Antigen-binding molecules targeting SARS-COV-2

Abstract

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

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 424,947, filed November 13, 2022, U.S. Provisional Patent Application No. 63 / 383,699, filed November 14, 2022, U.S. Provisional Patent Application No. 63 / 480,919, filed January 20, 2023, U.S. Provisional Patent Application No. 63 / 492,211, filed March 24, 2023, and U.S. Provisional Patent Application No. 63 / 520,549, filed August 18, 2023, the entire teachings of which are incorporated herein by reference.

[0002] Including material by reference in XML This application incorporates by reference the sequence listing contained in the following extensible markup language (XML) file filed concurrently herewith: a) File name: 5708_1076-005_SL.xml. Created on November 1, 2023, size 584,835 bytes. [Background technology]

[0003] The novel coronavirus SARS-coronavirus 2 (SARS-CoV-2) 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, and 2,873 had died, corresponding 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)). However, this figure may be an underestimate of the potential threat of COVID-19 in symptomatic patients (ibid.).

[0004] COVID-19 has rapidly spread worldwide, resulting in a pandemic. The World Health Organization's (WHO) Situation Report on Coronavirus Disease 2019 (COVID-19) released on April 21, 2020, reported 2,397,216 confirmed cases and 162,956 deaths. Of these, 83,006 new cases and 5,109 deaths were added within the past 24 hours. Preventing the spread of the disease and providing supportive care for those who become ill relies on quarantine, isolation, and infection control measures (Baden & Rubin, Covid-19—The Search for Effective Therapy, N Engl J Med. 382(19):1851–52 (2020)).

[0005] Despite the development and use of vaccines and therapeutics, SARS-CoV-2 outbreaks continue, and SARS-CoV-2 variants continue to evolve and evade these prevention and treatment strategies. Thus, there is a need for additional therapeutics that can be rapidly deployed, preferably those that combat escape variants, e.g., through broad neutralizing activity, and retain therapeutic efficacy. Summary of the Invention

[0006] There is an urgent need to develop specific antiviral therapeutics to prevent the transmission of COVID-19 and treat COVID-19 patients, preferably those that retain activity against new and emerging variants with broad neutralizing activity. The present disclosure provides such therapeutics.

[0007] The disclosure provided herein is based in part on the discovery that the 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 present disclosure generally relates to compositions (e.g., polypeptides, pharmaceutical compositions) and methods that are useful for reducing viral entry into cells mediated by the spike (e.g., SARS-CoV-2-spike).

[0008] In particular, provided herein are polypeptides (e.g., antibodies and antigen-binding fragments thereof) that specifically bind to the RBD of a spike glycoprotein of a betacoronavirus (e.g., the RBD of the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)). In some embodiments, the polypeptides have one or more properties selected from broad neutralizing activity against multiple known and predicted betacoronaviruses (e.g., past, present, emerging, and future betacoronaviruses) and binding affinity for an RBD epitope (e.g., an RBD class 4 epitope) that is highly conserved across multiple betacoronaviruses. In some embodiments, the polypeptides have broad neutralizing activity against multiple known and predicted betacoronaviruses and binding affinity for an RBD domain epitope (e.g., an RBD class 4 epitope) that is highly conserved across multiple betacoronaviruses.

[0009] The present disclosure provides, inter alia, a polypeptide that specifically binds to SARS-CoV-2-spike, the polypeptide comprising: 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 V selected from any combination of the above H / V L It comprises a paratope substantially similar to the paratope of the antibody comprising the pair.

[0010] The present disclosure provides, inter alia, a polypeptide that specifically binds to SARS-CoV-2-spike, the polypeptide comprising: 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 V selected from any combination of the above H / V L It comprises a paratope substantially similar to the paratope of the antibody comprising the pair.

[0011] The present disclosure also provides, inter alia, a polypeptide that specifically binds to SARS-CoV-2-spike, the polypeptide comprising: an immunoglobulin heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) substantially similar to heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3), respectively, of SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6; H ) an amino acid sequence; an immunoglobulin light chain variable domain (V) comprising an LCDR1, an LCDR2, and an LCDR3 substantially similar to light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (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; L ) amino acid sequence.

[0012] The present disclosure also provides, inter alia, a polypeptide that specifically binds to SARS-CoV-2-spike, the polypeptide comprising: an immunoglobulin heavy chain variable domain (V) comprising heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) substantially similar to SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:89, or SEQ ID NO:90, respectively; H ) an amino acid sequence; an immunoglobulin light chain variable domain (V) comprising an LCDR1, an LCDR2, and an LCDR3 substantially similar to light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (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; L ) amino acid sequence.

[0013] In some embodiments, the polypeptides disclosed herein are 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 It includes HCDR1, HCDR2, and HCDR3, and LCDR1, LCDR2, and LCDR3 of an antibody comprising an amino acid sequence selected from SEQ ID NO: 6 and SEQ ID NO: 20 (AB-3d).

[0014] In some embodiments, the polypeptides disclosed herein are 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 It includes HCDR1, HCDR2, and HCDR3, and LCDR1, LCDR2, and LCDR3 of an antibody comprising an amino acid sequence selected from SEQ ID NO: 90 and SEQ ID NO: 92 (AB-7a).

[0015] In some embodiments, the polypeptides disclosed herein are 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 It comprises a paratope that is identical to the paratope of an antibody comprising an amino acid sequence selected from SEQ ID NO: 6 and SEQ ID NO: 20 (AB-3d).

[0016] In some embodiments, the polypeptides disclosed herein are 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 It comprises a paratope that is identical to the paratope of an antibody comprising an amino acid sequence selected from SEQ ID NO: 90 and SEQ ID NO: 92 (AB-7a).

[0017] The present disclosure relates to, inter alia, V comprising SEQ ID NO:2 H Further provided is a polypeptide comprising: X1 is not G, X2 is not I, X3 is not F, The X4 is not an N. The X5 is not an M. The X6 is not an S. The X7 is not an M. X8 is not N, X9 is not G, X 10 is not N, X 11 is not I, or Any combination of the above.

[0018] In some embodiments, the polypeptides disclosed herein comprise a V comprising SEQ ID NO:7. L Including, X 12 is not N, X 13 is not D, X 14 is not C, X 15 is not N, X 16 is not S, X 17is not L, X 18 is not S, X 19 is not G, X 20 is not N, or Any combination of the above.

[0019] In some embodiments, the present disclosure provides a polypeptide that specifically binds to SARS-CoV-2-spike, comprising: V having at least 70% sequence identity to SEQ ID NO:3 H an array, or V having at least 70% sequence identity to SEQ ID NO:8 L an array, or and combinations thereof, V H The sequence does not include SEQ ID NO: 3 or V L The sequence does not include SEQ ID NO:8, or both.

[0020] In some embodiments, the polypeptides disclosed herein are fusion proteins.

[0021] In some embodiments, the present disclosure provides polynucleotides encoding the polypeptides disclosed herein, vectors comprising such polynucleotides, and host cells comprising such polynucleotides and / or vectors.

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

[0023] In some embodiments, the present disclosure provides for the use 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 with a SARS-CoV infection, such as COVID-19).

[0024] In some embodiments, the present 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, the pharmaceutical composition comprising one or more polypeptides disclosed herein and / or compositions comprising one or more polypeptides disclosed herein (e.g., pharmaceutical compositions), the method comprising administering an effective amount (e.g., a therapeutically effective amount) of one or more polypeptides disclosed herein and / or compositions comprising one or more polypeptides disclosed herein (e.g., pharmaceutical compositions) (e.g., for a time sufficient to treat the infection).

[0025] In some embodiments, the present disclosure provides a method of neutralizing a SARS-CoV-2 variant in a cell (e.g., a cell of a subject), comprising contacting the cell with an effective amount of a composition comprising a polypeptide disclosed herein or a composition (e.g., a pharmaceutical composition) comprising a polypeptide disclosed herein.

[0026] This 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 become apparent from the following more detailed description of exemplary embodiments, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views, and in which the drawings are not necessarily to scale, emphasis instead being placed upon illustrating the embodiments. [Brief explanation of the drawings]

[0028] [Figure 1]

[0023] Figure 1 shows an alignment of non-limiting examples of heavy chain variable domain (VH) amino acid sequences useful in the polypeptides disclosed herein. Heavy chain complementarity determining region (HCDR) amino acid sequences (shown 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 in the shown sequences (designated "Xn" throughout this disclosure). See also the VH consensus sequence (SEQ ID NO: 2) in Table 1. Antibody sequences were computer-generated using information from the sequences and structures of reference polypeptides (references). [Figure 2]

