) a light chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:592-603; or both a) and b).

[0486] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:578-591; and b) a light chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs:592-603.

[0487] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence comprising at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:578-591; or b) a light chain amino acid sequence comprising at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:592-603; or both a) and b).

[0488] In some embodiments, a polypeptide comprises: - 106 - 3839034.v15708.1076005 a) a heavy chain amino acid sequence comprising at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:578-591; and b) a light chain amino acid sequence comprising at least one amino acid substitution relative to the amino acid sequence of any one or more of SEQ ID NOs:592-603.

[0489] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:578-591; or b) a light chain amino acid sequence comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:592-603; or both a) and b).

[0490] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:578-591; and b) a light chain amino acid sequence comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of any one or more of SEQ ID NOs:592-603.

[0491] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:578-591; or b) a light chain amino acid sequence that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:592-603; or both a) and b).

[0492] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:578-591; and b) a light chain amino acid sequence that has 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:592-603. - 107 - 3839034.v15708.1076005

[0493] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:578; or b) a light chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:592; or both a) and b).

[0494] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:578; and b) a light chain amino acid sequence that has at least about 60% sequence identity to the amino acid sequence of SEQ ID NO:592.

[0495] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:578; or b) a light chain amino acid sequence comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:592; or both a) and b).

[0496] In some embodiments, a polypeptide comprises: a) a heavy chain amino acid sequence comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:578; and b) a light chain amino acid sequence comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:592.

[0497] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:578; and b) a light chain comprising the amino acid sequence of SEQ ID NO:592 (AB-2b).

[0498] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:579; and b) a light chain comprising the amino acid sequence of SEQ ID NO:592.

[0499] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:580; and b) a light chain comprising the amino acid sequence of SEQ ID NO:593.

[0500] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:581; and - 108 - 3839034.v15708.1076005 b) a light chain comprising the amino acid sequence of SEQ ID NO:592.

[0501] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:582; and b) a light chain comprising the amino acid sequence of SEQ ID NO:594.

[0502] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:583; and b) a light chain comprising the amino acid sequence of SEQ ID NO:594.

[0503] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:584; and b) a light chain comprising the amino acid sequence of SEQ ID NO:595.

[0504] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:585; and b) a light chain comprising the amino acid sequence of SEQ ID NO:594.

[0505] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:586; and b) a light chain comprising the amino acid sequence of SEQ ID NO:593.

[0506] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:585; and b) a light chain comprising the amino acid sequence of SEQ ID NO:593.

[0507] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:578; and b) a light chain comprising the amino acid sequence of SEQ ID NO:596.

[0508] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:587; and b) a light chain comprising the amino acid sequence of SEQ ID NO:597.

[0509] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:585; and b) a light chain comprising the amino acid sequence of SEQ ID NO:598.

[0510] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:588; and b) a light chain comprising the amino acid sequence of SEQ ID NO:597.

[0511] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:583; and - 109 - 3839034.v15708.1076005 b) a light chain comprising the amino acid sequence of SEQ ID NO:595.

[0512] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:585; and b) a light chain comprising the amino acid sequence of SEQ ID NO:599.

[0513] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:589; and b) a light chain comprising the amino acid sequence of SEQ ID NO:600.

[0514] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:585; and b) a light chain comprising the amino acid sequence of SEQ ID NO:601.

[0515] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:590; and b) a light chain comprising the amino acid sequence of SEQ ID NO:602.

[0516] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:584; and b) a light chain comprising the amino acid sequence of SEQ ID NO:603.

[0517] In some embodiments, a polypeptide comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO:591; and b) a light chain comprising the amino acid sequence of SEQ ID NO:603.

[0518] In some embodiments, a polypeptide is a single-domain antibody or an antigen- binding fragment thereof. As used herein, the term “single-domain antibody (sdAb)” or “nanobody” refers to an immunoglobulin molecule consisting of a single monomeric variable antibody domain and capable of specific binding to a target. A single-domain antibody can be of any species, such as a murine antibody, a human antibody or a humanized single-domain antibody.

[0519] In some embodiments, a VHdomain and a VLdomain may be linked together via a linker (e.g., a synthetic linker) to form various types of single-chain antibody designs in which the VH / VLdomains pair intramolecularly, or intermolecularly in those cases when the VHand VLdomains are expressed by separate chains, to form a monovalent antigen binding site.

[0520] In some embodiments, a polypeptide is a heavy-chain antibody comprising two or more heavy chains, but lacking light chain, or an antigen-binding fragment thereof. Non-limiting examples of heavy chain antibodies include camelid Vhh (also referred to as VHH or VHH) - 110 - 3839034.v15708.1076005 antibodies. Camelid antibodies are antibodies from the Camelidae family of mammals that include llamas, camels, and alpacas.

[0521] In some embodiments, a polypeptide is an antibody mimetic. The term “antibody mimetic” refers to polypeptides capable of mimicking an antibody’s ability to bind an antigen, but structurally differ from native antibody structures. Non-limiting examples of antibody mimetics include Adnectins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Anticalins, Avimers, DARPins, Fynomers, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMPs, and Versabodies.

[0522] In some embodiments, a polypeptide is an antigen-binding fragment of an antibody. The term “antigen-binding fragment” refers to a portion of an immunoglobulin molecule (e.g., antibody) that retains the antigen binding properties of the full-length Reference Antibody. Non- limiting examples of antigen-binding fragments include a VH region, a VL region, an Fab fragment, an F(ab’)2 fragment, an Fd fragment, an Fv fragment, and a domain antibody (dAb) consisting of one VH domain or one VL domain, etc. VH and VL domains may be linked together via a synthetic linker to form various types of single-chain antibody designs in which the VH / VL domains pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate chains, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody. In some embodiments, a polypeptide disclosed herein is an antigen binding fragment selected from Fab, F(ab’)2, Fab’, scFv, or Fv. In some embodiments, a polypeptide is a scFv.

[0523] In some embodiments, a polypeptide (e.g., an antibody or antigen-binding fragment) is incorporated into a cell-based therapy. In some embodiments, a polypeptide is an engineered T cell receptor. In some embodiments, a polypeptide is a chimeric antigen receptor (CAR) (e.g., expressed on a T (CAR-T) cell, natural killer (CAR-NK) cell, or macrophage (CAR-M) cell). In some embodiments, a CAR comprises a transmembrane domain and an antigen-recognition moiety, wherein the antigen-recognition moiety binds SARS-CoV-2 (e.g., an epitope within RBD such as RBD class 4 epitope).

[0524] In some embodiments, a polypeptide is an antibody mimetic.

[0525] In some embodiments, a polypeptide competes with a comparator antibody for binding to the wildtype SARS-CoV-2-Spike, a SARS-CoV-2-Spike variant, or a combination thereof, wherein the reference antibody specifically binds the wildtype SARS-CoV-2-Spike (e.g., RBD). The term “specifically binding” or “specifically binds” refers to preferential interaction, - 111 - 3839034.v15708.1076005 i.e., significantly higher binding affinity, between an antibody, or an antigen-binding fragment thereof, and its epitope relative to other antigens or amino acid sequences.

[0526] In some embodiments, a polypeptide is an isolated polypeptide. In some embodiments, a polypeptide (e.g., an isolated polypeptide) is recombinantly produced. In some embodiments, a polypeptide (e.g., an isolated polypeptide) is synthetically produced.

[0527] In some embodiments, a polypeptide is linked to a second polypeptide. The term “linked” means attached, via a covalent or noncovalent interaction. Conjugation can employ a suitable linking agent. Non-limiting examples include peptide linkers, compound linkers, and chemical cross-linking agents. In some embodiments, the linker is a disulfide bond.

[0528] In some embodiments, a polypeptide is conjugated to a heterologous moiety. The term “conjugated” refers to attached, via a covalent or noncovalent interaction. Conjugation can employ any one or more of suitable linking agents. Non-limiting examples include peptide linkers, compound linkers, and chemical cross-linking agents.

[0529] In some embodiments, a heterologous moiety comprises a therapeutic agent, a diagnostic agent, or both. In some embodiments, a heterologous moiety is selected from polyethylene glycol (PEG), hexadecanoic acid, hydrogels, nanoparticles, multimerization domains and carrier peptides.

[0530] In some embodiments, a nanoparticle is a lipid nanoparticle. In some embodiments, a nanoparticle is a polymer nanoparticle. In some embodiments, a polymer is an amphiphilic polymer. In some embodiments, a polymer is a hydrophobic or hydrophilic polymer. Non- limiting examples of polymers include poly(lactic acid)-poly(ethylene glycol), poly(lactic-co- glycolic acid)-poly(ethylene glycol), poly(lactic-co-glycolic) acid (PLGA), poly(lactic-co- glycolic acid)-d-α-tocopheryl polyethylene glycol succinate, poly(lactic-co-glycolic acid)- ethylene oxide fumarate, poly(glycolic acid)-poly(ethylene glycol), polycaprolactone- poly(ethylene glycol), or any salts thereof. In some embodiments, a polymer nanoparticle comprises poly(lactic-co-glycolic acid) (PLGA).

[0531] In some embodiments, a carrier polypeptide is albumin or an Fc polypeptide.

[0532] In some embodiments, a polypeptide: a) is capable of binding to an epitope in the RBD of SARS-CoV-2-Spike; b) binds SARS-CoV-1 and / or SARS-CoV-2 with a KDof 10 µM or less; c) neutralizes SARS-CoV-1 and / or SARS-CoV-2 infection of human host cells; d) has a weaker non-specific binding than the Reference Antibody; e) has a weaker self-association than the Reference Antibody; - 112 - 3839034.v15708.1076005 or a combination of any of the foregoing.