[0023] Figure 1 shows an alignment of non-limiting examples of light chain variable domain (VL) amino acid sequences useful in the polypeptides disclosed herein. Light chain complementarity determining region (LCDR) amino acid sequences (shown using boxes) are determined by IMGT numbering. Identical residues are represented by dots, and variable residues are represented by letters in the shown sequences (designated "Xn" throughout this disclosure). See also the VL consensus sequence in Table 2 (SEQ ID NO: 7). Antibody sequences were computer-generated using information from the sequences and structures of reference polypeptides (references). [Figure 3A-B] A-B show pseudovirus neutralization data for each antibody (shown as dots) against the indicated viruses, expressed as the Log fold change in IC50 value relative to the reference polypeptide (ref) (i.e., log10(FC of IC50) (Figure 3A) or percentage neutralization versus concentration (Figure 3B). [Figure 3C] Same as above. [Figure 3D] Same as above. [Figure 3E] Same as above. [Figure 4]A-B show pseudovirus neutralization data expressed as normalized signal versus antibody concentration. The term "seed" refers to the test antibody being selected for Project Learning. Sotrovimab is a clinical-stage antibody. [Figure 5A] Binding to BA.4 / 5 (expressed as Log EC50 fold change relative to sotrovimab) and pseudovirus neutralization data (expressed as percentage neutralization at 0.28 μg / ml) are shown, with each dot representing an antibody. [Figure 5B] Neutralization data for BA.4 / 5 (expressed as percentage neutralization at 0.28 μg / ml) as a function of Hamming distance from the reference are shown. [Figure 6] Figure 1 shows the developability of the top VS-341 hits (i.e., antibodies selected from Project Learning results). Benchmark comparison ranges: 1 (Tm > 60°C acceptable, Tm between 50 and 60°C may be acceptable, Tm < 50°C unacceptable); 2 (SEC monomer level > 95% acceptable, SEC monomer level between 95% and 90% not applicable; SEC monomer level < 90% unacceptable); 3 (for PRO-18404, Z-score < 1 acceptable, Z-score 1 to 1.5 not applicable, Z-score > 2 unacceptable; for comparison, 9.5 ± 0.3 and 7.5 ± 1.0 for the bococizumab controls, PSR-DNA and PSR-insulin); 4 (λ shift < 10 nm acceptable, λ shift 10 to 15 nm not applicable, λ shift > 15 nm unacceptable); and 5 (Δ% > -5% acceptable, Δ% -5 to -10% not applicable, Δ% < -10% unacceptable). Ranges based on TSLP developability studies, where appropriate, are arbitrary and separated by at least the mean std error or SD. Additional notes are: a (method optimization in progress), * (melting curve suggesting reduced Fab thermostability), † (acceptable), ‡ (potentially acceptable), ** (out of acceptable range), and N / A (not applicable). Values ​​+ / - range are the standard deviation of at least two replicates, where available. [Figure 7A]Pseudovirus neutralization profiles of selected class 4 anti-RBD screening hits (AB-1a, AB-2a, AB-3a, AB-4a, AB-7) and reference antibodies against BA.4 / 5 are shown. [Figure 7B] Pseudovirus neutralization profiles of selected class 4 anti-RBD screening hits (AB-1a, AB-2a, AB-3a, AB-4a, AB-7) and reference antibodies against BA.4 / 5 are shown. [Figure 8A] Figure 1 shows the binding profiles of selected class 4 anti-RBD screening hits (AB-3a, AB-4a) and clinical-stage antibodies (sotrovimab, bebuterovimab, AZD1061) to RBDs representing sarbecovirus clades expressed on yeast. [Figure 8B] Figure 1 shows the binding profiles of selected class 4 anti-RBD screening hits (AB-3a, AB-4a) and clinical-stage antibodies (sotrovimab, bebuterovimab, AZD1061) to RBDs representing sarbecovirus clades expressed on yeast. [Figure 8C] Neutralization of a VSV-dG pseudovirus representing SARS-CoV-2 BQ.1.1 by Class 4 anti-RBD screening hit AB-3a and clinical-stage antibodies (sotrovimab, bebuterovimab, AZD1061). Synagis® was used as an isotype control. [Figure 9A] Pseudovirus neutralization profiles of the class 4 anti-RBD antibody AB-4a identified in variant set VS-341, and anti-S2 monoclonal antibodies alone and in combination, and the clinical-stage antibodies sotrovimab, bebuterovimab, and silgavimab + tixagevimab (EVUSHELD®) against BA.4 / 5 are shown. Synagis® was used as an isotype control. [Figure 9B]Pseudovirus neutralization profiles of the class 4 anti-RBD antibody AB-4a identified in variant set VS-341, and anti-S2 monoclonal antibodies alone and in combination, as well as the clinical-stage antibodies sotrovimab, bebuterovimab, and silgavimab + tixagevimab (EVUSHELD®) against BA.4 / 5+K444T. Synagis® was used as an isotype control. [Figure 9C] Pseudovirus neutralization profiles of the class 4 anti-RBD antibody AB-4a identified in variant set VS-341, and anti-S2 monoclonal antibodies alone and in combination, as well as the clinical-stage antibodies sotrovimab, bebuterovimab, and silgavimab + tixagevimab (EVUSHELD®), against BA.4 / 5 (Figure 9A) and BA.4 / 5+K444T (Figure 9B). Synagis® was used as an isotype control. Respective EC50 and EC90 values ​​are reported as ng / ml. [Figure 10A] Pseudovirus neutralization profiles of class 4 anti-RBD hits AB-3a, sotrovimab, and bebuterovimab alone or in combination with anti-S2 monoclonal antibody (also tested alone) against BA.4 / 5 and BA.4 / 5+K444T. Synagis® was used as an isotype control. [Figure 10B] The results of the neutralization profile shown in Figure 10A are reported as area under the curve (AUC) and efficacy (% maximal neutralization). [Figure 11A] Two graphs show that AB-3a in combination with anti-S2 antibody ("S2_AB-1") demonstrates improved neutralization potency and efficacy against Omicron BQ.1.1 pseudovirus. Neutralization profiles are shown. Synagis® was used as an isotype control. Standard deviations (SD) are applied as error bars. [Figure 11B]1 is a chart showing that AB-3a in combination with anti-S2 antibody ("S2_AB-1") demonstrates improved neutralization potency and efficacy against Omicron BQ.1.1 pseudovirus. Neutralization profiles are shown. [Figure 11C] The results shown in Figure 11A are reported as values ​​for EC50 (95% confidence interval (CI)) and median % neutralization (95% CI) at 18 μg / ml. [Figure 11D] 1A-1C are two graphs showing that anti-S2 antibody (S2_AB-1) combined with class 4 anti-RBD antibody 3a ("RBD class 4 mAb-3a" or "AB-3a") demonstrated improved neutralization potency and efficacy against Omicron BQ.1.1 pseudovirus. Graphs are neutralization profiles. Synagis was used as an isotype control. Standard error of the mean (SEM) is applied as the error bars. [Figure 12A] Graph showing that AB-4a combined with anti-S2 antibody ("S2_AB-1") demonstrates improved neutralization potency and efficacy against Delta and Omicron BA.5 live viruses. Neutralization profile against SARS-CoV-2 Delta is shown. Synagis® was used as an isotype control. Standard deviation (SD) is applied as the error bar. [Figure 12B] 1 is a graph showing that AB-4a combined with anti-S2 antibody ("S2_AB-1") demonstrates improved neutralization potency and efficacy against Delta and Omicron BA.5 live viruses. The neutralization profile against BA.5 live virus is shown. Synagis® was used as an isotype control. Standard deviation (SD) is applied as the error bars. [Figure 12C] 12A-12B are charts showing that AB-4a combined with anti-S2 antibody ("S2_AB-1") demonstrates improved neutralization potency and efficacy against Delta and Omicron BA.5 live viruses. The results shown in Figures 12A-12B are reported as EC50 (95% CI) and median % neutralization at 18 μg / ml (95% CI). [Figure 13A]Figure 1 shows the binding profiles of the class 4 anti-RBD molecule AB-2b and the clinical-stage antibody bebuterovimab to RBDs representing sarbecovirus clades expressed in yeast. Synagis® was used as an isotype control. [Figure 13B] Figure 1 shows the binding profiles of the class 4 anti-RBD molecule AB-2b and the clinical-stage antibody bebuterovimab to RBDs representing sarbecovirus clades expressed in yeast. Synagis® was used as an isotype control. [Figure 14A] Neutralization profiles of the class 4 anti-RBD molecule AB-2b in combination with anti-S2 monoclonal antibody (S2_AB-1) or an isotype control against SARS-CoV-2 D614G, Delta, BQ.1.1, or XBB.1.5 are shown. The neutralization profiles of S2_AB-1 or the clinical-stage antibody bebuterovimab in combination with an isotype control are also shown. Synagis® was used as an isotype control. [Figure 14B] Corresponding EC50, EC90 values, and 95% confidence intervals (95% CI) are reported for the indicated pseudoviruses. [Figure 15A] Neutralization profiles of the class 4 anti-RBD molecule AB-2b in combination with anti-S2 monoclonal antibody (S2_AB-1) or an isotype control against SARS-CoV-2 D614G, SARS-CoV-1, or WIV1 are shown. The neutralization profiles of S2_AB-1 or the clinical-stage antibody bebuterovimab in combination with an isotype control are also shown. Synagis® was used as an isotype control. [Figure 15B] Corresponding EC90 values ​​and 95% confidence intervals (95% CI) are reported for the indicated pseudoviruses. [Figure 15C]Neutralization of SARS-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 bebuterovimab as single agents against pseudoviruses representing the indicated SARS-CoV-2 variants using TMPRSS2-Vero E6 cells. Anti-spike antibodies tested as single agents were combined with the same concentration of isotype to control for the total mass of anti-spike antibodies tested in combination. The x-axis shows the concentration of each individual antibody in the combination, or, if concentrations vary, the concentration of the antibody with the highest concentration. Results are reported as % neutralization and shown as the mean ± standard deviation (representative of three or four independent experiments, each with four technical replicates). [Figure 15D] Neutralization of SARS-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 bebuterovimab as single agents against pseudoviruses representing the indicated SARS-CoV-2 variants using Vero E6 cells. Anti-spike antibodies tested as single agents were combined with the same concentration of isotype to control for the total mass of anti-spike antibodies tested in combination. The x-axis shows the concentration of each individual antibody in the combination, or, if concentrations vary, the concentration of the antibody with the highest concentration. Results are reported as % neutralization and shown as the mean ± standard deviation (representative of three or four independent experiments, each with four technical replicates). [Figure 16] We show that AB-2b has comparable activity to sotrovimab VH / VL-hIgG1-LS in reducing lung viral titers (measured by TCID50) in a hamster challenge model with SARS-CoV-2 BA.2. However, the combination of AB-2b and S2_AB-1 achieved a much greater reduction in lung viral titers. [Figure 17A] Figure 1 shows the structural analysis of AB-2b Fab binding to the SARS-CoV-2 BA.1 RBD and associated contact residues. [Figure 17B]Figure 1 shows the structural analysis of AB-2b Fab binding to the SARS-CoV-2 BA.1 RBD and associated contact residues. [Figure 17C] Low-pass filtered cryo-EM maps of the SARS-CoV-2 BA.1 spike trimer with the AB-3a Fab bound to the RBD and an anti-S2 antibody (S2_AB-1) bound to the S2 stem helix. The maps show a side profile and a view from below. Each of the putative Fabs is labeled. [Figure 17D] Density-docked atomic model of the SARS-CoV-2 spike assembly with bound Fab. Spike trimer: High-resolution structure of the SARS-CoV-2 spike with resolved S2 stem helix. AB-3a: Designed model for the AB-3a Fab. Bottom: Three anti-S2 Fabs docked into the propeller-shaped density around the S2 stem helix. [Figure 18A] Neutralization of SARS-CoV-2 live virus variants by AB-2b in combination with S2_AB-1 is shown. The neutralization profiles of the AB-2b + S2_AB-1 combination, as well as AB-2b, S2_AB-1, and bebuterovimab as single agents, and an isotype control antibody, against SARS-CoV-2 ancestral strain (Eng20 (WT)), Delta, BQ.1.1, and XBB.1.1 live viruses are shown. Anti-spike antibodies tested as single agents were combined with the same concentration of isotype to control for the total mass of anti-spike antibodies tested in combination. The x-axis indicates the concentration of each individual antibody in the combination, or, if concentrations vary, the concentration of the antibody with the highest concentration. Results are reported as % neutralization and are shown as the mean ± standard deviation (one experiment, representative of 2–3 technical replicates). AB-2b in combination with S2_AB-1 demonstrates improved neutralization of SARS-CoV-2 Omicron BQ1.1 and XBB.1.1 live viruses. [Figure 18B]Neutralization of SARS-CoV-2 live virus variants by AB-2b in combination with S2_AB-1 is shown. The neutralization profiles of the AB-2b + S2_AB-1 combination, as well as AB-2b, S2_AB-1, and bebuterovimab as single agents, and an isotype control antibody, against SARS-CoV-2 ancestral strain (Eng20 (WT)), Delta, BQ.1.1, and XBB.1.1 live viruses are shown. Anti-spike antibodies tested as single agents were combined with the same concentration of isotype to control for the total mass of anti-spike antibodies tested in combination. The x-axis indicates the concentration of each individual antibody in the combination, or, if concentrations vary, the concentration of the antibody with the highest concentration. Results are reported as % neutralization and are shown as the mean ± standard deviation (one experiment, representative of 2–3 technical replicates). AB-2b in combination with S2_AB-1 demonstrates improved neutralization of SARS-CoV-2 Omicron BQ1.1 and XBB.1.1 live viruses. DETAILED DESCRIPTION OF THE INVENTION

[0029] A description of exemplary embodiments follows.

[0030] Several aspects of the present disclosure are described below with reference to examples for illustrative purposes only. It should be understood that several specific details, relationships, and methods are set forth to provide a thorough understanding of the present disclosure. However, one of ordinary skill in the art will readily recognize that the present disclosure can be practiced without one or more of the specific details, or can be practiced using other methods, protocols, reagents, cell lines, and animals. The present disclosure is not limited to the order of acts or events illustrated, as some acts may occur in a different order and / or simultaneously with other acts or events. Furthermore, not all illustrated acts, steps, or events are required to implement a methodology in accordance with the present disclosure.

[0031] definition Unless otherwise defined, all technical terms, notations, and other scientific terms or terms used herein are intended to have the meanings commonly understood by those skilled in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from what is commonly 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 consistent with their meaning in the context of the relevant art and / or as otherwise defined herein.

[0032] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0033] 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. Moreover, 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, as well as two or more polypeptides.

[0034] Unless the context requires otherwise, throughout this specification and in the claims that follow, the term "comprise," as well as variations such as "comprises" or "comprising," will be understood to imply, for example, the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "comprising" can be substituted with the words "containing" or "including."

[0035] As used herein, the term "consisting of" excludes any element, step, or ingredient not specified in the claim element. As 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.

[0036] Also, for any embodiment characterized by the terms "comprising," "containing," "including," or "having," corresponding embodiments are provided herein in which these terms are replaced by the terms "consisting of" and / or "consisting essentially of."

[0037] As used herein, the conjunction term "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, when two elements are joined by "and / or," the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second element without the first element. The third option refers to the applicability of the first and second elements together. Any one of these options is understood to be within the meaning and thus meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the options is also understood to be within the meaning and thus meets the requirements of the term "and / or."

[0038] It is to be understood that for all numerical boundaries describing certain parameters in this application, such as "about," "at least," "less than," "less than," and "more than," this description also necessarily encompasses any range bounded by the recited values. Thus, for example, a description of "at least 1, 2, 3, 4, or 5" also describes ranges such as 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, and 4 to 5, among others.

[0039] Where lists are presented, unless otherwise expressly stated, 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" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0040] As used herein, the term "about" refers to a value within an acceptable error range for a particular value, as determined by one of ordinary skill in the art. Typically, the acceptable error range for a particular value depends, at least in part, on how the value is measured or determined, e.g., on the limitations of the measurement system. For example, "about" may refer to within an acceptable standard deviation, as practiced in the art. Alternatively, "about" may refer to a range of ±20%, e.g., ±10%, ±5%, or ±1% of the given value. It should be understood that the term "about" can precede any particular value specified herein, except for specific values ​​used in the examples. When "about" precedes a range, such as in "90-99.9%," the term "about" should be read as applying to both given values ​​in that range, such that "about 90-99.9%" means about 90% repeatability to about 99.9%.

[0041] 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). Polypeptides can contain any suitable L-amino acids and / or D-amino acids, such as common α-amino acids (e.g., alanine, glycine, valine), non-α-amino acids (e.g., β-alanine, 4-aminobutyric acid, 6-aminocaproic acid, sarcosine, statins), and unusual amino acids (e.g., citrulline, homocitrulline, homoserine, norleucine, norvaline, ornithine). Amino, carboxyl, and / or other functional groups on a polypeptide can be free (e.g., unmodified) or protected with suitable protecting groups. Suitable protecting groups for amino and carboxyl groups, as well as methods for adding or removing protecting groups, are known in the art and are disclosed, for example, in Green and Wuts, "Protecting Groups in Organic Synthesis," John Wiley and Sons, 1991. Functional groups of polypeptides can also be derivatized (e.g., alkylated) or labeled (e.g., with a detectable label such as a fluorogen or hapten) using methods known in the art. Polypeptides can contain, if desired, one or more modifications (e.g., amino acid linkers, acylation, acetylation, amidation, methylation, terminal modifications (e.g., cyclization modifications), N-methyl-α-amino group substitutions). In addition, polypeptides can be analogs of known and / or naturally occurring peptides, e.g., peptide analogs having conservative amino acid residue substitution(s).

[0042] As used herein, a "polynucleotide" is defined as multiple nucleotides and / or nucleotide analogs linked together in a single molecule. In some embodiments, polynucleotides disclosed herein comprise deoxyribonucleotides. In some embodiments, polynucleotides comprise ribonucleotides. Non-limiting examples of polynucleotides include single-stranded, double-stranded, or multi-stranded DNA or RNA, DNA-RNA hybrids (e.g., each "T" position can be independently replaced by "U" or vice versa), or polymers containing purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of a polynucleotide can comprise sugar and phosphate groups, modified or substituted sugars or phosphate groups, polymers of synthetic subunits such as phosphoramidates, or combinations thereof.

[0043] As used herein, the term " sequence identity " refers to the degree, expressed as a percentage, that two nucleotide sequences have the same residue at the same position when the sequences are aligned to achieve maximum identity.For sequence alignment and comparison, typically, one sequence is designated as a reference sequence, and test sequence is compared to it.The sequence identity between a reference sequence and a test sequence is expressed as the percentage of positions in the entire length of the reference sequence that the reference and test sequences share the same nucleotide or amino acid when aligned to achieve maximum identity.As an example, when aligned to achieve maximum identity, if the test sequence has the same nucleotide residue at 70% of the same position throughout the entire length of the reference sequence, the two sequences are considered to have 70% sequence identity.

[0044] Alignment of sequences for comparison to achieve the maximum level of identity can be readily performed by one skilled in the art using an appropriate alignment method or algorithm. In some instances, the alignment may include gaps introduced to achieve the maximum 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, e.g., generally, Ausubel et al., Current Protocols in Molecular Biology).

[0045] When using sequence comparison algorithm, test and reference sequences are input into computer, and if necessary, coordinates are subsequently designated, and sequence algorithm program parameters are designated.Then, sequence comparison algorithm calculates the sequence identity percentage of test sequence (several) to reference sequence based on designated program parameters.The tool commonly used for determining sequence identity percentage is Protein Basic Local Alignment Search Tool (BLASTP), available from the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health (Altschul et al., 1990).

[0046] 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% amino acid residue amino acid sequence identity) and that substantially preserves one or more functional properties of a particular polypeptide disclosed herein (e.g., AB-1). In some embodiments, the one or more functional properties are selected from, but are not limited to, substantially similar binding affinity, substantially similar binding specificity, substantially similar inhibitory activity, substantially similar neutralizing activity, and substantially similar self-association properties.

[0047] As used herein, "complementarity determining region (CDR)" encompasses any CDR defined by art-recognized methods for identifying CDR residues on an antibody. For example, see Kabat, EA, et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment 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 CDRs as each other with respect to HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3 if the identity of the CDRs is determined for both antibodies using the same method.

[0048] The extent of the framework regions and CDRs of an antibody can be defined using any one of several suitable methodologies well known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, and / or the contact definition. Public 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, e.g., 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 Classification (ANARCI, accessible at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), or the Paratome web server (Vered Kunik, et al. al, Nucleic Acids Research, Volume 40, Issue W1, 1 July 2012, Pages W521-W524).

[0049] As used herein, the term "paratope" refers to the set of amino acid residues in an antibody or 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 Waals interaction, an ionic bond, or a combination thereof. The binding interaction can be direct or indirect, for example, through a cooperative intermediate molecule such as an ion or water. The residues of the paratope, in some embodiments, include only residues that are part of a defined CDR. In other embodiments, the residues of the paratope further include one or more residues that are not part of a defined CDR.

[0050] As used herein, the term "antibody mimetic" refers to a polypeptide that can mimic the ability of an antibody to bind to an antigen but that is structurally different from the natural antibody structure. Examples of antibody mimetics include, but are not limited to, adnectins, affibodies, affilins, affimers, affitins, alphabodies, anticalins, avimers, DARPins, finomers, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMPs, and versabodies.

[0051] As used herein, the "K" constant, also referred to as the "binding constant," "equilibrium dissociation constant," or "affinity constant," is DThe term "reversible binding affinity" is a measure of the degree of reversible association between two molecular species (e.g., an antibody and a target protein) and includes both actual and apparent binding affinity. Binding affinity can be determined using methods known in the art, including, for example, measuring surface plasmon resonance using biolayer interferometry (Octet, ForteBio) or surface plasmon resonance (Biacore) systems and assays. A reference comparing 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 herein by reference in their entirety.

[0052] The terms "subject" and "patient" are used interchangeably herein to refer to an animal (e.g., a mammal such as a human) treated according to the methods disclosed herein. A subject treated according to the methods described herein may be a subject who has been diagnosed with a particular condition (e.g., COVID-19) or who is at risk for developing such a condition. Diagnosis may be performed by any method or technique known in the art. One of skill in the art will understand that a subject treated according to the present disclosure may have been subjected to standard testing or may have been identified without testing as being at risk due to the presence of one or more risk factors associated with a disease or condition.

[0053] The term "pharmaceutically acceptable" means that the substance or composition it modifies is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without excessive toxicity, irritation, allergic response, or the like, and is commensurate with a reasonable benefit / risk ratio.

[0054] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that, within the scope of sound medical judgment, are suitable for use in contact with mammalian tissues without undue toxicity, irritation, allergic reaction, etc., and that 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.

[0055] Examples of salts derived from suitable acids include salts of amino groups 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 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, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethoxy ... Examples of the salts include 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, and valerate.

[0056] 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.

[0057] Salts derived from appropriate bases include those derived from inorganic bases such as alkali metal, alkaline earth metal, and ammonium bases, as well as salts derived from aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline; +((C1-C4) alkyl) salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxyls, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0058] "Pharmaceutically acceptable carrier" refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the drug formulated with the carrier and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the drug. Pharmaceutically acceptable carriers that can 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 phosphate, 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol, and wool fat.

[0059] As used herein, "treating" or "treatment" refers to taking steps to deliver a therapeutic agent to a subject, such as a mammal in need of treatment (e.g., by administering one or more therapeutic agents to the mammal). "Treating" or "treatment" includes inhibiting a disease or condition (e.g., by slowing or halting its progression or causing regression of the disease or condition), as well as alleviating symptoms caused by the disease or condition.

[0060] 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 symptom, or disorder, such as the specific indications exemplified herein. This term includes active treatment (treatment to improve the disease, pathological symptom, or disorder), causal treatment (treatment directed at the cause of the associated disease, pathological symptom, or disorder), palliative treatment (treatment designed to relieve symptoms), preventative treatment (treatment to minimize or partially or completely inhibit the onset of the associated disease, pathological symptom, or disorder), and supportive treatment (treatment used to complement another therapy). Treatment also includes the reduction of the extent of a disease or symptom, whether detectable or undetectable, the prevention of the spread of a disease or symptom, the delay or slowing of the progression of a disease or symptom, the improvement or palliation of a disease or symptom, and remission (whether partial or complete). "Ameliorating" or "alleviating" a disease or condition means reducing the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slowing or prolonging the time course of progression compared to the severity or time course in the absence of treatment. "Treatment" can also mean prolonging survival compared to expected survival in the absence of 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 whom the condition or disorder is to be prevented.

[0061] A "pharmaceutical composition" refers to a formulation of one or more therapeutic agents and a vehicle generally accepted in the art for delivering biologically active agents to a subject, e.g., a human. 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 the methods disclosed herein further includes one or more pharmaceutically acceptable carriers.

[0062] A "pharmaceutically acceptable carrier, diluent, or excipient" includes any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0063] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition, other than the active ingredient, that is nontoxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. In some embodiments, a carrier can be a diluent, adjuvant, excipient, or vehicle with which a drug (e.g., a polynucleotide) is administered. Such vehicles can 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, such as pH adjusters and buffers, stabilizers, thickeners, lubricants, and coloring agents, as needed to approximate physiological conditions. The concentration of the drug in such pharmaceutical formulations may vary widely, i.e., from less than about 0.5% by weight to at least about 1%, or even 15%, or 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. The concentration is selected primarily based on the required dose, fluid volume, viscosity, etc., according to the mode of administration. Suitable vehicles and formulations containing other human proteins, such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21 stEdition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing: 691-1092 (e.g., pages 958-89).

[0064] Non-limiting examples of pharmaceutically acceptable carriers are physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., such as salts, buffers, antioxidants, sugars, aqueous or nonaqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.

[0065] Non-limiting examples of buffers are acetate, citrate, formate, succinate, phosphate, carbonate, malate, aspartate, histidine, borate, Tris buffer, HEPPSO, and HEPES.

[0066] Non-limiting examples of antioxidants are ascorbic acid, methionine, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0067] 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.

[0068] Non-limiting examples of surfactants include 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, NJ), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (eg, PLURONICS®, PF68, etc.).

[0069] Non-limiting examples of preservatives are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof.

[0070] Non-limiting examples of sugars are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactose, maltulose, glucitol, maltitol, lactitol, or isomaltulose.

[0071] Non-limiting examples of salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid, as well as those derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, as well as those derived from non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine. In some embodiments, the salt is sodium chloride (NaCl).

[0072] The agents (e.g., polynucleotides) described herein may be prepared in accordance with standard procedures and administered at dosages selected to reduce, prevent, or eliminate the symptoms being treated, or to slow or halt their progression. (For general descriptions of methods for administering various agents for human therapy, 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, NY, the contents of which are incorporated herein by reference.)

[0073] As used herein, "administering" or "administration" 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, multiple times, and / or over one or more extended periods of time. Administering includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug or instructing a subject to take a drug). For example, as used herein, a person (e.g., a physician) who instructs a subject (e.g., a human patient) to self-administer a drug (e.g., a medication) or have a drug administered by another person, and / or who provides a patient with a drug prescription, is administering a drug to the subject.

[0074] A "therapeutically effective amount," "effective amount," or "effective dosage" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., treatment, cure, inhibition or amelioration of a physiological response or symptom, etc.). The full therapeutic effect does not necessarily occur by administration of a single dose, but 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 depending on factors such as the disease state, age, sex, and weight of the mammal (e.g., a human patient), mode of administration, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response.

[0075] The effective amount of drug 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 drug, pharmaceutical formulation, route of administration, type of disease or disorder, and the identity (e.g., age, sex, and body weight) of the subject or host being treated. For example, a suitable dosage may be about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.01 mg / kg to about 1 mg / kg body weight per treatment. Determining the dosage for a particular drug, subject, and disease is well within the capabilities of one of ordinary skill in the art. Preferably, the dosage will cause no or minimal adverse side effects.

[0076] The desired response or desired outcome can include an effect at the cellular level, tissue level, or clinical outcome. Thus, the term "therapeutically effective amount" or its synonyms depends on the context in which it is applied. For example, in some embodiments, it is an amount of a composition sufficient to achieve a therapeutic response compared to a response obtained without administration of the composition. In other embodiments, it is an amount that produces a beneficial or desired result in a subject compared to a control. As defined herein, a therapeutically effective amount of a composition (e.g., a pharmaceutical composition) disclosed herein can be readily determined by one of ordinary skill in the art by routine methods known in the art. Dosage regimens and routes of administration can be adjusted to provide an optimal therapeutic response.

[0077] Preferred features of each of the aspects or embodiments provided by the present invention are applicable mutatis mutandis to all other aspects or embodiments of the invention, and are exemplified, without limitation, by the dependent claims, and encompass combinations and permutations of individual features (e.g., elements (including numerical ranges and exemplary embodiments)) of specific embodiments and aspects (including examples) of the invention. For example, specific experimental parameters illustrated in the examples can be adapted, piecemeal, for use in the claimed invention without departing from the invention. For example, for the disclosed materials, specific reference to each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, but each is specifically contemplated and described herein. Thus, if a class of elements A, B, and C, and a class of elements D, E, and F, are disclosed, and an example combination of element A-D is disclosed, each is individually and collectively contemplated, even though each is not individually listed. Thus, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically contemplated and should be considered disclosed based on the disclosure of A, B, and C; D, E, and F; and the exemplary combination AD. Similarly, any subset or combination of these is specifically contemplated and disclosed. Thus, for example, subgroups of AE, BF, and CE are specifically contemplated and should be considered disclosed based on the disclosure of A, B, and C; D, E, and F; and the exemplary combination AD. This concept applies to all aspects of the present application, including the elements of the subject compositions and the steps of methods of making or using the compositions. The foregoing aspects of the invention may be claimed in any combination or permutation, so long as the elements are described in one or more references known to those skilled in the art, so long as they are novel and non-obvious over the prior art, as recognized by those skilled in the art following the teachings herein, and, inter alia, may be excluded from the claimed invention by a negative disclaimer or disclaimer of a feature or combination of features.

[0078] Polypeptides that specifically bind to the spike protein of betacoronavirus In particular, provided herein are polypeptides that specifically bind to the receptor-binding domain (RBD) of the spike glycoprotein of a betacoronavirus. In some embodiments, the polypeptides have one or more properties selected from broad neutralizing activity against multiple known and predicted betacoronaviruses (e.g., past, current, emerging, and future betacoronaviruses), binding affinity for an RBD domain epitope (e.g., an RBD class 4 epitope) that is highly conserved across multiple betacoronaviruses, and inhibitory activity against potentially emerging betacoronavirus escape variants. In some embodiments, the polypeptides specifically bind to the RBD of the spike protein of a sarbecovirus (e.g., SARS-CoV-1 virus, SARS-CoV-2 virus). In some embodiments, the polypeptides specifically bind to the RBD of the spike protein of a SARS-CoV-1 virus (e.g., multiple SARS-CoV-1 variants). In some embodiments, the polypeptides specifically bind to the RBD of the spike protein of a SARS-CoV-2 virus (e.g., multiple SARS-CoV-2 variants). In some embodiments, the polypeptide specifically binds to the RBD of the spike protein of the SARS-CoV-1 virus (e.g., multiple SARS-CoV-1 variants) and the RBD of the spike protein of the SARS-CoV-2 virus (e.g., multiple SARS-CoV-2 variants).