[0533] In some embodiments, a polypeptide is capable of binding to one or more epitope residues in RBD of SARS-CoV-2-Spike, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 residues of the RBD. In some embodiments, a polypeptide is capable of binding to one or more epitope residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all 16 residues) of SEQ ID NO:1.

[0534] In some embodiments, a polypeptide binds SARS-CoV-2-Spike with a binding constant (KD) of about 10 µM or less.

[0535] In some embodiments, a polypeptide binds SARS-CoV-1-Spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-Spike (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) or a fragment thereof (e.g., the RBD of SARS-CoV-2-Spike) with a KDof about: 5 µM, 2 µM, 1 µM, 500 nM, 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.2 nM, or 0.1 nM or less. In some embodiments, a polypeptide binds SARS-CoV-1-Spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-Spike (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) or a fragment thereof (e.g., the RBD of SARS-CoV-2-Spike) with a KDof 100 nM or less.

[0536] In some embodiments, a polypeptide binds SARS-CoV-1-Spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-Spike (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) or a fragment thereof (e.g., the RBD of SARS-CoV-2-Spike) with a KDof about: 10-10-10-5M, 10-10-5x10-6M, 2x10-10-5x10-6M, 2x10-10-2x10-6M, 5x10-10-2x10-6M, 5x10-10-10-7M, 10-9- 10-7M, 10-9-5x10-8M, 2x10-9-5x10-8M, 2x10-9-2x10-8M, 5x10-9-2x10-8M, or 5x10-9-10-8M. - 113 - 3839034.v15708.1076005

[0537] In some embodiments, a polypeptide (e.g., full-length IgG1 antibody) binds SARS- CoV-1-Spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-Spike (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) or a fragment thereof (e.g., the RBD of SARS-CoV-2-Spike) with a KDof about 10-6M or less, e.g., about: 500 nM, 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.2 nM, or 0.1 nM or less; or about: 10-10-10-6M, 10-10-5x10-7M, 2x10-10-5x10-7M, 2x10-10-2x10-7M, 5x10-10-2x10-7M, 5x10-10-10-7M, 10-9- 10-7M, 10-9-5x10-8M, 2x10-9-5x10-8M, 2x10-9-2x10-8M, 5x10-9-2x10-8M, or 5x10-9-10-8M.

[0538] In some embodiments, a polypeptide competes with the Reference Antibody for binding to a SARS-CoV-2-Spike (e.g., RBD such as RBD class 4 epitope). Techniques and assays for assessing competition between antibodies are known in the art.

[0539] In some embodiments, a polypeptide neutralizes SARS-CoV-1 (e.g., CoV-1 and / or WIV1) and / or SARS-CoV-2 (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) with an IC50of 10 µM or less.

[0540] In some embodiments, a polypeptide (e.g., full-length IgG1 antibody) neutralizes SARS-CoV-2 (e.g. of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) infection of a human host cells with an IC50of about 25,000 ng / mL or less, e.g., about: 20,000 ng / mL, 15,000 ng / mL, 10,000 ng / mL, 5,000 ng / mL, 2,500 ng / mL, 1,000 ng / mL, 750 ng / mL, 500 ng / mL, 250 ng / mL, 100 ng / mL, 75 ng / mL, 50 ng / mL, 25 ng / mL or 10 ng / mL or less; e.g., about: 10-25,000 ng / mL, 10-20,000 ng / mL, 25-20,000 ng / mL, 25-15,000 ng / mL, 50-15,000 ng / mL, 50-10,000 ng / mL, 75-10,000 ng / mL, 75-5,000 ng / mL, 100-5,000 ng / mL, 100-2,500 ng / mL, 250-2,500 ng / mL, 250-1,000 ng / mL, 500-1,000 ng / mL, or 500-750 ng / mL. - 114 - 3839034.v15708.1076005

[0541] In some embodiments, host cells are selected from the group consisting of lung type II pneumocytes, ileal absorptive enterocytes, nasal goblet secretory cells, and combinations thereof.

[0542] In some embodiments, a polypeptide (e.g., full-length IgG1 antibody) neutralizes SARS-CoV-2 (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB) infection of human host cells with an IC80of about 50,000 ng / mL or less, e.g., about: 25,000 ng / mL, 15,000 ng / mL, 10,000 ng / mL, 5,000 ng / mL, 2,500 ng / mL, 1,000 ng / mL, 750 ng / mL, 500 ng / mL, 250 ng / mL, 100 ng / mL, 75 ng / mL, 50 ng / mL, 25 ng / mL or 10 ng / mL or less; e.g., about: 10-50,000 ng / mL, 10-25,000 ng / mL, 25-25,000 ng / mL, 25-15,000 ng / mL, 50-15,000 ng / mL, 50-10,000 ng / mL, 75-10,000 ng / mL, 75-5,000 ng / mL, 100-5,000 ng / mL, 100-2,500 ng / mL, 250-2,500 ng / mL, 250-1,000 ng / mL, 500-1,000 ng / mL, or 500-750 ng / mL.

[0543] In some embodiments, a polypeptide (e.g., full-length IgG1 antibody) neutralizes SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infection of human host cells with an IC50of about 25,000 ng / mL or less, e.g., about: 20,000 ng / mL, 15,000 ng / mL, 10,000 ng / mL, 5,000 ng / mL, 2,500 ng / mL, 1,000 ng / mL, 750 ng / mL, 500 ng / mL, 250 ng / mL, 100 ng / mL, 75 ng / mL, 50 ng / mL, 25 ng / mL, or 10 ng / mL or less; e.g., about: 10-25,000 ng / mL, 10-20,000 ng / mL, 25- 20,000 ng / mL, 25-15,000 ng / mL, 50-15,000 ng / mL, 50-10,000 ng / mL, 75-10,000 ng / mL, 75- 5,000 ng / mL, 100-5,000 ng / mL, 100-2,500 ng / mL, 250-2,500 ng / mL, 250-1,000 ng / mL, 500- 1,000 ng / mL, or 500-750 ng / mL.

[0544] In some embodiments, a polypeptide (e.g., full-length IgG1 antibody) neutralizes SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infection of human host cells with an IC80of about 50,000 ng / mL or less, e.g., about: 25,000 ng / mL, 15,000 ng / mL, 10,000 ng / mL, 5,000 ng / mL, 2,500 ng / mL, 1,000 ng / mL, 750 ng / mL, 500 ng / mL, 250 ng / mL, 100 ng / mL, 75 ng / mL, 50 ng / mL, 25 ng / mL, or 10 ng / mL or less; e.g., about: 10-50,000 ng / mL, 10-25,000 ng / mL, 25- 25,000 ng / mL, 25-15,000 ng / mL, 50-15,000 ng / mL, 50-10,000 ng / mL, 75-10,000 ng / mL, 75- 5,000 ng / mL, 100-5,000 ng / mL, 100-2,500 ng / mL, 250-2,500 ng / mL, 250-1,000 ng / mL, 500- 1,000 ng / mL, or 500-750 ng / mL.

[0545] In some embodiments, a polypeptide reduces betacoronavirus (e.g., SARS-CoV-2) infectivity of host cells (e.g., human host cells). In some embodiments, a polypeptide reduces - 115 - 3839034.v15708.1076005 betacoronavirus (e.g., SARS-CoV-2) infectivity of host cells (e.g., human host cells) by at least about 10%, e.g., by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a polypeptide reduces betacoronavirus (e.g., SARS-CoV-2) infectivity of human cells by at least about 30%.

[0546] In some embodiments, a polypeptide reduces betacoronavirus (such as SARS-CoV-2 (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB)) re-infection of host cells (e.g., human host cells). In some embodiments, a polypeptide reduces betacoronavirus (such as SARS- CoV-2 (e.g., Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB)) re-infection of host cells (e.g., human host cells) by at least about 10%, e.g., by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a polypeptide reduces betacoronavirus (such as SARS-CoV-2 (e.g., of Alpha, Beta, Gamma, Delta, Kappa, Epsilon, Eta, Iota, Lambda, Mu, and / or Omicron, for example, 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.1.617.1,B.1.617.2, B.1.621, BA.1, BA.1.1, BA.2, 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, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB)) re-infection of human cells by at least about 30%.

[0547] Infectivity or re-infection can be measured using techniques such as a pseudovirus neutralization assay or a live virus neutralization assay (see, e.g., Pinto et al., Cross- neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody, Nature 583: 290-95 (2020), the contents of which are incorporated herein by reference). A kit, for example, the GenScript cPass™ SARS-CoV-2 neutralization antibody detection kit, can be used according to manufacturer's protocol. - 116 - 3839034.v15708.1076005

[0548] In some embodiments, a polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infectivity of host cells (e.g., human host cells). In some embodiments, a polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infectivity of host cells (e.g., human host cells) by at least about 10%, e.g., by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infectivity of human cells by at least about 30%.

[0549] In some embodiments, a polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) re-infection of host cells (e.g., human host cells). In some embodiments, a polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) re-infection of host cells (e.g., human host cells) by at least about 10%, e.g., by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) re- infection of human cells by at least about 30%.

[0550] In some embodiments, a polypeptide has a weaker self-association than the Reference Antibody, for example, as determined by an affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) value. AC-SINS value is the change in maximum absorbance wavelength in the coated-nanoparticle absorption spectra compared to the spectra of the nanoparticle alone. Thus, the greater the change in maximum absorbance wavelength, the more self-interaction of the antibody coated on the nanoparticle. Self-association is an unwanted property that correlates with poor viscosity and poor PK properties. Techniques and assays for assessing self-association of proteins are known in the art. See, e.g., Patro & Przybycien, Biotechnol Bioeng.52(2):193-203 (1996), the contents of which are incorporated herein in their entirety. In some embodiments, a polypeptide has a weaker self-association than the Reference Antibody.