[0079] In some embodiments, the polypeptide has broad neutralizing activity against multiple betacoronaviruses (e.g., as measured using a neutralization assay described herein or otherwise known to one of skill in the art). In some embodiments, the polypeptide has neutralizing activity against multiple sarbecoviruses (e.g., SARS-CoV-1 virus, SARS-CoV-2 virus). In some embodiments, the polypeptide has neutralizing activity against multiple SARS-CoV-1 viruses (e.g., multiple SARS-CoV-1 variants). In some embodiments, the polypeptide has neutralizing activity against multiple SARS-CoV-2 viruses (e.g., multiple SARS-CoV-2 variants). In some embodiments, the polypeptide has neutralizing activity against multiple SARS-CoV-1 viruses (e.g., multiple SARS-CoV-1 variants) and multiple SARS-CoV-2 viruses (e.g., multiple SARS-CoV-2 variants).

[0080] In some embodiments, the polypeptide has binding affinity for an RBD epitope (e.g., an RBD class 4 epitope) that is conserved (e.g., highly conserved) across multiple betacoronaviruses. In some embodiments, the RBD epitope is highly conserved across multiple sarbecoviruses (e.g., SARS-CoV-1 virus, SARS-CoV-2 virus). In some embodiments, the RBD epitope is highly conserved across multiple SARS-CoV-1 viruses (e.g., multiple SARS-CoV-1 variants). In some embodiments, the RBD epitope is highly conserved across multiple SARS-CoV-2 viruses (e.g., multiple SARS-CoV-2 variants). In some embodiments, the RBD epitope is highly conserved across multiple SARS-CoV-1 viruses (e.g., multiple SARS-CoV-1 variants) and multiple SARS-CoV-2 viruses (e.g., multiple SARS-CoV-2 variants).

[0081] SARS-CoV-2 is the causative agent of COVID-19. The SARS-CoV-2 genome encodes 16 nonstructural proteins, as well as a nucleoprotein (N), membrane glycoprotein (M), small envelope glycoprotein (E), and spike protein (S) (Song et al., Cytokine storm induced by SARS-CoV-2, Clin Chim Acta. 509:280-7 (2020)). The SARS-CoV-2 spike, or S of SARS-CoV-2, facilitates entry of the SARS-CoV-2 virus into host cells, including human host cells. The S is a trimer with a protomer composed of S1 and S2 subunits. S1 contains the RBD that binds to the ACE2 receptor, and S2 is required for viral fusion with the host membrane.

[0082] A non-limiting example of a wild-type SARS-CoV-2-spike (S) sequence is NCBI RefSeq YP_009724390 (SEQ ID NO: 1).

[0083]

[0084] As used herein, SARS-CoV-2-spike includes the wild-type SARS-CoV-2 spike protein (e.g., SEQ ID NO: 1 (RefSeq YP_009724390) or homologs thereof) and truncated forms thereof, mutants and engineered versions of the full-length and truncated SARS-CoV-2 spike protein, and modified forms (e.g., post-translationally modified forms) of the full-length and truncated SARS-CoV-2 spike protein.

[0085] In some embodiments, the polypeptide binds to the spike protein of SARS-CoV-2 comprising SEQ ID NO:1.

[0086] In some embodiments, the polypeptide binds to a mutant, engineered, and / or modified form of the SARS-CoV-2 spike. In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises an amino acid sequence having at least about 90% sequence identity to the wild-type SARS-CoV-2 spike sequence (e.g., SEQ ID NO: 1), e.g., 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 to the wild-type SARS-CoV-2 spike sequence. In some embodiments, mutant, engineered, or modified forms of SARS-CoV-2-spike comprise an amino acid sequence having 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 the wild-type SARS-CoV-2-spike sequence (e.g., SEQ ID NO: 1).

[0087] In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2-spike is selected from the group consisting of L5F, S13I, T19R, A67V, del69, del70, del69-70, D80G, T95I, G142D, del142-144, del144, Y145D, W152C, E154K, F157S, del211, L212I, with respect to SEQ ID NO: 1. , ins214EPE, A222V, D253G, G261D, G339D, V367F, S371L, S371L, S373P, S375F, K417N, N439K, N440K, G4 46S, L452R, Y453F, S477N, T478K, E484A, E484K, E484Q, F486L, S494P, Q493R, G496S, Q498R, N501T, N501 Y, 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 Combinations thereof, for example, including one or more mutations selected from 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.

[0088] In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises one or more mutations selected from 69del, 70del, 144del, E484K, S494P, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H, or K1191N, or a combination thereof, relative to SEQ ID NO: 1. In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises 69del, 70del, 144del, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H. In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2-spike further comprises E484K, S494P, or K1191N, or a combination thereof.

[0089] In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises one or more mutations selected from D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, or A701V, or a combination thereof, relative to SEQ ID NO: 1. In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises D80A, D215G, 241del, 242del, 243del, K417N, E484K, N501Y, D614G, and A701V.

[0090] In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises one or more mutations selected from T19R, G142D, 156del, 157del, R158G, L452R, T478K, D614G, P681R, or D950N, or a combination thereof, relative to SEQ ID NO: 1. In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises T19R, 156del, 157del, R158G, L452R, T478K, D614G, P681R, and D950N. In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike further comprises G142D.

[0091] In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2-spike comprises 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, relative to SEQ ID NO:1.

[0092] In some embodiments, the mutant, engineered, or modified form of the SARS-CoV-2 spike comprises one or more mutations selected from E484K, N501Y, or D614G, or a combination thereof, relative to SEQ ID NO: 1.

[0093] In some embodiments, the mutant, engineered, or modified form of the spike protein of SARS-CoV-2 comprises one or more mutations selected from F817P, A892P, A899P, A942P, K986P, or V987P, or a combination thereof, relative to SEQ ID NO:1.

[0094] In some embodiments, the mutant, engineered, or modified form of the spike protein of SARS-CoV-2 comprises one or more mutations selected from L452R, F486V, or R493Q, or a combination thereof, relative to SEQ ID NO:1.

[0095] In some embodiments, the mutant, engineered, or modified form of the spike protein of SARS-CoV-2 is selected from the group consisting of A67V, del69-70, T95I, del142-144, Y145D, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N44 0K, 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.

[0096] In some embodiments, the modified SARS-CoV-2 spike protein comprises 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, relative to SEQ ID NO:1.

[0097] In some embodiments, the modified SARS-CoV-2 spike protein comprises 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, relative to SEQ ID NO:1.

[0098] In some embodiments, the modified SARS-CoV-2 spike protein comprises 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, relative to SEQ ID NO:1.

[0099] In some embodiments, the modified SARS-CoV-2 spike protein comprises 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, relative to SEQ ID NO:1.

[0100] 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 mutations, e.g., 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.1.617.3, B.1.617.4, B.1.617.5, B.1.617.6, B.1.617.7, B.1.617.8, B.1.617.9, B.1.617.10, B.1.617.11, B.1.617.12, B.1.617.13, B.1.617.14, B.1.617.15, B.1.617.16, B.1.617.17, B.1.617.18, B.1.617.19, B.1.617.20, B.1.617.21, B.1.617.22, B.1.617.23, B.1.617.24, B.1.617.25, B.1.617.26, B.1.617.27, B.1.617.28, B.1.617.29, B.1.617.29, B.1.617.29, .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.

[0101] In some embodiments, the polypeptide binds to the RBD of the spike (S) protein of SARS-CoV-2. As used herein, RBD includes full-length RBD (e.g., having the amino acid sequence of SEQ ID NO: 46 or a homolog thereof) and truncated forms thereof, mutants and engineered versions of full-length and truncated RBDs (e.g., epitopes within the RBD (e.g., RBD class 4 epitopes), and modified forms (e.g., post-translationally modified forms) of full-length and truncated RBDs.

[0102] In some embodiments, the polypeptides include the SARS-CoV-1-spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-spike (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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.1.61 7.2, 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.2.1 2.1, 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, B Q.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, XBB.1.5, XBB.1.5.10, XBB.1.9.1, and / or EG.5.1), or fragments thereof (e.g., the S2 domain and / or epitopes of the SARS-CoV-2 spike in Figure 1 ), with a K of 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. DIn some embodiments, the polypeptide binds to the SARS-CoV-1 spike (e.g., of CoV-1 and / or WIV1) and / or the SARS-CoV-2 spike (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., AY.3, AY.4, AY.41, AY.44, AY.50, AY.51, AY.52, AY.53, AY.54, AY.55, AY.56, AY.57, AY.58, AY.59, AY.60, AY.61, AY.62, AY.63, AY.64, AY.65, AY.66, AY.67, AY.68, AY.69, AY.69, AY.70, AY.71, AY.72, AY.73, AY.74, AY.75, AY.76, AY.77, AY.78, AY.79, AY.80, AY.81, AY.82, AY.83, AY.84, AY.85, AY.86, AY.87, AY.88, AY.89, AY.90, AY.91, AY.92, AY.93, AY.94, AY.95, AY.96, AY.97, AY.98, AY.9 ... .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.1.5 25, 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, B A.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 RBD domain of SARS-CoV-2 spike).

[0103] RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF (SEQ ID NO: 46).

[0104] In some embodiments, the polypeptide binds to a mutant, engineered, or modified form of the RBD. In some embodiments, the mutant, engineered, or modified form of the RBD comprises an amino acid sequence having at least about 90% sequence identity to a wild-type full-length RBD (e.g., SEQ ID NO: 46), e.g., 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, mutant, engineered, or modified forms of SARS-CoV-2-spike comprise an amino acid sequence having 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 the wild-type full-length RBD (e.g., SEQ ID NO: 46).

[0105] Comparator Polypeptides As used herein, the term "comparator" or "comparator polypeptide" refers to a polypeptide (e.g., an immunoglobulin molecule) that specifically binds to the SARS-CoV-2 spike and is not a polypeptide of the present disclosure. The sequences of a comparator polypeptide and a polypeptide of the present disclosure can be compared to illustrate structural differences therebetween (e.g., differences at one or more amino acid positions, such as amino acid substitutions). A polypeptide of the present disclosure has more than insubstantial differences (e.g., one or more substantial differences) compared to a comparator polypeptide, such that the polypeptide disclosed herein exhibits one or more (i.e., one, two, or all three) of different functions, in a different manner, or to achieve a different result compared to a comparator polypeptide under controlled conditions. A comparator polypeptide may differ from a polypeptide of the present disclosure by one or more amino acids, for example, in some embodiments, 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 differs from a polypeptide of the present 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 percent amino acid identity.

[0106] In some embodiments, the comparator polypeptide is a) immunoglobulin heavy chain variable (V) sequences comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 amino acid sequences of SEQ ID NO: 22, SEQ ID NO: 26, and SEQ ID NO: 31, respectively; H )domain, b) immunoglobulin light chain variable (V) sequences comprising the light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 38, and SEQ ID NO: 42, respectively; L ) domain, or An antibody comprising both a) and b).

[0107] In some embodiments, the comparator polypeptide is a) V comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 22, SEQ ID NO: 26, and SEQ ID NO: 31, respectively H domain, and b) V comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 35, SEQ ID NO: 38, and SEQ ID NO: 42, respectively L domain, an antibody comprising the

[0108] For SEQ ID NOs: 22, 26, 31, 35, 38, and 42, see Table 3 and Figures 1 and 2.

[0109] In some embodiments, the comparator polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 3 H domain, b) V comprising the amino acid sequence of SEQ ID NO: 8 L domain, or An antibody comprising both a) and b).

[0110] In some embodiments, the comparator polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 3 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 8 L domain, an antibody comprising the

[0111] For SEQ ID NO: 3, see Table 1 and Figure 1. For SEQ ID NO: 8, see Table 2 and Figure 2.

[0112] In some embodiments, the comparator polypeptide comprises a V polypeptide comprising the amino acid sequence of SEQ ID NO:3. H Domain V comprising the amino acid sequence of SEQ ID NO:8 LThe antibody referred to herein as the "reference antibody" comprises a domain, 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 to the RBD of SARS-CoV-2 and neutralizes SARS-CoV-2 variants.

[0113] QVQLVQSGAEVKKPGSSVKVSCKASGGIFNTYTISWVRQAPGQGLEWMGRIILMSGMANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGNYYGWGDDDAFDIWGQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC (SEQ ID NO: 47).

[0114] QVQLVQSGAEVKKPGSSVKVSCKASGGIFTYTISWVRQAPGQGLEWMGRIILMSGMANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGNYYGWGDDDAFDIW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 48).

[0115] QTVLTQPPSVSGAPGQRVTISCTGSNSNIGAGYDVHWYQQLPGTAPKLLICGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLSGPNWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 49).

[0116] Complementarity-Determining Regions (CDRs) The CDRs (e.g., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and / or LCDR3) may be CDRs defined by any art-recognized method for identifying antibody CDR residues (e.g., Kabat-defined CDRs, Chothia-defined CDRs, or IMGT-defined CDRs), as further described herein.

[0117] In some embodiments, the polypeptide (e.g., antibody or antigen-binding fragment thereof) comprises V of SEQ ID NO:3. H Amino acid sequence and V of SEQ ID NO:8 L The polypeptide does not include all six CDRs of the antibody comprising the amino acid sequence. In some embodiments, the polypeptide does not include all six of the sequences set forth in 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.