[0551] In some embodiments, a polypeptide has an AC-SINS value of no more than about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, 24, or 25. In some embodiments, a polypeptide has an AC-SINS value of no more than about 14. In some embodiments, a polypeptide has an AC-SINS value of no more than about 8. In some embodiments, a polypeptide has an AC-SINS value of about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, 24, or 25. In some embodiments, a polypeptide has an AC-SINS value of about 0-25, e.g., 0-20, 0-15, 0-10, 0-8, 0-5, 2-20, 2-15, 2-10, 2-8, 2-5, 5-20, 5- 15, 5-10, 5-8, 7-8, or 13-15. In some embodiments, a polypeptide has an AC-SINS value of - 117 - 3839034.v15708.1076005 about 13-14, 13-15, 7-9, or 7-8. In some embodiments, a polypeptide has an AC-SINS value of about: 8 or 14.

[0552] In some embodiments, a polypeptide has an improved developability (e.g., reduced AC-SINS) relative to the Reference Antibody. In some embodiments, self-association of a polypeptide is at least about 10% lower than that of the Reference Antibody, for example, by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% lower than that of the Reference Antibody. In some embodiments, self-association of a polypeptide is at least about 30% lower than that of the Reference Antibody.

[0553] In some embodiments, self-association of a polypeptide is less than about 90% of that of the Reference Antibody, for example, less than about: 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of that of the Reference Antibody.

[0554] In some embodiments, self-association of a polypeptide is about 1-90% relative to that of the Reference Antibody, for example, about: 2-90%, 2-85%, 3-85%, 3-80%, 4-80%, 4- 75%, 5-75%, 5-70%, 6-70%, 6-65%, 7-65%, 7-60%, 8-60%, 8-55%, 9-55%, 9-50%, 10-50%, 10-45%, 15-45%, 15-40%, 20-40%, 20-35%, 25-35%, or 25-30%, relative to that of the Reference Antibody.

[0555] In some embodiments, reduction in self-association relative to the Reference Antibody is at least about 10%, for example, by at least about: 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Fusion Proteins

[0556] The disclosure also provides, among other things, a fusion protein comprising one or more of the polypeptides disclosed herein.

[0557] The term “fusion protein” refers to a synthetic, semi-synthetic or recombinant single protein molecule. A fusion protein can comprise all or a portion of two or more different proteins and / or polypeptides that are attached by covalent bonds (e.g., peptide bonds). For example, a fusion protein can comprise a full-length polypeptide disclosed herein (e.g., a whole antibody), or a fragment thereof (e.g., an antigen-binding fragment of an antibody). The heterologous partner can be a full-length protein or a fragment thereof (e.g., a truncated protein).

[0558] Fusion proteins of the disclosure can be produced recombinantly or synthetically, using routine methods and reagents that are well known in the art. For example, a fusion protein - 118 - 3839034.v15708.1076005 of the disclosure can be produced recombinantly in a suitable host cell (e.g., bacteria) according to methods known in the art. See, e.g., Current Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley & Sons, 1992; and Molecular Cloning: a Laboratory Manual, 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press. For example, a nucleic acid molecule comprising a nucleotide sequence encoding a fusion protein described herein can be introduced and expressed in suitable host cell (e.g., E. coli), and the expressed fusion protein can be isolated / purified from the host cell (e.g., in inclusion bodies) using routine methods and readily available reagents. For example, DNA fragments coding for different protein sequences (e.g., a light-responsive domain, a heterologous peptide component) can be ligated together in-frame in accordance with conventional techniques. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of nucleic acid fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive nucleic acid fragments that can subsequently be annealed and re-amplified to generate a chimeric nucleic acid sequence (see Ausubel et al., Current Protocols in Molecular Biology, 1992). Nucleic Acids, Vectors, Host Cells

[0559] The disclosure also provides, among other things, one or more polynucleotides (e.g., DNA, RNA, or analogs of either, e.g., optionally including one or more modified nucleotides; a polynucleotide may be linear or circular, e.g., a linear or circular RNA) encoding any one of the polypeptides or fusion proteins described herein. In some embodiments, a polypeptide or fusion protein disclosed herein is encoded by a single polynucleotide. In some embodiments, a polypeptide or fusion protein disclosed herein is encoded by multiple polynucleotides.

[0560] In some embodiments, a polynucleotide comprises a nucleotide sequence that is codon-optimized for a chosen host cell.

[0561] The disclosure also provides, among other things, a vector (e.g., an expression vector, including a viral-delivery vector) comprising any one or more of the polynucleotides disclosed herein.

[0562] The term “expression vector” refers to a replicable nucleic acid from which one or more proteins can be expressed when the expression vector is transformed into a suitable expression host cell.

[0563] In some embodiments, a vector (e.g., expression vector) further comprises an expression control polynucleotide sequence operably linked to the polynucleotide, a polynucleotide sequence encoding a selectable marker, or both. In some embodiments, an - 119 - 3839034.v15708.1076005 expression control polynucleotide sequence comprises a promoter sequence, an enhancer sequence, or both. In some embodiments, an expression control polynucleotide sequence comprises an inducible promoter sequence. The term “promoter” refers to a region of DNA to which RNA polymerase binds and initiates the transcription of a gene. The term “operably linked” means that the nucleic acid is positioned in the recombinant polynucleotide, e.g., vector, in such a way that enables expression of the nucleic acid under control of the element (e.g., promoter) to which it is linked. The term “selectable marker element” is an element that confers a trait suitable for artificial selection. Selectable marker elements can be negative or positive selection markers.

[0564] The disclosure also provides, among other things, an expression host cell comprising any one or more of the polynucleotides or expression vectors disclosed herein.

[0565] The term “expression host cell” refers to a cell useful for receiving, maintaining, reproducing and / or amplifying a vector. Non-limiting examples of expression host cells include mammalian cells such as hybridoma cells, Chinese hamster ovary (CHO) cells, COS cells, human embryonic kidney (HEK), yeast cells such as Pichia pastoris cells, or bacterial cells such as E. coli, including DH5α, etc. Compositions

[0566] The disclosure also provides, among other things, a composition comprising any one of the polypeptides, the polynucleotides, or fusion proteins disclosed herein. In some embodiments, a composition is a pharmaceutical composition.

[0567] In some embodiments, a composition (e.g., pharmaceutical composition) further comprises pharmaceutically acceptable carriers, excipients, stabilizers, diluents or tonifiers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Suitable pharmaceutically acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed. Non-limiting examples of pharmaceutically acceptable carriers, excipients, stabilizers, diluents or tonifiers include buffers (e.g., phosphate, citrate, histidine), antioxidants (e.g., ascorbic acid or methionine), preservatives, proteins (e.g., serum albumin, gelatin or immunoglobulins); hydrophilic polymers, amino acids, carbohydrates (e.g., monosaccharides, disaccharides, glucose, mannose or dextrins); chelating agents (e.g., EDTA), sugars (e.g., sucrose, mannitol, trehalose or sorbitol), salt-forming counter-ions (e.g., sodium), metal complexes (e.g., Zn-protein complexes); non-ionic surfactants (e.g., Tween), PLURONICS™ and polyethylene glycol (PEG). - 120 - 3839034.v15708.1076005

[0568] In some embodiments, a composition (e.g., a pharmaceutical composition) is formulated for a suitable administration schedule and route. Non-limiting examples of administration routes include oral, rectal, mucosal, intravenous, intramuscular, subcutaneous, and topical, etc. In some embodiments, a composition (e.g., a pharmaceutical composition) is stored in the form of an aqueous solution or a dried formulation (e.g., lyophilized).

[0569] In some embodiments, a composition is formulated to be administered by infusion (e.g., intravenous infusion). In other embodiments a composition is formulated for subcutaneous administration.

[0570] In some embodiments, a composition is provided in a dosage form, e.g., in a prefilled syringe or autoinjector.

[0571] In some embodiments, a pharmaceutical composition comprises from about 50 mg to about 300 mg of a polypeptide or fusion protein disclosed herein, for example, about: 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, or 300 mg. In some embodiments, a pharmaceutical composition comprises from about 60 mg to about 300 mg of a polypeptide or fusion protein disclosed herein, for example, about: 60-280 mg, 80-280 mg, 80-260 mg, 100-260 mg, 100-250 mg, 120-250 mg, 120-240 mg, 140-240 mg, 140-220 mg, 150-250 mg, 150-200 mg, 160-220 mg, 160-200 mg, or 180-200 mg.

[0572] In some embodiments, a pharmaceutical composition comprises from about 50 mg / ml to about 200 mg / ml of a polypeptide or fusion protein disclosed herein, for example, about: 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 120 mg / ml, 140 mg / ml, 150 mg / ml, 160 mg / ml, 180 mg / ml, or 200 mg / ml of a polypeptide or fusion protein disclosed herein. In some embodiments, a pharmaceutical composition comprises from about 60 mg / ml to about 200 mg / ml of a polypeptide or fusion protein disclosed herein, for example, about: 60-180 mg / ml, 80-180 mg / ml, 80-160 mg / ml, 100-160 mg / ml, 100-150 mg / ml, 120-150 mg / ml or 120- 140 mg / ml.

[0573] In some embodiments, a composition is formulated to be administered with at least one additional therapeutic agent as a combination therapy.

[0574] In some embodiments, a composition further comprises at least one additional therapeutic agent.

[0575] In some embodiments, at least one additional therapeutic agent comprises any one of the polypeptides described herein (e.g., the Reference Antibody, a different RBD 4 binder, a S2 binder, or any combination thereof). In some embodiments, at least one additional therapeutic - 121 - 3839034.v15708.1076005 agent comprises bamlanivimab, etesevimab, casirivimab, imdevimab, Cilgavimab, Tixagevimab, AZD7442 (Tixagevimab-Cilgavimab), Regdanvimab, or Sotrovimab. In some embodiments, a second therapeutic agent comprises Sotrovimab.