[0118] In some embodiments, the polypeptide comprises V of SEQ ID NO:3. H Amino acid sequence and V of SEQ ID NO:8 LThe polypeptide comprises fewer than six (e.g., one, two, three, four, or five) CDRs of an antibody comprising the amino acid sequences. In some embodiments, the polypeptide comprises one, two, three, four, or five, but not all six, 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.

[0119] In some embodiments, the polypeptide comprises all six CDRs of a particular polypeptide disclosed herein. In some embodiments, the polypeptide comprises fewer than six (e.g., one, two, three, four, or five) of the CDRs of a particular polypeptide disclosed herein.

[0120] In some embodiments, the polypeptide is a) V shown in any of SEQ ID NOs: 4 to 6 H V comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to HCDR1, HCDR2, and HCDR3, respectively. H domain, b) V shown in any of SEQ ID NOs: 9 to 20 L V comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to LCDR1, LCDR2, and LCDR3, respectively. L domain, Or includes both a) and b).

[0121] See Table 3 and Figures 1-2 for non-limiting examples of corresponding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences.

[0122] In some embodiments, the polypeptide is a) V shown in any of SEQ ID NOs: 4 to 6 HV comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to HCDR1, HCDR2, and HCDR3, respectively. H domain, b) V shown in any of SEQ ID NOs: 9 to 20 L V comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to LCDR1, LCDR2, and LCDR3, respectively. L domain, Or includes both a) and b).

[0123] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively. H domain, b) any one or more V of SEQ ID NOs: 9 to 20 L V comprising LCDR1, LCDR2, and LCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, Or includes both a) and b).

[0124] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively. H domain, and b) any one or more V of SEQ ID NOs: 9 to 20 LV comprising LCDR1, LCDR2, and LCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0125] In some embodiments, the polypeptide comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 that substantially preserve one or more functional characteristics of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and 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.

[0126] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence, respectively. H domain, or b) any one or more V of SEQ ID NOs: 9 to 20 L V comprising LCDR1, LCDR2, and LCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, or Includes both a) and b).

[0127] In some embodiments, the amino acid substitution is a conservative substitution. The term "conservative amino acid substitution" or "conservative substitution" refers to an amino acid substitution that has a value of 0 or greater in BLOSUM62.

[0128] In some embodiments, the amino acid substitution is a highly conservative substitution. The term "highly conservative amino acid substitution" or "highly conservative substitution" refers to an amino acid substitution having a value of at least 1 (e.g., at least 2) in BLOSUM62.

[0129] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence, respectively. H domain, and b) any one or more V of SEQ ID NOs: 9 to 20 L V comprising LCDR1, LCDR2, and LCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0130] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence. H domain, or b) any one or more V of SEQ ID NOs: 9 to 20 L V comprising LCDR1, LCDR2, and LCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) for the amino acid sequences LCDR1, LCDR2, and LCDR3, respectively. L domain, or Includes both a) and b).

[0131] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence. H domain, and b) any one or more V of SEQ ID NOs: 9 to 20 L V comprising LCDR1, LCDR2, and LCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0132] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, or b) any one or more V of SEQ ID NOs: 9 to 20 L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L domain, or Includes both a) and b).

[0133] In some embodiments, the polypeptide is a) any one or more V of SEQ ID NOs: 4 to 6 H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, and b) any one or more V of SEQ ID NOs: 9 to 20L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L Includes the domain.

[0134] In some embodiments, the polypeptide is 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 V selected from SEQ ID NO: 6 and SEQ ID NO: 20 (AB-3d) H / V L The antibody comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the pair.

[0135] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to HCDR1, HCDR2, and HCDR3, respectively. H domain, b) V of SEQ ID NO: 14 LV comprising LCDR1, LCDR2, and LCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to LCDR1, LCDR2, and LCDR3, respectively. L domain, or Includes both a) and b).

[0136] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to HCDR1, HCDR2, and HCDR3, respectively. H domain, and b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0137] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively. H domain, or b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, or Includes both a) and b).

[0138] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 HV comprising HCDR1, HCDR2, and HCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively. H domain, and b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0139] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence, respectively. H domain, or b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, or Includes both a) and b).

[0140] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence, respectively. H domain, and b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0141] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, or b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L domain, or Includes both a) and b).

[0142] In some embodiments, the polypeptide is a) V of SEQ ID NO: 5 H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, and b) V of SEQ ID NO: 14 L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L Includes the domain.

[0143] In some embodiments, the polypeptide is a) HCDR1 containing at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NO: 22 to 24 (for example, at least one amino acid sequence shown in SEQ ID NO: 23 or SEQ ID NO: 24); b) HCDR2 containing at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NOs: 26 to 29 (for example, at least one amino acid sequence shown in SEQ ID NOs: 27 to 29); c) HCDR3 containing at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NO: 31 to 33 (for example, at least one amino acid sequence shown in SEQ ID NO: 32 or SEQ ID NO: 33); d) LCDR1 containing at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NO: 35 to 37 (for example, at least one amino acid sequence shown in SEQ ID NO: 36 or SEQ ID NO: 37); e) LCDR2 containing at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NOs: 38 to 40 (for example, at least one amino acid sequence shown in SEQ ID NOs: 39 to 40); f) LCDR3 containing at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NOs: 42 to 45 (for example, at least one amino acid sequence shown in SEQ ID NOs: 43 to 45); or any combination of the foregoing.

[0144] In some embodiments, the polypeptide comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 that comprise only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and 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.

[0145] In some embodiments, the polypeptide comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 that comprise up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) relative to the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and 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.

[0146] In some embodiments, the polypeptide comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 that have 100% sequence identity to the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and 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.

[0147] In some embodiments, the polypeptide is a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 24; b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 28; c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 33; d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 37; e) 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 Including any combination of the above.

[0148] In some embodiments, the polypeptide is a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 24; b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 28; c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 33; d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 37; e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 40, and f) comprises an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0149] In some embodiments, the polypeptide is a) HCDR1 consisting of the amino acid sequence of SEQ ID NO: 24; b) HCDR2 consisting of the amino acid sequence of SEQ ID NO: 28; c) HCDR3 consisting of the amino acid sequence of SEQ ID NO: 33; d) LCDR1 consisting of the amino acid sequence of SEQ ID NO: 37; e) LCDR2 consisting of the amino acid sequence of SEQ ID NO: 40; f) LCDR3 consisting of the amino acid sequence of SEQ ID NO: 44, or Including any combination of the above.

[0150] In some embodiments, the polypeptide is a) HCDR1 consisting of the amino acid sequence of SEQ ID NO: 24; b) HCDR2 consisting of the amino acid sequence of SEQ ID NO: 28; c) HCDR3 consisting of the amino acid sequence of SEQ ID NO: 33; d) LCDR1 consisting of the amino acid sequence of SEQ ID NO: 37; e) LCDR2 consisting of the amino acid sequence of SEQ ID NO: 40, and f) Contains an LCDR3 consisting of the amino acid sequence of SEQ ID NO: 44.

[0151] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 of this specification H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, b) V shown in Table 2 or Table 4 of this specification LV comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L domain, or both a) and b), Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0152] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 herein H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, and b) V shown in Table 2 or Table 4 herein L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L domain, including Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0153] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 of this specification H V comprising HCDR1, HCDR2, and HCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to HCDR1, HCDR2, and HCDR3, respectively. H domain, b) V shown in Table 2 or Table 4 of this specification LV comprising LCDR1, LCDR2, and LCDR3 whose amino acid sequences are substantially similar (e.g., have at least about 90% sequence identity) to LCDR1, LCDR2, and LCDR3, respectively. L domain, or both a) and b), Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0154] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 of this specification H V comprising HCDR1, HCDR2, and HCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively. H domain, b) V shown in Table 2 or Table 4 of this specification L V comprising LCDR1, LCDR2, and LCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, or both a) and b), Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0155] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 herein H V comprising HCDR1, HCDR2, and HCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively. H domain, and b) V shown in Table 2 or Table 4 herein LV comprising LCDR1, LCDR2, and LCDR3 that substantially conserve one or more functional characteristics of the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, including Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0156] In some embodiments, the polypeptide comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 that substantially preserve one or more functional characteristics of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of a polypeptide selected from any of the antibodies shown in Table 5 herein.

[0157] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 of this specification H V comprising HCDR1, HCDR2, and HCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence, respectively. H domain, or b) V shown in Table 2 or Table 4 of this specification L V comprising LCDR1, LCDR2, and LCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, or a) and b) Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0158] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 herein H V comprising HCDR1, HCDR2, and HCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence, respectively. H domain, and b) V shown in Table 2 or Table 4 herein L V comprising LCDR1, LCDR2, and LCDR3 that contain only one or more conservative substitutions (e.g., one or more highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, including Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0159] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 of this specification H V comprising HCDR1, HCDR2, and HCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence. H domain, or b) V shown in Table 2 or Table 4 of this specification L V comprising LCDR1, LCDR2, and LCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) for the amino acid sequences LCDR1, LCDR2, and LCDR3, respectively. L domain, or a) and b) Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein LThe amino acid sequences are the sequence pairs shown in Table 5 herein.

[0160] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 herein H V comprising HCDR1, HCDR2, and HCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) for HCDR1, HCDR2, and HCDR3 of the amino acid sequence. H domain, and b) V shown in Table 2 or Table 4 herein L V comprising LCDR1, LCDR2, and LCDR3, each of which contains up to one, two, or three conservative substitutions (e.g., up to one, two, or three highly conservative substitutions) relative to the amino acid sequences of LCDR1, LCDR2, and LCDR3, respectively. L domain, including Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0161] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 of this specification H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, or b) V shown in Table 2 or Table 4 of this specification L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L domain, or a) and b) Optionally, V as shown in Table 1 or Table 4 herein HThe amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0162] In some embodiments, the polypeptide is a) V shown in Table 1 or Table 4 herein H V comprising HCDR1, HCDR2, and HCDR3 with 100% sequence identity to HCDR1, HCDR2, and HCDR3, respectively, in amino acid sequence. H domain, and b) V shown in Table 2 or Table 4 herein L V comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity to LCDR1, LCDR2, and LCDR3, respectively, in amino acid sequence. L domain, including Optionally, V as shown in Table 1 or Table 4 herein H The amino acid sequences and V sequences shown in Table 2 or Table 4 herein L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0163] In some embodiments, the polypeptide is a V selected from Table 5 herein. H / V L The antibody comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the pair.

[0164] In some embodiments, a) The HCDR1 amino acid sequence is V shown in Table 4 H It corresponds to positions 26 to 33 of the amino acid sequence. b) The HCDR2 amino acid sequence is V shown in Table 4 H Corresponding to positions 51 to 58 of the amino acid sequence, c) The HCDR3 amino acid sequence is V shown in Table 4 H It corresponds to positions 97 to 115 of the amino acid sequence. d) The LCDR1 amino acid sequence is V shown in Table 4 L It corresponds to positions 26 to 34 of the amino acid sequence. e) The LCDR2 amino acid sequence is V shown in Table 4 L It corresponds to positions 52 to 54 of the amino acid sequence. f) The LCDR3 amino acid sequence is V shown in Table 4 L It corresponds to positions 91 to 103 of the amino acid sequence.

[0165] In some embodiments, the polypeptide is a) HCDR1 comprising at least one amino acid substitution relative to at least one amino acid sequence shown in SEQ ID NOs: 22 to 24 and Table 4 (HCDR1 amino acid sequence shown in) (e.g., at least one amino acid sequence shown in SEQ ID NOs: 23 to 24 and Table 4); b) HCDR2 containing at least one amino acid substitution relative to at least one amino acid sequence shown in SEQ ID NOs: 26 to 29 and Table 4 (HCDR2 amino acid sequence shown in) (e.g., at least one amino acid sequence shown in SEQ ID NOs: 27 to 29 and Table 4); c) an HCDR3 comprising at least one amino acid substitution relative to at least one amino acid sequence shown in SEQ ID NOs: 31 to 33 and Table 4 (the HCDR3 amino acid sequence shown in) (e.g., at least one amino acid sequence shown in SEQ ID NOs: 32 to 33 and Table 4); d) LCDR1 comprising at least one amino acid substitution with respect to at least one amino acid sequence shown in SEQ ID NOs: 35 to 37 and Table 4 (LCDR1 amino acid sequence shown in) (e.g., at least one amino acid sequence shown in SEQ ID NOs: 36 to 37 and Table 4); e) LCDR2 comprising at least one amino acid substitution relative to at least one amino acid sequence shown in SEQ ID NOs: 38 to 40 and Table 4 (LCDR2 amino acid sequence shown in) (e.g., at least one amino acid sequence shown in SEQ ID NOs: 39 to 40 and Table 4); f) LCDR3 containing at least one amino acid substitution relative to at least one amino acid sequence shown in SEQ ID NOs: 42 to 45 and Table 4 (LCDR3 amino acid sequence shown in) (e.g., at least one amino acid sequence shown in SEQ ID NOs: 43 to 45 and Table 4); or any combination of the foregoing, Optionally, V including HCDR1, HCDR2, and HCDR3 H Amino acid sequence and V including LCDR1, LCDR2, and LCDR3 L The amino acid sequences are the sequence pairs shown in Table 5 herein.