[0576] In some embodiments, at least one additional therapeutic agent comprises: a) an antibody or an antigen-binding fragment thereof that specifically binds SARS- CoV-2-Spike; b) a polynucleotide comprising a nucleotide sequence encoding the antibody or the antigen-binding fragment thereof of a); c) an antiviral agent; d) an ACE2 inhibitor; e) an antibiotic; f) an antimalarial agent; g) a vaccine; or any combination of a) to g).

[0577] In some embodiments: a) an antibody or an antigen-binding fragment thereof that specifically binds SARS- CoV-2-Spike comprises bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, Cilgavimab, Tixagevimab, AZD7442 (Tixagevimab-Cilgavimab), Regdanvimab, Sotrovimab, or a combination thereof; b) an antibody or an antigen-binding fragment thereof that specifically binds SARS- CoV-2-Spike binds an S2 domain of SARS-CoV-2-Spike; c) an antiviral agent comprises oseltamivir (Tamiflu), favipiravir, amantadine, remdesivir, rimantadine, pleconaril, an anti-sense RNA to SARS-CoV-2, a siRNA to SARS-CoV-2, or a combination thereof; d) an ACE2 inhibitor comprises an RNAi to ACE2, a siRNA to ACE2, a CRISPR- based inhibitor of ACE2, a soluble ACE2, a soluble ACE2 variant, an anti-ACE2 antibody, or a combination thereof; e) an antibiotic comprises azithromycin; f) an antimalarial agent comprises a chloroquine; g) a vaccine comprises a nucleic acid vaccine and / or an inactivated virus vaccine; or any combination of a) to g).

[0578] Non-limiting examples of additional therapeutic agents include antibiotics (e.g., azithromycin), antibodies or antigen-binding fragments thereof (e.g., other SARS-CoV-2- - 122 - 3839034.v15708.1076005 binding antibodies or antigen-binding fragments), antimalarial agents (e.g., chloroquine or hydroxychloroquine), antiviral agents (e.g., Molnupiravir (LAGEVRIO, Merck), PF-07817883 (Pfizer), STI-1558 (Sorrento Therapeutics), PBI-0451 (Pardes Biosciences), EDP-235 (Enanta Pharmaceuticals), favipiravir, lopinavir, and / or ritonavir), cytokines (e.g., type 1 interferons such as interferon beta-1a), nucleotide analogs (e.g., remdesivir), protease inhibitors (e.g., danoprevir), and Renin-Angiotensin-Aldosterone System Inhibitors (e.g., ACE2 inhibitors or angiotensin-receptor blockers (ARBs)).

[0579] In some embodiments, an antiviral agent comprises amantadine, Molnupiravir (LAGEVRIO, Merck), PF-07817883 (Pfizer), STI-1558 (Sorrento Therapeutics), PBI-0451 (Pardes Biosciences), EDP-235 (Enanta Pharmaceuticals), favipiravir, lopinavir, oseltamivir (Tamiflu), pleconaril, rimantadine, ritonavir, an anti-sense RNA to SARS-CoV-2, an siRNA to SARS-CoV-2, an additional anti-SARS-CoV-2 monoclonal antibody, or any combination thereof.

[0580] In some embodiments, an antiviral agent comprises Molnupiravir (LAGEVRIO, Merck), PF-07817883 (Pfizer), STI-1558 (Sorrento Therapeutics), PBI-0451 (Pardes Biosciences), EDP-235 (Enanta Pharmaceuticals), or any combination thereof.

[0581] In some embodiments, an anti-SARS-CoV-2 antibody targets S1 domain of a Spike protein of SARS-CoV-2. In some embodiments, an anti-SARS-CoV-2 antibody targets class 4 region of a S1 domain. In some embodiments, an anti-SARS-CoV-2 monoclonal antibody targets RBD (e.g., RBD class 1, 2, or 3 epitopes) of S1 domain of SARS-CoV-2. In some embodiments, an anti-SARS-CoV-2 antibody targets class 3 region of S1 domain. In some embodiments, an anti-SARS-CoV-2 antibody targets the N-terminal domain (NTD)-nonsupersite region of S1 domain. In some embodiments, an anti-SARS-CoV-2 antibody targets SD1 region of S1 domain.

[0582] In some embodiments, an anti-SARS-CoV-2 monoclonal antibody targets (e.g., binds) S2 domain of a Spike protein of SARS-CoV-2. In some embodiments, an anti-SARS- CoV-2 monoclonal antibody comprises a neutralizing monoclonal antibody (e.g., as determined using a neutralization assay described herein or otherwise known in the art). Non-limiting examples of anti-SARS-CoV-2 monoclonal antibodies include Bamlanivimab (LY-CoV555 or LY3819253), Etesevimab (LY-CoV016 or LY3832479), Bebtelovimab (LY-CoV1404, LY3853113), Casirivimab (REGN10933), Imdevimab (REGN10987), Cilgavimab, Tixagevimab, AZD7442 / EVUSHELD® (Tixagevimab-Cilgavimab), Regdanvimab, Sotrovimab (Vir Biotechnology, Inc.), ADG20 (Adagio Therapeutics, Inc.), Ensovibep (MP0420) (DARPin, Novartis), and P2G3 (Aerium Tx). - 123 - 3839034.v15708.1076005

[0583] In some embodiments, at least one additional therapeutic agent comprises an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2- Spike.

[0584] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3, and a VLdomain comprising an LCDR1, an LCDR2, and an LCDR3 of an antibody comprising a VHamino acid sequence and a VLamino acid sequence, respectively, of: SEQ ID NO:53 and SEQ ID NO:75 (S2_AB-1); SEQ ID NO:57 and SEQ ID NO:76 (S2_AB-2); SEQ ID NO:58 and SEQ ID NO:77 (S2_AB-3); SEQ ID NO:59 and SEQ ID NO:78 (S2_AB-4); SEQ ID NO:60 and SEQ ID NO:75 (S2_AB-5); SEQ ID NO:61 and SEQ ID NO:79 (S2_AB-6); SEQ ID NO:62 and SEQ ID NO:80 (S2_AB-7); SEQ ID NO:63 and SEQ ID NO:81 (S2_AB-8); SEQ ID NO:64 and SEQ ID NO:82 (S2_AB-9); SEQ ID NO:65 and SEQ ID NO:83 (S2_AB-10); SEQ ID NO:66 and SEQ ID NO:84 (S2_AB-11); SEQ ID NO:67 and SEQ ID NO:80 (S2_AB-12); SEQ ID NO:68 and SEQ ID NO:75 (S2_AB-13); SEQ ID NO:62 and SEQ ID NO:74 (S2_AB-14); SEQ ID NO:69 and SEQ ID NO:85 (S2_AB-15); SEQ ID NO:70 and SEQ ID NO:86 (S2_AB-16); SEQ ID NO:58 and SEQ ID NO:87 (S2_AB-17); SEQ ID NO:71 and SEQ ID NO:88 (S2_AB-18); SEQ ID NO:53 and SEQ ID NO:85 (S2_AB-19); SEQ ID NO:72 and SEQ ID NO:85 (S2_AB-20); SEQ ID NO:94 and SEQ ID NO:113 (S2_AB-21); SEQ ID NO:95 and SEQ ID NO:114 (S2_AB-22); SEQ ID NO:53 and SEQ ID NO:115 (S2_AB-23); SEQ ID NO:96 and SEQ ID NO:80 (S2_AB-24); SEQ ID NO:97 and SEQ ID NO:116 (S2_AB-25); - 124 - 3839034.v15708.1076005 SEQ ID NO:98 and SEQ ID NO:75 (S2_AB-26); SEQ ID NO:99 and SEQ ID NO:80 (S2_AB-27); SEQ ID NO:100 and SEQ ID NO:85 (S2_AB-28); SEQ ID NO:101 and SEQ ID NO:80 (S2_AB-29); SEQ ID NO:101 and SEQ ID NO:117 (S2_AB-30); SEQ ID NO:102 and SEQ ID NO:118 (S2_AB-31); SEQ ID NO:103 and SEQ ID NO:119 (S2_AB-32); SEQ ID NO:104 and SEQ ID NO:120 (S2_AB-33); SEQ ID NO:105 and SEQ ID NO:115 (S2_AB-34); SEQ ID NO:106 and SEQ ID NO:80 (S2_AB-35); SEQ ID NO:107 and SEQ ID NO:121 (S2_AB-36); SEQ ID NO:108 and SEQ ID NO:75 (S2_AB-37); SEQ ID NO:109 and SEQ ID NO:80 (S2_AB-38); SEQ ID NO:110 and SEQ ID NO:87 (S2_AB-39); SEQ ID NO:111 and SEQ ID NO:117 (S2_AB-40); SEQ ID NO:562 and SEQ ID NO:573 (S2_AB-41); SEQ ID NO:563 and SEQ ID NO:76 (S2_AB-42); SEQ ID NO:564 and SEQ ID NO:75 (S2_AB-43); SEQ ID NO:565 and SEQ ID NO:574 (S2_AB-44); SEQ ID NO:566 and SEQ ID NO:80 (S2_AB-45); SEQ ID NO:567 and SEQ ID NO:75 (S2_AB-46); SEQ ID NO:568 and SEQ ID NO:574 (S2_AB-47); SEQ ID NO:569 and SEQ ID NO:77 (S2_AB-48); SEQ ID NO:570 and SEQ ID NO:76 (S2_AB-49); SEQ ID NO:571 and SEQ ID NO:575 (S2_AB-50); or SEQ ID NO:56 and SEQ ID NO:80 (S2_AB-51).

[0585] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of an antibody comprising a VHamino acid sequence of SEQ ID NO:53 and a VLamino acid sequence of SEQ ID NO:75 (S2_AB-1).