[0166] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLPGYA (SEQ ID NO: 604), and iii. HCDR3 comprising ARGFNRDYYGWGDDDAFDF (SEQ ID NO: 605), H domain, and b) i. LCDR1 comprising SSNIGAGYR (SEQ ID NO: 37), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0167] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTEDTYT (SEQ ID NO: 606), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 comprising ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0168] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYG (SEQ ID NO: 607), iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising SSNIGAGYR (SEQ ID NO: 37), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0169] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDYSDVYT (SEQ ID NO: 609), ii. HCDR2 comprising IILLLGYA (SEQ ID NO: 610), and iii. HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 comprising SSNIGAGYY (SEQ ID NO: 611), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0170] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYT (SEQ ID NO: 612), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising LSNIGAGYR (SEQ ID NO: 613), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0171] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYS (SEQ ID NO: 614), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising ESNIGAGYD (SEQ ID NO: 615), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0172] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising LSNIGAGYR (SEQ ID NO: 613), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0173] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSDYT (SEQ ID NO: 609), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0174] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0175] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 comprising SSNIGAGYD (SEQ ID NO: 36), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSYFDPHWV (SEQ ID NO: 610), L Includes the domain.

[0176] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYT (SEQ ID NO: 612), and iii. HCDR3 comprising ARGFNEDYYGWGDDDAFDF (SEQ ID NO: 614), H domain, and b) i. LCDR1 comprising VSNIGAGYD (SEQ ID NO: 615), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0177] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising PSNIGAGYR (SEQ ID NO: 616), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0178] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDIYT (SEQ ID NO: 617), ii. HCDR2 comprising IILLSGYT (SEQ ID NO: 612), and iii. HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 comprising VSNIGAGYD (SEQ ID NO: 615), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0179] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYT (SEQ ID NO: 612), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising ESNIGAGYD (SEQ ID NO: 615), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0180] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising VSNIGAGYR (SEQ ID NO: 618), ii. LCDR2 containing GSS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0181] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYV (SEQ ID NO: 619), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising SSNIGAGYD (SEQ ID NO: 36), ii. LCDR2 containing GRS; iii. LCDR3 comprising QSYDSSSFDPHWV (SEQ ID NO: 620), L Includes the domain.

[0182] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising SSNIGAGYR (SEQ ID NO: 37), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSYFDPHWV (SEQ ID NO: 610), L Includes the domain.

[0183] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 comprising ARGFNYDYYGWGDDDAFDF (SEQ ID NO: 621), H domain, and b) i. LCDR1 comprising VSNIGAGYR (SEQ ID NO: 618), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0184] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYS (SEQ ID NO: 614), and iii. HCDR3 comprising ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608), H domain, and b) i. LCDR1 comprising SSNIGAGYD (SEQ ID NO: 36), ii. LCDR2 containing GRS; iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0185] In some embodiments, the polypeptide is a) i. HCDR1 comprising GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 comprising IILLSGYG (SEQ ID NO: 607), and iii. HCDR3 comprising ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 comprising ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 containing GRS, and iii. LCDR3 comprising QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0186] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLPGYA (SEQ ID NO: 604), and iii. A V comprising an HCDR3 consisting of ARGFNRDYYGWGDDDAFDF (SEQ ID NO: 605). H domain, and b) i. LCDR1 consisting of SSNIGAGYR (SEQ ID NO: 37), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0187] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTEDTYT (SEQ ID NO: 606), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 consisting of ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0188] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYG (SEQ ID NO: 607), iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of SSNIGAGYR (SEQ ID NO: 37), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0189] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDYSDVYT (SEQ ID NO: 609), ii. HCDR2 consisting of IILLLGYA (SEQ ID NO: 610), and iii. HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 consisting of SSNIGAGYY (SEQ ID NO: 611), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0190] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYT (SEQ ID NO: 612), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608).H domain, and b) i. LCDR1 consisting of LSNIGAGYR (SEQ ID NO: 613), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0191] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYS (SEQ ID NO: 614), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of ESNIGAGYD (SEQ ID NO: 615), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0192] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of LSNIGAGYR (SEQ ID NO: 613), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0193] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSDYT (SEQ ID NO: 609), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0194] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0195] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 consisting of SSNIGAGYD (SEQ ID NO: 36), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSYFDPHWV (SEQ ID NO: 610), L Includes the domain.

[0196] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYT (SEQ ID NO: 612), and iii. A V comprising an HCDR3 consisting of ARGFNEDYYGWGDDDAFDF (SEQ ID NO: 614). H domain, and b) i. LCDR1 consisting of VSNIGAGYD (SEQ ID NO: 615), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0197] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of PSNIGAGYR (SEQ ID NO: 616), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0198] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDIYT (SEQ ID NO: 617), ii. HCDR2 consisting of IILLSGYT (SEQ ID NO: 612), and iii. HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 consisting of VSNIGAGYD (SEQ ID NO: 615), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0199] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYT (SEQ ID NO: 612), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of ESNIGAGYD (SEQ ID NO: 615), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0200] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of VSNIGAGYR (SEQ ID NO: 618), ii. LCDR2 consisting of GSS; and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0201] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYV (SEQ ID NO: 619), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of SSNIGAGYD (SEQ ID NO: 36), ii. LCDR2 consisting of GRS; iii. LCDR3 consisting of QSYDSSSFDPHWV (SEQ ID NO: 620), L Includes the domain.

[0202] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of SSNIGAGYR (SEQ ID NO: 37), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSYFDPHWV (SEQ ID NO: 610), L Includes the domain.

[0203] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. an HCDR2 consisting of IILLSGYA (SEQ ID NO: 28), and iii. A V comprising an HCDR3 consisting of ARGFNYDYYGWGDDDAFDF (SEQ ID NO: 621). H domain, and b) i. LCDR1 consisting of VSNIGAGYR (SEQ ID NO: 618), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0204] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYS (SEQ ID NO: 614), and iii. A V comprising an HCDR3 consisting of ARGFNPDYYGWGDDDAFDF (SEQ ID NO: 608). H domain, and b) i. LCDR1 consisting of SSNIGAGYD (SEQ ID NO: 36), ii. LCDR2 consisting of GRS; iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0205] In some embodiments, the polypeptide is a) i. HCDR1 consisting of GDTSDTYT (SEQ ID NO: 24), ii. HCDR2 consisting of IILLSGYG (SEQ ID NO: 607), and iii. HCDR3 consisting of ARGFNGDYYGWGDDDAFDF (SEQ ID NO: 33), H domain, and b) i. LCDR1 consisting of ESNIGAGYR (SEQ ID NO: 606), ii. LCDR2 consisting of GRS, and iii. LCDR3 consisting of QSYDSSLFDPHWV (SEQ ID NO: 44), L Includes the domain.

[0206] variable domain In some embodiments, the polypeptide binds to the spike protein of SARS-CoV-2 (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, and 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.

[0207] In some embodiments, the polypeptide binds to one or more epitope residues of the spike protein of wild-type SARS-CoV-2 (e.g., one or more epitope residues within the S1 subunit of SARS-CoV-2).

[0208] In some embodiments, the polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises a V H Domain, V L In some embodiments, the polypeptide comprises a V domain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO:3. H Domain, V having less than 100% sequence identity to the amino acid sequence of SEQ ID NO:8 L domain, or both.

[0209] In some embodiments, the polypeptide is H (e.g., rodent (e.g., mouse) V H , primate (e.g., human) V H Mammals such as V H In some embodiments, the polypeptide is humanized (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% humanized), or comprises a V domain that includes human framework regions, or both. H Includes the domain.

[0210] In some embodiments, the polypeptide has a V that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:3. H Includes the domain.

[0211] In some embodiments, the polypeptide has a V having at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:3. H In some embodiments, the polypeptide comprises a V domain having 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. H In some embodiments, the polypeptide comprises a V domain having at least about 85% sequence identity to the amino acid sequence of SEQ ID NO:3. H In some embodiments, the polypeptide comprises a V domain having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:3. H Includes the domain.

[0212] In some embodiments, the polypeptide comprises a V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative substitution) relative to the amino acid sequence of SEQ ID NO:3. HFor 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 polypeptide comprises a V domain containing about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:3. H In some embodiments, at least one amino acid substitution replaces only residues in HCDR1, HCDR2, and / or HCDR3 of SEQ ID NO: 3. In some embodiments, at least one amino acid substitution replaces only residues in non-CDRs of SEQ ID NO: 3 (e.g., within framework regions).

[0213] In some embodiments, the polypeptide has a V that has 100% sequence identity to the amino acid sequence of SEQ ID NO:3. H In some embodiments, the polypeptide comprises a V domain comprising the amino acid sequence of SEQ ID NO:3. H Includes the domain.

[0214] In some embodiments, the polypeptide 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). H domain. Human V H The sequences identified as SEQ ID NOS: 4-6, 89, and 90 corresponding to the domains are shown in Table 1. In some embodiments, the polypeptide 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). HIn some embodiments, the polypeptide comprises a V domain having at least about 85% sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 4-6, 89, and 90 (e.g., SEQ ID NOs: 4-6). H In some embodiments, the polypeptide comprises a V domain having at least about 90% sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 4-6, 89, and 90 (e.g., SEQ ID NOs: 4-6). H Includes the domain.

[0215] In some embodiments, the polypeptide comprises a V that contains 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). H 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 polypeptide comprises a V domain containing 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). H Includes the domain.

[0216] In some embodiments, the amino acid substitutions are conservative substitutions.

[0217] In some embodiments, the amino acid substitutions are highly conservative substitutions.

[0218] In some embodiments, the polypeptide has a V 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). HIn some embodiments, the polypeptide comprises a V domain comprising the amino acid sequence of any one of SEQ ID NOs: 4-6, 89, and 90 (e.g., SEQ ID NOs: 4-6). H Includes the domain.

[0219] In some embodiments, the polypeptide is L (e.g., rodent (e.g., mouse) V L , primate (e.g., human) V L Mammals such as V L In some embodiments, the polypeptide is humanized (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% humanized), or comprises a V domain that includes human framework regions, or both. L Includes the domain.

[0220] In some embodiments, the polypeptide has a V that has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:8. L Includes the domain.

[0221] In some embodiments, the polypeptide has a V having at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:8. L In some embodiments, the polypeptide comprises a V domain having 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. L In some embodiments, the polypeptide comprises a V domain having at least about 85% sequence identity to the amino acid sequence of SEQ ID NO:8. L In some embodiments, the polypeptide comprises a V domain having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:8. L Includes the domain.

[0222] In some embodiments, the polypeptide comprises a V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative substitution) relative to the amino acid sequence of SEQ ID NO: 8. L 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 polypeptide comprises a V domain containing about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:8. L domain. In some embodiments, at least one amino acid substitution replaces only residues in LCDR1, LCDR2, and / or LCDR3 of SEQ ID NO: 8. In some embodiments, at least one amino acid substitution replaces only residues in non-CDRs of SEQ ID NO: 8 (e.g., within framework regions).

[0223] In some embodiments, the amino acid substitutions are conservative substitutions.

[0224] In some embodiments, the amino acid substitutions are highly conservative substitutions.

[0225] In some embodiments, the polypeptide has a V that has 100% sequence identity to the amino acid sequence of SEQ ID NO:8. L In some embodiments, the polypeptide comprises a V domain comprising the amino acid sequence of SEQ ID NO:8. L Includes the domain.

[0226] In some embodiments, the polypeptide 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). L domain. Human V LThe sequences identified as SEQ ID NOS: 9-20, 91, and 92 (e.g., SEQ ID NOS: 9-20) corresponding to the domains are shown in Table 2. In some embodiments, the polypeptide 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 any one or more of the amino acid sequences of 9-20, 91, and 92 (e.g., SEQ ID NOS: 9-20). L In some embodiments, the polypeptide comprises a V having at least about 85% sequence identity to any one or more amino acid sequences of SEQ ID NOs: 20-30. L In some embodiments, the polypeptide comprises a V domain having at least about 90% sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 9-20, 91, and 92 (e.g., SEQ ID NOs: 9-20). L Includes the domain.

[0227] In some embodiments, the polypeptide comprises a V that contains at least one 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). L 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 polypeptide comprises a V domain containing 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). L Includes the domain.

[0228] In some embodiments, the amino acid substitutions are conservative substitutions.

[0229] In some embodiments, the amino acid substitutions are highly conservative substitutions.

[0230] In some embodiments, the polypeptide has a V 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). L In some embodiments, the polypeptide comprises a V domain comprising the amino acid sequence of any one of SEQ ID NOS: 9-20, 91, and 92 (e.g., SEQ ID NOS: 9-20). L Includes the domain.

[0231] In some embodiments, the polypeptide is H (e.g., rodent (e.g., mouse) V H , primate (e.g., human) V H Mammals such as V H ) domain, and V L (e.g., rodent (e.g., mouse) V L , primate (e.g., human) V L Mammals such as V L In some embodiments, the polypeptide is humanized (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% humanized), or comprises a V domain that includes human framework regions, or both. H Domains and V L Includes the domain.

[0232] In some embodiments, the polypeptide is a) V having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 3 H domain, b) V having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 8 L domain, or Includes both a) and b).

[0233] In some embodiments, the polypeptide is a) V having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 3 H domain, and b) V having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 8 L Includes the domain.

[0234] In some embodiments, the polypeptide is a) V having 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 H domain, b) V having 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 L domain, or a) and b) The polypeptide is V of SEQ ID NO:3 H Amino acid sequence and V of SEQ ID NO:8 L It does not include all six CDRs of an antibody containing amino acid sequence.

[0235] In some embodiments, the polypeptide is a) V having 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 H domain, and b) V having 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 L domain, including The polypeptide is V of SEQ ID NO:3 H Amino acid sequence and V of SEQ ID NO:8 LIt does not include all six CDRs of an antibody containing amino acid sequence.