[0586] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a) an HCDR1 comprising GYTFTRYW (SEQ ID NO:557); - 125 - 3839034.v15708.1076005 b) an HCDR2 comprising IYPGDSDV (SEQ ID NO:558); c) an HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); d) an LCDR1 comprising QGISSW (SEQ ID NO:560); e) an LCDR2 comprising AAS; and f) an LCDR3 comprising QQGHSFPYT (SEQ ID NO:561).

[0587] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a) an HCDR1 consisting of GYTFTRYW (SEQ ID NO:557); b) an HCDR2 consisting of IYPGDSDV (SEQ ID NO:558); c) an HCDR3 consisting of ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); d) an LCDR1 consisting of QGISSW (SEQ ID NO:560); e) an LCDR2 consisting of AAS; and f) an LCDR3 consisting of QQGHSFPYT (SEQ ID NO:561).

[0588] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a VHdomain comprising the amino acid sequence of SEQ ID NO:53 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-1); a VHdomain comprising the amino acid sequence of SEQ ID NO:57 and a VLdomain comprising the amino acid sequence of SEQ ID NO:76 (S2_AB-2); a VHdomain comprising the amino acid sequence of SEQ ID NO:58 and a VLdomain comprising the amino acid sequence of SEQ ID NO:77 (S2_AB-3); a VHdomain comprising the amino acid sequence of SEQ ID NO:59 and a VLdomain comprising the amino acid sequence of SEQ ID NO:78 (S2_AB-4); a VHdomain comprising the amino acid sequence of SEQ ID NO:60 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-5); a VHdomain comprising the amino acid sequence of SEQ ID NO:61 and a VLdomain comprising the amino acid sequence of SEQ ID NO:79 (S2_AB-6); a VHdomain comprising the amino acid sequence of SEQ ID NO:62 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-7); a VHdomain comprising the amino acid sequence of SEQ ID NO:63 and a VLdomain comprising the amino acid sequence of SEQ ID NO:81 (S2_AB-8); a VHdomain comprising the amino acid sequence of SEQ ID NO:64 and a VLdomain comprising the amino acid sequence of SEQ ID NO:82 (S2_AB-9); - 126 - 3839034.v15708.1076005 a VHdomain comprising the amino acid sequence of SEQ ID NO:65 and a VLdomain comprising the amino acid sequence of SEQ ID NO:83 (S2_AB-10); a VHdomain comprising the amino acid sequence of SEQ ID NO:66 and a VLdomain comprising the amino acid sequence of SEQ ID NO:84 (S2_AB-11); a VHdomain comprising the amino acid sequence of SEQ ID NO:67 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-12); a VHdomain comprising the amino acid sequence of SEQ ID NO:68 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-13); a VHdomain comprising the amino acid sequence of SEQ ID NO:62 and a VLdomain comprising the amino acid sequence of SEQ ID NO:74 (S2_AB-14); a VHdomain comprising the amino acid sequence of SEQ ID NO:69 and a VLdomain comprising the amino acid sequence of SEQ ID NO:85 (S2_AB-15); a VHdomain comprising the amino acid sequence of SEQ ID NO:70 and a VLdomain comprising the amino acid sequence of SEQ ID NO:86 (S2_AB-16); a VHdomain comprising the amino acid sequence of SEQ ID NO:58 and a VLdomain comprising the amino acid sequence of SEQ ID NO:87 (S2_AB-17); a VHdomain comprising the amino acid sequence of SEQ ID NO:71 and a VLdomain comprising the amino acid sequence of SEQ ID NO:88 (S2_AB-18); a VHdomain comprising the amino acid sequence of SEQ ID NO:53 and a VLdomain comprising the amino acid sequence of SEQ ID NO:85 (S2_AB-19); a VHdomain comprising the amino acid sequence of SEQ ID NO:72 and a VLdomain comprising the amino acid sequence of SEQ ID NO:85 (S2_AB-20); a VHdomain comprising the amino acid sequence of SEQ ID NO:94 and a VLdomain comprising the amino acid sequence of SEQ ID NO:113 (S2_AB-21); a VHdomain comprising the amino acid sequence of SEQ ID NO:95 and a VLdomain comprising the amino acid sequence of SEQ ID NO:114 (S2_AB-22); a VHdomain comprising the amino acid sequence of SEQ ID NO:53 and a VLdomain comprising the amino acid sequence of SEQ ID NO:115 (S2_AB-23); a VHdomain comprising the amino acid sequence of SEQ ID NO:96 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-24); a VHdomain comprising the amino acid sequence of SEQ ID NO:97 and a VLdomain comprising the amino acid sequence of SEQ ID NO:116 (S2_AB-25); - 127 - 3839034.v15708.1076005 a VHdomain comprising the amino acid sequence of SEQ ID NO:98 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-26); a VHdomain comprising the amino acid sequence of SEQ ID NO:99 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-27); a VHdomain comprising the amino acid sequence of SEQ ID NO:100 and a VLdomain comprising the amino acid sequence of SEQ ID NO:85 (S2_AB-28); a VHdomain comprising the amino acid sequence of SEQ ID NO:101 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-29); a VHdomain comprising the amino acid sequence of SEQ ID NO:101 and a VLdomain comprising the amino acid sequence of SEQ ID NO:117 (S2_AB-30); a VHdomain comprising the amino acid sequence of SEQ ID NO:102 and a VLdomain comprising the amino acid sequence of SEQ ID NO:118 (S2_AB-31); a VHdomain comprising the amino acid sequence of SEQ ID NO:103 and a VLdomain comprising the amino acid sequence of SEQ ID NO:119 (S2_AB-32); a VHdomain comprising the amino acid sequence of SEQ ID NO:104 and a VLdomain comprising the amino acid sequence of SEQ ID NO:120 (S2_AB-33); a VHdomain comprising the amino acid sequence of SEQ ID NO:105 and a VLdomain comprising the amino acid sequence of SEQ ID NO:115 (S2_AB-34); a VHdomain comprising the amino acid sequence of SEQ ID NO:106 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-35); a VHdomain comprising the amino acid sequence of SEQ ID NO:107 and a VLdomain comprising the amino acid sequence of SEQ ID NO:121 (S2_AB-36); a VHdomain comprising the amino acid sequence of SEQ ID NO:108 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-37); a VHdomain comprising the amino acid sequence of SEQ ID NO:109 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-38); a VHdomain comprising the amino acid sequence of SEQ ID NO:110 and a VLdomain comprising the amino acid sequence of SEQ ID NO:87 (S2_AB-39); a VHdomain comprising the amino acid sequence of SEQ ID NO:111 and a VLdomain comprising the amino acid sequence of SEQ ID NO:117 (S2_AB-40); a VHdomain comprising the amino acid sequence of SEQ ID NO:562 and a VLdomain comprising the amino acid sequence of SEQ ID NO:573 (S2_AB-41); - 128 - 3839034.v15708.1076005 a VHdomain comprising the amino acid sequence of SEQ ID NO:563 and a VLdomain comprising the amino acid sequence of SEQ ID NO:76 (S2_AB-42); a VHdomain comprising the amino acid sequence of SEQ ID NO:564 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-43); a VHdomain comprising the amino acid sequence of SEQ ID NO:565 and a VLdomain comprising the amino acid sequence of SEQ ID NO:574 (S2_AB-44); a VHdomain comprising the amino acid sequence of SEQ ID NO:566 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-45); a VHdomain comprising the amino acid sequence of SEQ ID NO:567 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75 (S2_AB-46); a VHdomain comprising the amino acid sequence of SEQ ID NO:568 and a VLdomain comprising the amino acid sequence of SEQ ID NO:574 (S2_AB-47); a VHdomain comprising the amino acid sequence of SEQ ID NO:569 and a VLdomain comprising the amino acid sequence of SEQ ID NO:77 (S2_AB-48); a VHdomain comprising the amino acid sequence of SEQ ID NO:570 and a VLdomain comprising the amino acid sequence of SEQ ID NO:76 (S2_AB-49); a VHdomain comprising the amino acid sequence of SEQ ID NO:571 and a VLdomain comprising the amino acid sequence of SEQ ID NO:575 (S2_AB-50); or a VHdomain comprising the amino acid sequence of SEQ ID NO:56 and a VLdomain comprising the amino acid sequence of SEQ ID NO:80 (S2_AB-51).

[0589] In some embodiments, an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:53; and b) a VLdomain comprising the amino acid sequence of SEQ ID NO:75.

[0590] In some embodiments, a composition (e.g., a pharmaceutical composition) comprises: a) an antibody or an antigen-binding fragment thereof comprising: i. a VHdomain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:24, an HCDR2 comprising the amino acid sequence of SEQ ID NO:28, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:33; and ii. a VLdomain comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:37, an LCDR2 comprising the amino acid sequence of - 129 - 3839034.v15708.1076005 SEQ ID NO:40; and an LCDR3 comprising the amino acid sequence of SEQ ID NO:44; and b) an antibody or an antigen-binding fragment thereof comprising: i. a VHdomain comprising an HCDR1 comprising GYTFTRYW (SEQ ID NO:557), an HCDR2 comprising IYPGDSDV (SEQ ID NO:558), and an HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); and ii. a VLdomain comprising an LCDR1 comprising QGISSW (SEQ ID NO:560), an LCDR2 comprising AAS, and an LCDR3 comprising QQGHSFPYT (SEQ ID NO:561).