[0236] In some embodiments, the polypeptide is a) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative substitution) relative to the amino acid sequence of SEQ ID NO: 3 H domain, b) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative substitution) relative to the amino acid sequence of SEQ ID NO: 8 L domain, or Includes both a) and b).

[0237] In some embodiments, the polypeptide is a) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO: 3 H domain, and b) V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO: 8 L Includes the domain.

[0238] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in HCDR1, HCDR2, and / or HCDR3 of SEQ ID NO: 3; H domain, b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue of LCDR1, LCDR2, and / or LCDR3 of SEQ ID NO: 8. L domain, or Includes both a) and b).

[0239] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in HCDR1, HCDR2, and / or HCDR3 of SEQ ID NO: 3; H domain, and b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue of LCDR1, LCDR2, and / or LCDR3 of SEQ ID NO: 8. L Includes the domain.

[0240] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 3; H domain, b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 8. L domain, or Includes both a) and b).

[0241] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 3; H domain, and b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 8. L Includes the domain.

[0242] In some embodiments, the polypeptide is a) V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 4 to 6, 89, and 90 (e.g., SEQ ID NOs: 4 to 6). H domain, b) V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 9 to 20, 91, and 92 (e.g., SEQ ID NOs: 9 to 20). L domain, or Includes both a) and b).

[0243] In some embodiments, the polypeptide is a) V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 4 to 6, 89, and 90 (e.g., SEQ ID NOs: 4 to 6). H domain, and b) V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to any one or more of the amino acid sequences of SEQ ID NOs: 9 to 20, 91, and 92 (e.g., SEQ ID NOs: 9 to 20). L Includes the domain.

[0244] In some embodiments, the polypeptide is a) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) with respect to any one or more amino acid sequences of SEQ ID NOs: 4 to 6, 89, and 90 (e.g., SEQ ID NOs: 4 to 6). H domain, b) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) with respect to any one or more amino acid sequences of SEQ ID NOs: 9 to 20, 91, and 92 (e.g., SEQ ID NOs: 9 to 20).L domain, or Includes both a) and b).

[0245] In some embodiments, the polypeptide is a) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) with respect to any one or more amino acid sequences of SEQ ID NOs: 4 to 6, 89, and 90 (e.g., SEQ ID NOs: 4 to 6). H domain, and b) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) with respect to any one or more amino acid sequences of SEQ ID NOs: 9 to 20, 91, and 92 (e.g., SEQ ID NOs: 9 to 20). L Includes the domain.

[0246] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of any one or more HCDR1, HCDR2, and / or HCDR3 residues of SEQ ID NOs: 4 to 6, 89, and 90 (e.g., SEQ ID NOs: 4 to 6). H domain, b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of any one or more LCDR1, LCDR2, and / or LCDR3 residues of SEQ ID NOs: 9-20, 91, and 92 (e.g., SEQ ID NOs: 9-20). L domain, or Includes both a) and b).

[0247] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of any one or more HCDR1, HCDR2, and / or HCDR3 residues of SEQ ID NOs: 4 to 6, 89, and 90 (e.g., SEQ ID NOs: 4 to 6).H domain, and b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of any one or more LCDR1, LCDR2, and / or LCDR3 residues of SEQ ID NOs: 9-20, 91, and 92 (e.g., SEQ ID NOs: 9-20). L Includes the domain.

[0248] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a 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). H domain, b) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a 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). L domain, or Includes both a) and b).

[0249] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a 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). H domain, and b) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a 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). L Includes the domain.

[0250] In some embodiments, the polypeptide is a) V comprising any one of the amino acid sequences of SEQ ID NOs: 4 to 6, 89, and 90 (for example, SEQ ID NOs: 4 to 6) H domain, and b) V comprising any one of the amino acid sequences of SEQ ID NOs: 9 to 20, 91, and 92 (for example, SEQ ID NOs: 9 to 20) L Includes the domain.

[0251] In some embodiments, the polypeptide is a) V comprising any one of the amino acid sequences of SEQ ID NOs: 4 to 6, 89, and 90 (for example, SEQ ID NOs: 4 to 6) H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 8 L Includes the domain.

[0252] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 3 H domain, and b) V comprising any one of the amino acid sequences of SEQ ID NOs: 9 to 20, 91, and 92 (for example, SEQ ID NOs: 9 to 20) L Includes the domain.

[0253] In some embodiments, the polypeptide is a) V having 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 H domain, b) V having 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 L domain, or Includes both a) and b).

[0254] In some embodiments, the polypeptide is a) V having 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 H domain, and b) V having 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 L Includes the domain.

[0255] In some embodiments, the polypeptide is a) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO: 5 H domain, b) V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO: 14. L domain, or Includes both a) and b).

[0256] In some embodiments, the polypeptide is a) V containing at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO: 5 H domain, and b) V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO: 14. L Includes the domain.

[0257] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in HCDR1, HCDR2, and / or HCDR3 of SEQ ID NO: 5; H domain, b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue of LCDR1, LCDR2, and / or LCDR3 of SEQ ID NO: 14. L domain, or Includes both a) and b).

[0258] In some embodiments, the amino acid substitutions are conservative substitutions.

[0259] In some embodiments, the amino acid substitutions are highly conservative substitutions.

[0260] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in HCDR1, HCDR2, and / or HCDR3 of SEQ ID NO: 5; H domain, and b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of residues in LCDR1, LCDR2, and / or LCDR3 of SEQ ID NO: 14. L Includes the domain.

[0261] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 5; H domain, b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 14. L domain, or Includes both a) and b).

[0262] In some embodiments, the polypeptide is a) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 5; H domain, and b) V comprising at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of SEQ ID NO: 14. L Includes the domain.

[0263] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 5 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 14 L Contains domain (AB-2b).

[0264] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 9 L Contains domain (AB-1a).

[0265] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 10 L Contains domain (AB-1b).

[0266] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 11 L Contains domain (AB-1c).

[0267] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 12 L Contains domain (AB-1d).

[0268] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 5 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 13 L Contains domain (AB-2a).

[0269] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 5 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 15 L Contains domain (AB-2c).

[0270] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 5 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 16 L Contains domain (AB-2d).

[0271] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 6 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 17 L Contains domain (AB-3a).

[0272] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 6 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 18 L Contains domain (AB-3b).

[0273] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 6 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 19 L Contains domain (AB-3c).

[0274] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 6 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 20 L Contains domain (AB-3d).

[0275] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 89 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 91 L Contains domain (AB-4a).

[0276] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 90 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 92 L Contains domain (AB-7a).

[0277] In some embodiments, the polypeptide comprises a V sequence set forth in any of SEQ ID NOs: 4-6, 89, and 90 (e.g., SEQ ID NOs: 4-6). H V comprising HCDR1, HCDR2, and HCDR3 having amino acid sequences substantially similar to HCDR1, HCDR2, and HCDR3, respectively. H Includes the domain.

[0278] In some embodiments, the polypeptide comprises a V sequence set forth in any of SEQ ID NOs: 9-20, 91, and 92 (e.g., SEQ ID NOs: 9-20). LV comprising LCDR1, LCDR2, and LCDR3 that are substantially similar in amino acid sequence to LCDR1, LCDR2, and LCDR3, respectively. L Includes the domain.

[0279] In some embodiments, the polypeptide comprises a V sequence set forth in any of SEQ ID NOs: 4-6, 89, and 90 (e.g., SEQ ID NOs: 4-6). H V containing HCDR1, HCDR2, and HCDR3 whose amino acid sequences are identical to those of HCDR1, HCDR2, and HCDR3, respectively H Includes the domain.

[0280] In some embodiments, the polypeptide comprises a V sequence set forth in any of SEQ ID NOs: 9-20, 91, and 92 (e.g., SEQ ID NOs: 9-20). L V comprising LCDR1, LCDR2, and LCDR3 whose amino acid sequences are identical to LCDR1, LCDR2, and LCDR3, respectively L Includes the domain.

[0281] In some embodiments, the polypeptide 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. H In some embodiments, the V H The domain may 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. HThe domain 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.

[0282] In some embodiments, the polypeptide has a V having at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:8. L In some embodiments, the V L The V domain may 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 V domain may 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. L The domain has at least about 85% or at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 8. L The sequence corresponding to the domain, identified as SEQ ID NO: 8, is shown in Table 2.

[0283] In some embodiments, the polypeptide 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. L In some embodiments, the V LA domain may 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, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:91, SEQ ID NO:92, or any combination of the foregoing. L The domain 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.

[0284] In some embodiments, the polypeptide comprises a V that includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) relative to the amino acid sequence of SEQ ID NO:3. H 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. H The domain comprises about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 3. In some embodiments, at least one amino acid substitution replaces only a residue in HCDR1, HCDR2, and / or HCDR3 of SEQ ID NO: 3. In some embodiments, at least one amino acid substitution replaces only a residue in a non-CDR of SEQ ID NO: 3 (e.g., within a framework region).

[0285] In some embodiments, the polypeptide comprises a V that contains at least one 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. H 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. H The domain 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.

[0286] In some embodiments, at least one amino acid substitution replaces only HCDR1, HCDR2, and / or HCDR3 residues 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 certain embodiments, at least one amino acid substitution replaces only non-CDR residues (e.g., within framework regions) 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.

[0287] In some embodiments, the polypeptide comprises a V that contains at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:8. L 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. LThe domain comprises about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 8. In some embodiments, at least one amino acid substitution replaces only residues in LCDR1, LCDR2, and / or LCDR3 of SEQ ID NO: 8. In certain embodiments, at least one amino acid substitution replaces only residues in non-CDRs of SEQ ID NO: 8 (e.g., within framework regions).

[0288] In some embodiments, the polypeptide comprises a V that contains at least one 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. L 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. L The domain contains about 1 to 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.

[0289] In some embodiments, at least one amino acid substitution replaces only LCDR1, LCDR2, and / or LCDR3 residues 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 certain embodiments, at least one amino acid substitution replaces only non-CDR residues (e.g., within the framework regions) 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.

[0290] In some embodiments, the polypeptide comprises a V H In some embodiments, the polypeptide comprises a V domain comprising 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. H Includes the domain.

[0291] In some embodiments, the polypeptide comprises a V L In some embodiments, the polypeptide comprises a V domain comprising 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. L Includes the domain.

[0292] In some embodiments, the polypeptide comprises a V L In some embodiments, the polypeptide comprises a V domain comprising 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. LIncludes the domain.

[0293] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 8 L Includes the domain.

[0294] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 3 H domain, and b) V 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 L Includes the domain.

[0295] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 8 L Includes the domain.

[0296] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 H domain, and b) V 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 L Includes the domain.

[0297] In some embodiments, V H and V L The domains are linked together via a linker (e.g., a synthetic linker) to form a V H / VL Domains are intramolecular or V H and V L When the domains are expressed by separate chains, they can pair intermolecularly to form a monovalent antigen-binding site, creating various types of single-chain antibody designs.

[0298] In some embodiments, the polypeptide comprises one or more V sequences shown in Tables 1 and 4 herein. H V having at least about 70% sequence identity to the amino acid sequence H In some embodiments, the polypeptide comprises one or more V domains shown in Tables 1 and 4 herein. H V having 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 H In some embodiments, the polypeptide comprises one or more V domains shown in Tables 1 and 4 herein. H V having at least about 85% sequence identity to the amino acid sequence H In some embodiments, the polypeptide comprises one or more V domains shown in Tables 1 and 4 herein. H V having at least about 90% sequence identity to the amino acid sequence H Includes the domain.

[0299] In some embodiments, the polypeptide comprises one or more V sequences shown in Tables 1 and 4 herein. H V containing at least one amino acid substitution relative to the amino acid sequence HFor 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 polypeptide comprises one or more V domains set forth in Tables 1 and 4 herein. H V containing approximately 1 to 10 amino acid substitutions relative to the amino acid sequence H Includes the domain.

[0300] In some embodiments, the amino acid substitutions are conservative substitutions.

[0301] In some embodiments, the amino acid substitutions are highly conservative substitutions.

[0302] In some embodiments, the polypeptide is a V polypeptide as shown in Tables 1 and 4 herein. H V with 100% sequence identity to any one of the amino acid sequences H In some embodiments, the polypeptide comprises a V domain as shown in Tables 1 and 4 herein. H V containing any one of the amino acid sequences H Includes the domain.

[0303] In some embodiments, the polypeptide comprises one or more V sequences shown in Tables 2 and 4 herein. L V having at least about 70% sequence identity to the amino acid sequence L In some embodiments, the polypeptide comprises one or more V domains shown in Tables 2 and 4 herein. LV having 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 L In some embodiments, the polypeptide comprises one or more of the V L V having at least about 85% sequence identity to the amino acid sequence L In some embodiments, the polypeptide comprises one or more V domains shown in Tables 2 and 4 herein. L V having at least about 90% sequence identity to the amino acid sequence L Includes the domain.

[0304] In some embodiments, the polypeptide comprises one or more V sequences shown in Tables 2 and 4 herein. L V containing at least one amino acid substitution relative to the amino acid sequence L 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 polypeptide comprises one or more V domains set forth in Tables 2 and 4 herein. L V containing approximately 1 to 10 amino acid substitutions relative to the amino acid sequence L Includes the domain.

[0305] In some embodiments, the amino acid substitutions are conservative substitutions.

[0306] In some embodiments, the amino acid substitutions are highly conservative substitutions.