[0591] In some embodiments, a composition (e.g., a pharmaceutical composition) comprises: a) an antibody or an antigen-binding fragment thereof comprising: i. a VHdomain comprising an HCDR1 consisting of the amino acid sequence of SEQ ID NO:24, an HCDR2 consisting of the amino acid sequence of SEQ ID NO:28, and an HCDR3 consisting of the amino acid sequence of SEQ ID NO:33; and ii. a VLdomain comprising an LCDR 1 consisting of the amino acid sequence of SEQ ID NO:37, an LCDR2 consisting of the amino acid sequence of SEQ ID NO:40, and an LCDR3 consisting of the amino acid sequence of SEQ ID NO:44; and b) an antibody or an antigen-binding fragment thereof comprising: i. a VHdomain comprising an HCDR1 consisting of GYTFTRYW (SEQ ID NO:557), an HCDR2 consisting of IYPGDSDV (SEQ ID NO:558), and an HCDR3 consisting of ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); and ii. a VLdomain comprising an LCDR1 consisting of QGISSW (SEQ ID NO:560), an LCDR2 consisting of AAS, and an LCDR3 consisting of QQGHSFPYT (SEQ ID NO:561).

[0592] In some embodiments, a composition (e.g., a pharmaceutical composition) comprises: a) an antibody or an antigen-binding fragment thereof comprising a VHdomain comprising the amino acid sequence of SEQ ID NO:5 and a VLdomain comprising the amino acid sequence of SEQ ID NO:14; and - 130 - 3839034.v15708.1076005 b) an antibody or an antigen-binding fragment thereof comprising a VHdomain comprising the amino acid sequence of SEQ ID NO:53 and a VLdomain comprising the amino acid sequence of SEQ ID NO:75.

[0593] In some embodiments, a composition (e.g., a pharmaceutical composition) comprises: a) an antibody or an antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:578 and a light chain comprising the amino acid sequence of SEQ ID NO:592; and b) an antibody or an antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:622 and a light chain comprising the amino acid sequence of SEQ ID NO:623.

[0594] S2_AB-1 heavy chain sequence: EVQLVESGAEVKKPGESLKISCKGSGYTFTRYWIGWVRQMPGKGLEWMGIIYPGDSD VRYSPSFQGHVTISADKSISTAYLQWNSLKASDTAMYYCARLPQYCSKGVCYRWFDP WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO:622).

[0595] S2_AB-1 light chain sequence:

[0596] EIVLTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHSFPYTFGQGTNLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:623). Methods of Use

[0597] The disclosure also provides, among other things, a method of neutralizing a SARS- CoV-2 protein in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0598] The disclosure also provides, among other things, a method of treating a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active - 131 - 3839034.v15708.1076005 ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0599] The disclosure also provides, among other things, a method of treating a SARS-CoV- 2 infection in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0600] The disclosure also provides, among other things, a method of reducing viral load of SARS-CoV-2 in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0601] The disclosure also provides, among other things, a method of reducing (e.g., preventing) a SARS-CoV-2 infection in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0602] The disclosure also provides, among other things, a method of reducing (e.g., preventing) a SARS-CoV-2 infection in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, wherein as an active ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0603] In some embodiments, a method disclosed herein (e.g., neutralizing a SARS-CoV-2 protein in a subject, treating a subject in need thereof, treating a SARS-CoV-2 infection in a subject, reducing viral load of SARS-CoV-2 in a subject, reducing (e.g., preventing) a SARS- CoV-2 infection in a subject, or reducing (e.g., preventing) a SARS-CoV-2 infection in a subject) comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or an antigen- binding fragment thereof comprising: a) a VHdomain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:24, an HCDR2 comprising the amino acid sequence of SEQ ID NO:28, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:33; and - 132 - 3839034.v15708.1076005 b) a VLdomain comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:37, an LCDR2 comprising the amino acid sequence of SEQ ID NO:40; and an LCDR3 comprising the amino acid sequence of SEQ ID NO:44.

[0604] In some embodiments, a method disclosed herein (e.g., neutralizing a SARS-CoV-2 protein in a subject, treating a subject in need thereof, treating a SARS-CoV-2 infection in a subject, reducing viral load of SARS-CoV-2 in a subject, reducing (e.g., preventing) a SARS- CoV-2 infection in a subject, or reducing (e.g., preventing) a SARS-CoV-2 infection in a subject) comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and: a) an antibody or an antigen-binding fragment thereof comprising: i. a VHdomain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:24, an HCDR2 comprising the amino acid sequence of SEQ ID NO:28, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:33; and ii. a VLdomain comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:37, an LCDR2 comprising the amino acid sequence of SEQ ID NO:40; and an LCDR3 comprising the amino acid sequence of SEQ ID NO:44; and b) an antibody or an antigen-binding fragment thereof comprising: i. a VHdomain comprising an HCDR1 comprising GYTFTRYW (SEQ ID NO:557), an HCDR2 comprising IYPGDSDV (SEQ ID NO:558), and an HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); and ii. a VLdomain comprising an LCDR1 comprising QGISSW (SEQ ID NO:560), an LCDR2 comprising AAS, and an LCDR3 comprising QQGHSFPYT (SEQ ID NO:561).

[0605] In some embodiments, a method disclosed herein (e.g., neutralizing a SARS-CoV-2 protein in a subject, treating a subject in need thereof, treating a SARS-CoV-2 infection in a subject, reducing viral load of SARS-CoV-2 in a subject, reducing (e.g., preventing) a SARS- CoV-2 infection in a subject, or reducing (e.g., preventing) a SARS-CoV-2 infection in a subject) comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or an antigen- binding fragment thereof comprising: - 133 - 3839034.v15708.1076005 a) a VHdomain comprising an HCDR1 consisting of the amino acid sequence of SEQ ID NO:24, an HCDR2 consisting of the amino acid sequence of SEQ ID NO:28, and an HCDR3 consisting of the amino acid sequence of SEQ ID NO:33; and b) a VLdomain comprising an LCDR 1 consisting of the amino acid sequence of SEQ ID NO:37, an LCDR2 consisting of the amino acid sequence of SEQ ID NO:40, and an LCDR3 consisting of the amino acid sequence of SEQ ID NO:44.

[0606] In some embodiments, a method disclosed herein (e.g., neutralizing a SARS-CoV-2 protein in a subject, treating a subject in need thereof, treating a SARS-CoV-2 infection in a subject, reducing viral load of SARS-CoV-2 in a subject, reducing (e.g., preventing) a SARS- CoV-2 infection in a subject, or reducing (e.g., preventing) a SARS-CoV-2 infection in a subject) comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and: a) a...

Claims

5708.1076005 CLAIMS What is claimed is:

1. A polypeptide comprising: a) an immunoglobulin heavy chain variable (VH) domain comprising a heavy chain complementarity-determining region (HCDR) 1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VHdomain set forth in Table 1 or Table 4 herein; and b) an immunoglobulin light chain variable (VL) domain comprising a light chain complementarity-determining region (LCDR) 1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VLdomain set forth in Table 2 or Table 4 herein, wherein the polypeptide is an antibody or an antigen-binding fragment thereof.

2. The polypeptide of claim 1, wherein: a) the VHdomain of the polypeptide comprises an HCDR1, an HCDR2, and an HCDR3, of a VHcomprising the amino acid sequence of SEQ ID NO:5; and b) the VLdomain comprises an LCDR1, an LCDR2, and an LCDR3, of a VLcomprising the amino acid sequence of SEQ ID NO:

14.

3. The polypeptide of claim 1 or 2, comprising: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO:24, b) an HCDR2 comprising the amino acid sequence of SEQ ID NO:28, c) an HCDR3 comprising the amino acid sequence of SEQ ID NO:33; d) an LCDR 1 comprising the amino acid sequence of SEQ ID NO:37; e) an LCDR2 comprising the amino acid sequence of SEQ ID NO:40; and f) an LCDR3 comprising the amino acid sequence of SEQ ID NO:

44.

4. The polypeptide of any one of claims 1-3, comprising: a) an HCDR1 consisting of the amino acid sequence of SEQ ID NO:24, b) an HCDR2 consisting of the amino acid sequence of SEQ ID NO:28, c) an HCDR3 consisting of the amino acid sequence of SEQ ID NO:33; d) an LCDR 1 consisting of the amino acid sequence of SEQ ID NO:37; e) an LCDR2 consisting of the amino acid sequence of SEQ ID NO:40; and f) an LCDR3 consisting of the amino acid sequence of SEQ ID NO:

44. - 199 - 3839034.v15708.1076005 5. The polypeptide of any one of claims 1-4, comprising: a) a VHthat is humanized and / or contains human framework regions; b) a VLthat is humanized and / or contains human framework regions; or both a) and b).

6. The polypeptide of any one of claims 1-5, wherein: a) the VHdomain of the polypeptide comprises an amino acid sequence having 100% sequence identity to the amino acid sequence of a VHdomain set forth in Table 1 or Table 4 herein; and b) the VLdomain of the polypeptide comprises an amino acid sequence having 100% sequence identity to the amino acid sequence of a VLdomain set forth in Table 2 or Table 4 herein, wherein the VHdomain and the VLdomain are selected from a VH / VLcombination set forth in Table 5 herein.

7. The polypeptide of any one of claims 1-6, comprising: a) a VHcomprising the amino acid sequence of SEQ ID NO:5; and b) a VLcomprising the amino acid sequence of SEQ ID NO:

14.

8. The polypeptide of any one of claims 1-7, wherein the polypeptide is an antigen-binding fragment comprising a single-chain fragment variable (scFv), a variable heavy domain of heavy chain (VHH), a fragment antigen-binding (Fab), a Fab’, or a F(ab’)2.

9. The polypeptide of any one of claims 1-8, comprising: a) an antibody heavy chain constant domain; b) an antibody light chain constant domain; or both.

10. The polypeptide of any one of claims 1-9, comprising an IgG1, IgG2, IgG3, or IgG4 antibody heavy chain constant domain.

11. The polypeptide of any one of claims 1-10, comprising an IgG1 antibody heavy chain constant domain. - 200 - 3839034.v15708.1076005 12. The polypeptide of any one of claims 9-11, wherein the antibody heavy chain constant domain comprises at least one mutation which increases serum half-life of the antibody or antigen-binding fragment thereof in humans.

13. The polypeptide of claim 12, wherein the antibody heavy chain constant domain comprises, relative to a wild-type human IgG constant domain, amino acid substitutions with methionine and serine at amino acid residues 428 and 434, respectively, and wherein the amino acid residues are numbered according to the EU index as in Kabat.

14. The polypeptide of any one of claims 1-13, comprising: a) an antibody heavy chain (HC) having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:576; b) an antibody light chain (LC) having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:577; or both a) and b).

15. The polypeptide of any one of claims 1-14, comprising: a) an antibody HC comprising the amino acid sequence of SEQ ID NO:576; b) an antibody LC comprising the amino acid sequence of SEQ ID NO:577; or both a) and b).

16. The polypeptide of any one of claims 1-13, comprising: a) an antibody heavy chain (HC) having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:576; b) an antibody light chain (LC) having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:52; or both a) and b).

17. The polypeptide of any one of claims 1-13 and 16, comprising: a) an antibody HC comprising the amino acid sequence of SEQ ID NO:576; b) an antibody LC comprising the amino acid sequence of SEQ ID NO:52; or both a) and b).

18. The polypeptide of any one of claims 1-17, wherein the polypeptide specifically binds a spike receptor-binding domain (RBD) class 4 epitope of a betacoronavirus Spike glycoprotein (SARS-CoV-2-Spike). - 201 - 3839034.v15708.1076005 19. The polypeptide of any one of claims 1-18, wherein the polypeptide is conjugated to a heterologous moiety.

20. The polypeptide of claim 19, wherein the heterologous moiety is a therapeutic agent, a diagnostic agent or a combination thereof 21. The polypeptide of claim 19 or 20, wherein the heterologous moiety comprises polyethylene glycol (PEG), hexadecanoic acid, a hydrogel, a lipid nanoparticle, a polymer nanoparticle, a heterologous polypeptide sequence, or a combination thereof.

22. The polypeptide of claim 21, wherein the polymer nanoparticle comprises poly(lactic-co- glycolic acid) (PLGA).

23. The polypeptide of claim 21, wherein the heterologous polypeptide sequence comprises a carrier polypeptide.

24. The polypeptide of claim 23, wherein the carrier polypeptide is albumin or an Fc polypeptide.

25. A polynucleotide comprising a nucleotide sequence encoding the polypeptide of any one of claims 1-24.

26. A host cell comprising the polynucleotide of claim 25.

27. A method of making the polypeptide of any one of claims 1-24, comprising culturing a host cell comprising a nucleotide sequence encoding the polypeptide under conditions where the polypeptide is expressed in the host cell.

28. A composition comprising the polypeptide of any one of claims 1-24 or the polynucleotide of claim 25.

29. The composition of claim 28, further comprising at least one additional therapeutic agent.

30. The composition of claim 29, wherein the at least one additional therapeutic agent comprises: a) an antibody or an antigen-binding fragment thereof that specifically binds SARS- CoV-2-Spike; - 202 - 3839034.v15708.1076005 b) a polynucleotide comprising a nucleotide sequence encoding the antibody or the antigen-binding fragment thereof of a); c) an antiviral agent; d) an ACE2 inhibitor; e) an antibiotic; f) an antimalarial agent; g) a vaccine; or any combination of a) to g).

31. The composition of claim 30, wherein: a) the antibody or the antigen-binding fragment thereof that specifically binds SARS-CoV-2-Spike comprises bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, Cilgavimab, Tixagevimab, AZD7442 (Tixagevimab- Cilgavimab), Regdanvimab, Sotrovimab, or a combination thereof; b) the antibody or the antigen-binding fragment thereof that specifically binds SARS-CoV-2-Spike binds an S2 domain of SARS-CoV-2-Spike; c) the antiviral agent comprises oseltamivir (Tamiflu), favipiravir, amantadine, remdesivir, rimantadine, pleconaril, an anti-sense RNA to SARS-CoV-2, a siRNA to SARS-CoV-2, or a combination thereof; d) the ACE2 inhibitor comprises an RNAi to ACE2, a siRNA to ACE2, a CRISPR- based inhibitor of ACE2, a soluble ACE2, a soluble ACE2 variant, an anti-ACE2 antibody, or a combination thereof; e) the antibiotic comprises azithromycin; f) the antimalarial agent comprises a chloroquine; g) the vaccine comprises a nucleic acid vaccine and / or an inactivated virus vaccine; or any combination of a) to g).

32. The composition of any one of claims 29-31, wherein the at least one additional therapeutic agent comprises an antibody or an antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike.

33. The composition of claim 32, wherein the antibody or the antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises a VHdomain comprising an HCDR1, an HCDR2, and an HCDR3, and a VLdomain - 203 - 3839034.v15708.1076005 comprising an LCDR1, an LCDR2, and an LCDR3 of an antibody comprising a VHamino acid sequence and a VLamino acid sequence, respectively, of: SEQ ID NO:53 and SEQ ID NO:75 (S2_AB-1); SEQ ID NO:57 and SEQ ID NO:76 (S2_AB-2); SEQ ID NO:58 and SEQ ID NO:77 (S2_AB-3); SEQ ID NO:59 and SEQ ID NO:78 (S2_AB-4); SEQ ID NO:60 and SEQ ID NO:75 (S2_AB-5); SEQ ID NO:61 and SEQ ID NO:79 (S2_AB-6); SEQ ID NO:62 and SEQ ID NO:80 (S2_AB-7); SEQ ID NO:63 and SEQ ID NO:81 (S2_AB-8); SEQ ID NO:64 and SEQ ID NO:82 (S2_AB-9); SEQ ID NO:65 and SEQ ID NO:83 (S2_AB-10); SEQ ID NO:66 and SEQ ID NO:84 (S2_AB-11); SEQ ID NO:67 and SEQ ID NO:80 (S2_AB-12); SEQ ID NO:68 and SEQ ID NO:75 (S2_AB-13); SEQ ID NO:62 and SEQ ID NO:74 (S2_AB-14); SEQ ID NO:69 and SEQ ID NO:85 (S2_AB-15); SEQ ID NO:70 and SEQ ID NO:86 (S2_AB-16); SEQ ID NO:58 and SEQ ID NO:87 (S2_AB-17); SEQ ID NO:71 and SEQ ID NO:88 (S2_AB-18); SEQ ID NO:53 and SEQ ID NO:85 (S2_AB-19); SEQ ID NO:72 and SEQ ID NO:85 (S2_AB-20); SEQ ID NO:94 and SEQ ID NO:113 (S2_AB-21); SEQ ID NO:95 and SEQ ID NO:114 (S2_AB-22); SEQ ID NO:53 and SEQ ID NO:115 (S2_AB-23); SEQ ID NO:96 and SEQ ID NO:80 (S2_AB-24); SEQ ID NO:97 and SEQ ID NO:116 (S2_AB-25); SEQ ID NO:98 and SEQ ID NO:75 (S2_AB-26); SEQ ID NO:99 and SEQ ID NO:80 (S2_AB-27); SEQ ID NO:100 and SEQ ID NO:85 (S2_AB-28); SEQ ID NO:101 and SEQ ID NO:80 (S2_AB-29); SEQ ID NO:101 and SEQ ID NO:117 (S2_AB-30); SEQ ID NO:102 and SEQ ID NO:118 (S2_AB-31); - 204 - 3839034.v15708.1076005 SEQ ID NO:103 and SEQ ID NO:119 (S2_AB-32); SEQ ID NO:104 and SEQ ID NO:120 (S2_AB-33); SEQ ID NO:105 and SEQ ID NO:115 (S2_AB-34); SEQ ID NO:106 and SEQ ID NO:80 (S2_AB-35); SEQ ID NO:107 and SEQ ID NO:121 (S2_AB-36); SEQ ID NO:108 and SEQ ID NO:75 (S2_AB-37); SEQ ID NO:109 and SEQ ID NO:80 (S2_AB-38); SEQ ID NO:110 and SEQ ID NO:87 (S2_AB-39); SEQ ID NO:111 and SEQ ID NO:117 (S2_AB-40); SEQ ID NO:562 and SEQ ID NO:573 (S2_AB-41); SEQ ID NO:563 and SEQ ID NO:76 (S2_AB-42); SEQ ID NO:564 and SEQ ID NO:75 (S2_AB-43); SEQ ID NO:565 and SEQ ID NO:574 (S2_AB-44); SEQ ID NO:566 and SEQ ID NO:80 (S2_AB-45); SEQ ID NO:567 and SEQ ID NO:75 (S2_AB-46); SEQ ID NO:568 and SEQ ID NO:574 (S2_AB-47); SEQ ID NO:569 and SEQ ID NO:77 (S2_AB-48); SEQ ID NO:570 and SEQ ID NO:76 (S2_AB-49); SEQ ID NO:571 and SEQ ID NO:575 (S2_AB-50); or SEQ ID NO:56 and SEQ ID NO:80 (S2_AB-51).

34. The composition of any one of claims 31-33, wherein the antibody or the antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises an HCDR1, an HCDR2, an HCDR3, an LCDR1, an LCDR2, and an LCDR3 of an antibody comprising a VHamino acid sequence of SEQ ID NO:53 and a VLamino acid sequence of SEQ ID NO:75 (S2_AB-1).

35. The composition of any one of claims 31-34, wherein the antibody or the antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a) an HCDR1 comprising GYTFTRYW (SEQ ID NO:557); b) an HCDR2 comprising IYPGDSDV (SEQ ID NO:558); c) an HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); d) an LCDR1 comprising QGISSW (SEQ ID NO:560); e) an LCDR2 comprising AAS; and - 205 - 3839034.v15708.1076005 f) an LCDR3 comprising QQGHSFPYT (SEQ ID NO:561).

36. The composition of any one of claims 31-35, wherein the antibody or the antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a) an HCDR1 consisting of GYTFTRYW (SEQ ID NO:557); b) an HCDR2 consisting of IYPGDSDV (SEQ ID NO:558); c) an HCDR3 consisting of ARLPQYCSKGVCYRWFDP (SEQ ID NO:559); d) an LCDR1 consisting of QGISSW (SEQ ID NO:560); e) an LCDR2 consisting of AAS; and f) an LCDR3 consisting of QQGHSFPYT (SEQ ID NO:561).

37. The composition of any one of claims 31-36, wherein the antibody or the antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a VHcomprising the amino acid sequence of SEQ ID NO:53 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-1); a VHcomprising the amino acid sequence of SEQ ID NO:57 and a VLcomprising the amino acid sequence of SEQ ID NO:76 (S2_AB-2); a VHcomprising the amino acid sequence of SEQ ID NO:58 and a VLcomprising the amino acid sequence of SEQ ID NO:77 (S2_AB-3); a VHcomprising the amino acid sequence of SEQ ID NO:59 and a VLcomprising the amino acid sequence of SEQ ID NO:78 (S2_AB-4); a VHcomprising the amino acid sequence of SEQ ID NO:60 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-5); a VHcomprising the amino acid sequence of SEQ ID NO:61 and a VLcomprising the amino acid sequence of SEQ ID NO:79 (S2_AB-6); a VHcomprising the amino acid sequence of SEQ ID NO:62 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-7); a VHcomprising the amino acid sequence of SEQ ID NO:63 and a VLcomprising the amino acid sequence of SEQ ID NO:81 (S2_AB-8); a VHcomprising the amino acid sequence of SEQ ID NO:64 and a VLcomprising the amino acid sequence of SEQ ID NO:82 (S2_AB-9); a VHcomprising the amino acid sequence of SEQ ID NO:65 and a VLcomprising the amino acid sequence of SEQ ID NO:83 (S2_AB-10); - 206 - 3839034.v15708.1076005 a VHcomprising the amino acid sequence of SEQ ID NO:66 and a VLcomprising the amino acid sequence of SEQ ID NO:84 (S2_AB-11); a VHcomprising the amino acid sequence of SEQ ID NO:67 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-12); a VHcomprising the amino acid sequence of SEQ ID NO:68 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-13); a VHcomprising the amino acid sequence of SEQ ID NO:62 and a VLcomprising the amino acid sequence of SEQ ID NO:74 (S2_AB-14); a VHcomprising the amino acid sequence of SEQ ID NO:69 and a VLcomprising the amino acid sequence of SEQ ID NO:85 (S2_AB-15); a VHcomprising the amino acid sequence of SEQ ID NO:70 and a VLcomprising the amino acid sequence of SEQ ID NO:86 (S2_AB-16); a VHcomprising the amino acid sequence of SEQ ID NO:58 and a VLcomprising the amino acid sequence of SEQ ID NO:87 (S2_AB-17); a VHcomprising the amino acid sequence of SEQ ID NO:71 and a VLcomprising the amino acid sequence of SEQ ID NO:88 (S2_AB-18); a VHcomprising the amino acid sequence of SEQ ID NO:53 and a VLcomprising the amino acid sequence of SEQ ID NO:85 (S2_AB-19); a VHcomprising the amino acid sequence of SEQ ID NO:72 and a VLcomprising the amino acid sequence of SEQ ID NO:85 (S2_AB-20); a VHcomprising the amino acid sequence of SEQ ID NO:94 and a VLcomprising the amino acid sequence of SEQ ID NO:113 (S2_AB-21); a VHcomprising the amino acid sequence of SEQ ID NO:95 and a VLcomprising the amino acid sequence of SEQ ID NO:114 (S2_AB-22); a VHcomprising the amino acid sequence of SEQ ID NO:53 and a VLcomprising the amino acid sequence of SEQ ID NO:115 (S2_AB-23); a VHcomprising the amino acid sequence of SEQ ID NO:96 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-24); a VHcomprising the amino acid sequence of SEQ ID NO:97 and a VLcomprising the amino acid sequence of SEQ ID NO:116 (S2_AB-25); a VHcomprising the amino acid sequence of SEQ ID NO:98 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-26); - 207 - 3839034.v15708.1076005 a VHcomprising the amino acid sequence of SEQ ID NO:99 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-27); a VHcomprising the amino acid sequence of SEQ ID NO:100 and a VLcomprising the amino acid sequence of SEQ ID NO:85 (S2_AB-28); a VHcomprising the amino acid sequence of SEQ ID NO:101 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-29); a VHcomprising the amino acid sequence of SEQ ID NO:101 and a VLcomprising the amino acid sequence of SEQ ID NO:117 (S2_AB-30); a VHcomprising the amino acid sequence of SEQ ID NO:102 and a VLcomprising the amino acid sequence of SEQ ID NO:118 (S2_AB-31); a VHcomprising the amino acid sequence of SEQ ID NO:103 and a VLcomprising the amino acid sequence of SEQ ID NO:119 (S2_AB-32); a VHcomprising the amino acid sequence of SEQ ID NO:104 and a VLcomprising the amino acid sequence of SEQ ID NO:120 (S2_AB-33); a VHcomprising the amino acid sequence of SEQ ID NO:105 and a VLcomprising the amino acid sequence of SEQ ID NO:115 (S2_AB-34); a VHcomprising the amino acid sequence of SEQ ID NO:106 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-35); a VHcomprising the amino acid sequence of SEQ ID NO:107 and a VLcomprising the amino acid sequence of SEQ ID NO:121 (S2_AB-36); a VHcomprising the amino acid sequence of SEQ ID NO:108 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-37); a VHcomprising the amino acid sequence of SEQ ID NO:109 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-38); a VHcomprising the amino acid sequence of SEQ ID NO:110 and a VLcomprising the amino acid sequence of SEQ ID NO:87 (S2_AB-39); a VHcomprising the amino acid sequence of SEQ ID NO:111 and a VLcomprising the amino acid sequence of SEQ ID NO:117 (S2_AB-40); a VHcomprising the amino acid sequence of SEQ ID NO:562 and a VLcomprising the amino acid sequence of SEQ ID NO:573 (S2_AB-41); a VHcomprising the amino acid sequence of SEQ ID NO:563 and a VLcomprising the amino acid sequence of SEQ ID NO:76 (S2_AB-42); - 208 - 3839034.v15708.1076005 a VHcomprising the amino acid sequence of SEQ ID NO:564 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-43); a VHcomprising the amino acid sequence of SEQ ID NO:565 and a VLcomprising the amino acid sequence of SEQ ID NO:574 (S2_AB-44); a VHcomprising the amino acid sequence of SEQ ID NO:566 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-45); a VHcomprising the amino acid sequence of SEQ ID NO:567 and a VLcomprising the amino acid sequence of SEQ ID NO:75 (S2_AB-46); a VHcomprising the amino acid sequence of SEQ ID NO:568 and a VLcomprising the amino acid sequence of SEQ ID NO:574 (S2_AB-47); a VHcomprising the amino acid sequence of SEQ ID NO:569 and a VLcomprising the amino acid sequence of SEQ ID NO:77 (S2_AB-48); a VHcomprising the amino acid sequence of SEQ ID NO:570 and a VLcomprising the amino acid sequence of SEQ ID NO:76 (S2_AB-49); a VHcomprising the amino acid sequence of SEQ ID NO:571 and a VLcomprising the amino acid sequence of SEQ ID NO:575 (S2_AB-50); or a VHcomprising the amino acid sequence of SEQ ID NO:56 and a VLcomprising the amino acid sequence of SEQ ID NO:80 (S2_AB-51).

38. The composition of any one of claims 31-37, wherein the antibody or the antigen-binding fragment thereof that specifically binds an S2 domain of SARS-CoV-2-Spike comprises: a) a VHcomprising the amino acid sequence of SEQ ID NO:53; and b) a VLcomprising the amino acid sequence of SEQ ID NO:

75.

39. The composition of any one of claims 28-38, wherein the composition further comprises one or more pharmaceutical excipients, diluents, and / or carriers.

40. A method of treating a subject in need thereof, comprising administering an effective amount of the polypeptide of any one of claims 1-24, the polynucleotide of claim 25, or the composition of any one of claims 28-39 to the subject.

41. A method of reducing infectivity of SARS-CoV-2 of a cell in a subject, comprising contacting the cell with an effective amount of the polypeptide of any one of claims 1-24 or the composition of any one of claims 28-39.

42. The method of claim 40 or 41, wherein the subject is a human. - 209 - 3839034.v15708.1076005 43. The method of any one of claims 40-42, wherein the subject has COVID-19, is suspected of having COVID-19, or is at risk of developing COVID-19.

44. The method of any one of claims 40-43, wherein the subject has a heart disease, has diabetes, has a lung disease, is a tobacco smoker, is on immunosuppressive therapy, is 40 years or older, or any combination thereof.

45. The method of claim 44, wherein: a) the heart disease comprises a congestive 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, or a combination thereof, optionally wherein: i) the heart failure comprises a congestive heart failure; and / or ii) the inflammatory heart disease comprises endocarditis, cardiomegaly, myocarditis, or a combination thereof; b) the lung disease comprises acute respiratory distress syndrome, asthma, bronchitis, COPD, emphysema, a lung tumor, a pleural cavity disease, a pulmonary vascular disease, a respiratory tract infection, or a combination thereof, optionally wherein: i) the respiratory tract infection comprises an upper respiratory tract infection, a lower respiratory tract infection, and / or pneumonia; ii) the pleural cavity disease comprises pleural mesothelioma and / or tension pneumothorax; iii) the pulmonary vascular disease comprises embolisms, edema, arterial hypertension, and / or hemorrhages; or a combination thereof; or both a) and b). - 210 - 3839034.v1

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