[0307] In some embodiments, the polypeptide is a V polypeptide as shown in Tables 2 and 4 herein. L V with 100% sequence identity to any one of the amino acid sequences L In some embodiments, the polypeptide comprises a V domain as shown in Tables 2 and 4 herein. L V containing any one of the amino acid sequences L Includes the domain.

[0308] In some embodiments, the polypeptide is a) one or more V shown in Tables 1 and 4 herein H V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to the amino acid sequence H domain, b) one or more V shown in Tables 2 and 4 herein L V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to the amino acid sequence L domain, or Includes both a) and b).

[0309] In some embodiments, the polypeptide is a) one or more V shown in Tables 1 and 4 herein H V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to the amino acid sequence H domain, and b) one or more V shown in Tables 2 and 4 herein L V having at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99%) sequence identity to the amino acid sequence L Includes the domain.

[0310] In some embodiments, the polypeptide is a) one or more V shown in Tables 1 and 4 herein H For an amino acid sequence, a V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) H domain, b) one or more V shown in Tables 2 and 4 herein L For an amino acid sequence, a V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) L domain, or Includes both a) and b).

[0311] In some embodiments, the polypeptide is a) one or more V shown in Tables 1 and 4 herein H For an amino acid sequence, a V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) H domain, and b) one or more V shown in Tables 2 and 4 herein L For an amino acid sequence, a V that contains at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) L Includes the domain.

[0312] In some embodiments, the polypeptide is a) any one or more of the V shown in Tables 1 and 4 herein H V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in HCDR1, HCDR2, and / or HCDR3 of the amino acid sequence. H domain, b) any one or more of the V shown in Tables 2 and 4 herein L V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in LCDR1, LCDR2, and / or LCDR3 of the amino acid sequence. L domain, or Includes both a) and b).

[0313] In some embodiments, the polypeptide is a) any one or more of the V shown in Tables 1 and 4 herein H V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in HCDR1, HCDR2, and / or HCDR3 of the amino acid sequence. H domain, and b) any one or more of the V shown in Tables 2 and 4 herein L V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a residue in LCDR1, LCDR2, and / or LCDR3 of the amino acid sequence. L Includes the domain.

[0314] In some embodiments, the polypeptide is a) any one or more of the V shown in Tables 1 and 4 herein H V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of the amino acid sequence. H domain, b) any one or more of the V shown in Tables 2 and 4 herein L V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of the amino acid sequence. L domain, or Includes both a) and b).

[0315] In some embodiments, the polypeptide is a) any one or more of the V shown in Tables 1 and 4 herein HV includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of the amino acid sequence. H domain, and b) any one or more of the V shown in Tables 2 and 4 herein L V includes at least one amino acid substitution (e.g., at least one conservative substitution, such as a highly conservative amino acid substitution) of a non-CDR residue (e.g., within a framework region) of the amino acid sequence. L Includes the domain.

[0316] In some embodiments, the polypeptide is a) V shown in Tables 1 and 4 herein H V containing any one of the amino acid sequences H domain, and b) V shown in Tables 2 and 4 herein L V containing any one of the amino acid sequences L Includes the domain.

[0317] In some embodiments, the polypeptide is a) V shown in Tables 1 and 4 herein H V containing any one of the amino acid sequences H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 8 L Includes the domain.

[0318] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 3 H domain, and b) V shown in Tables 2 and 4 herein L V containing any one of the amino acid sequences L Includes the domain.

[0319] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 255 Hdomain, and b) V comprising the amino acid sequence of SEQ ID NO: 14 L Includes the domain.

[0320] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 292 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 477 L Includes the domain.

[0321] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 206 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 14 L Includes the domain.

[0322] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 202 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 434 L Includes the domain.

[0323] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 140 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 472 L Includes the domain.

[0324] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 240 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 449 L Includes the domain.

[0325] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 213 Hdomain, and b) V comprising the amino acid sequence of SEQ ID NO: 472 L Includes the domain.

[0326] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 258 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 477 L Includes the domain.

[0327] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 213 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 477 L Includes the domain.

[0328] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 5 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 512 L Includes the domain.

[0329] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 158 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 469 L Includes the domain.

[0330] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 213 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 452 L Includes the domain.

[0331] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 232 Hdomain, and b) V comprising the amino acid sequence of SEQ ID NO: 469 L Includes the domain.

[0332] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 140 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 449 L Includes the domain.

[0333] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 213 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 484 L Includes the domain.

[0334] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 204 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 455 L Includes the domain.

[0335] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 213 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 461 L Includes the domain.

[0336] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 137 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 426 L Includes the domain.

[0337] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 240 Hdomain, and b) V comprising the amino acid sequence of SEQ ID NO: 424 L Includes the domain.

[0338] In some embodiments, the polypeptide is a) V comprising the amino acid sequence of SEQ ID NO: 130 H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 477 L Includes the domain.

[0339] Paratope The amino acid residues of the paratope contribute to the interaction between the antibody and its target protein epitope. The interaction can be hydrogen bonding, salt bridges, van der Waals interactions, electrostatic interactions, hydrophobic interactions, pi-interaction effects, ionic bonds, and / or any combination thereof. The interaction can be direct or indirect, for example, via a cooperating intermediate molecule such as an ion or water. The residues of the paratope, in some embodiments, include only residues that are part of a defined CDR. In some embodiments, the residues of the paratope further include one or more residues that are not part of a defined CDR (e.g., residues in a defined framework region).

[0340] In some embodiments, the paratope is less than about 5.0 angstroms from the epitope on the target antigen when the polypeptide binds 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 from the epitope, or less than about 0. 9 to 5.0, 0.9 to 4.8, 1.0 to 5, 1.0 to 4.5, 1.0 to 4.0, 1.0 to 3.5, 1.1 to 3.5, 1.1 to 3.0, 1.2 to 3.0, 1.2 to 2.5, 1.3 to 2.5, 1.3 to 2.4, 1.4 to 2.4, 1.4 to 2.3, 1.5 to 2.3, 1.5 to 2.2, 1.6 to 2.2, 1.6 to 2.1, 1.7 to 2.1, 1.7 to 2.0, or 1.8 to 2.0 angstroms. In some embodiments, fewer than all of the amino acid residues within the 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) that make up the paratope are oriented less than about 5.0 angstroms from the epitope on the target antigen when the polypeptide binds to the target antigen.

[0341] In some embodiments, the polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprising the paratope is V H Domains and V L In some embodiments, the paratope residues comprise the V domain of the polypeptide. H and V L Included within.

[0342] In some embodiments, the polypeptide comprises the V H / V L The antibody comprises a paratope different from the paratope of the antibody comprising the combination of

[0343] In some embodiments, the polypeptide has a V having at least about 70% sequence identity to the amino acid sequence of SEQ ID NO:3. H Contains domains, e.g., V Hmay 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, V H has at least about 85% or at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 3. H The sequence corresponding to the domain, identified as SEQ ID NO: 3, is shown in Table 1.

[0344] In some embodiments, the polypeptide comprises the V H / V L In some embodiments, the polypeptide comprises a paratope substantially similar (e.g., having at least about 90% sequence identity) to the paratope of an antibody comprising the combination of SEQ ID NO:3 / SEQ ID NO:8. H / V L and a paratope that is substantially similar (e.g., has at least about 90% sequence identity) to the paratope of an antibody comprising a combination of:

[0345] In some embodiments, the polypeptide comprises the V H / V L The antibody comprises a paratope having 100% sequence identity to the paratope of the antibody comprising the combination of:

[0346] In some embodiments, the polypeptide comprises one to three (e.g., one, two, or three) residue substitutions (e.g., conservative substitutions, such as highly conservative substitutions) to replace V of SEQ ID NO:3 / SEQ ID NO:8. H / V L The antibody comprises a paratope different from the paratope of the antibody comprising the combination of

[0347] In some embodiments, the polypeptide is 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) of one to three (e.g., one, two, or three) residues. H / V L See Table 1 for SEQ ID NOs: 4 to 6, and Table 2 for SEQ ID NOs: 9 to 20.

[0348] In some embodiments, the polypeptide is 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 V selected from any combination thereof H / V LIt comprises a paratope that is substantially similar (eg, has at least about 90% sequence identity) to the paratope of the antibody that comprises the pair.

[0349] In some embodiments, the polypeptide is 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 V selected from any combination thereof H / V L It comprises a paratope that is substantially similar (eg, has at least about 90% sequence identity) to the paratope of the antibody that comprises the pair and substantially preserves one or more functional properties thereof.

[0350] In some embodiments, the polypeptide is 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 V selected from any combination thereof H / V L The paratope comprises a paratope that contains only one or more conservative substitutions (eg, one or more highly conservative substitutions) relative to the paratope of the antibody comprising the pair.

[0351] In some embodiments, the present disclosure provides a polypeptide that specifically binds to SARS-CoV-2-spike, the polypeptide comprising: 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 V selected from SEQ ID NO: 6 and SEQ ID NO: 20 (AB-3d) H / V L It contains a paratope that has 100% sequence identity to the paratope of the antibody that contains the pair.

[0352] In some embodiments, the polypeptide comprises a paratope substantially similar to the 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, the polypeptide comprises a paratope that comprises only conservative substitutions (e.g., highly conservative substitutions) relative to the 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, the 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 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, the 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.

[0353] In some embodiments, the polypeptide is a V 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). H / V L The paratopes include those substantially similar to the paratopes of the combinations of

[0354] In some embodiments, the polypeptide is a V 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). H / V L This includes paratopes that are identical to the paratopes of the combinations.

[0355] Consensus sequence In some embodiments, the polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises a V H Including, X1 is not G, X2 is not I, X3 is not F, The X4 is not an N. The X5 is not an M. The X6 is not an S. The X7 is not an M. X8 is not N, X9 is not G, X 10 is not N, X 11 is not I, or Any combination of the above.

[0356] Consensus V for SEQ ID NOs: 3 to 6 herein H The sequence, identified as SEQ ID NO:2, is shown in Table 1.

[0357] In some embodiments, X1 is G or D, X2 is I, T, or Y; X3 is F, S, or D, X4 is N or D; X5 is M or L, X6 is S or F, X7 is M, Y, or A, X8 is N or H; X9 is G or P, X 10 is N or D, X 11 is I or F, or Any combination of the above.

[0358] In some embodiments, X1 is D, X2 is T or Y; X3 is S or D, X4 is D, X5 is L, X6 is F, X7 is Y or A; X8 is H, X9 is P, X 10 is D, X 11 is F, or Any combination of the above.

[0359] In some embodiments, X1 is not G. In some embodiments, X1 is G or D. In some embodiments, X1 is G. In some embodiments, X1 is D.

[0360] In some embodiments, X2 is not I. In some embodiments, X2 is I, T, or Y. In some embodiments, X2 is T or Y. In some embodiments, X2 is I. In some embodiments, X2 is T. In some embodiments, X2 is Y.

[0361] In some embodiments, X3 is not F. In some embodiments, X3 is F, S, or D. In some embodiments, X3 is S or D. In some embodiments, X3 is F. In some embodiments, X3 is S. In some embodiments, X3 is D.

[0362] In some embodiments, X4 is not N. In some embodiments, X4 is N or D. In some embodiments, X4 is N. In some embodiments, X4 is D.

[0363] In some embodiments, X5 is not M. In some embodiments, X5 is M or L. In some embodiments, X5 is M. In some embodiments, X5 is L.

[0364] In some embodiments, X6 is not S. In some embodiments, X6 is S or F. In some embodiments, X6 is S. In some embodiments, X6 is F.

[0365] In some embodiments, X7 is not M. In some embodiments, X7 is M, Y, or A. In some embodiments, X7 is Y or A. In some embodiments, X7 is M. In some embodiments, X7 is Y. In some embodiments, X7 is A.

[0366] In some embodiments, X8 is not N. In some embodiments, X8 is N or H. In some embodiments, X8 is N. In some embodiments, X8 is H.

[0367] In some embodiments, X9 is not G. In some embodiments, X9 is G or P. In some embodiments, X9 is G. In some embodiments, X9 is P.

[0368] In some embodiments, X 10 is not N. In some embodiments, X 10 is N or D. In some embodiments, X 10 is N. In some embodiments, X 10 is D.

[0369] In some embodiments, X 11 is not I. In some embodiments, X 11 is I or F. In some embodiments, X 11 is I. In some embodiments, X 11 is F.

[0370] In some embodiments, the polypeptide (e.g., an antibody or antigen-binding fragment thereof) comprises a V L Including, X 12 is not N, X 13 is not D, X 14 is not C, X 15 is not N, X 16 is not S, X 17 is not L, X 18 is not S, X 19 is not G, X 20 is not N, or Any combination of the above.

[0371] Consensus V for SEQ ID NOs: 8 to 20 herein L The sequence, identified as SEQ ID NO:7, is shown in Table 2.

[0372] In some embodiments, X 12 is either N or S, X 13 is D or R, X 14 is C, A, S, or Y, X 15 is N or R, X 16 is S or D, X 17 is L or S, X 18 is S or F, X 19 is G or D, X 20 is N or H, or Any combination of the above.

[0373] In some embodiments, X 12 is S, X 13 is R, X 14 is A, S, or Y, X 15 is R, X 16 is D, X 17is S, X 18 is F, X 19 is D, X 20 is H, or Any combination of the above.

[0374] In some embodiments, X 12 is not N. In some embodiments, X 12 is N or S. In some embodiments, X 12 is N. In some embodiments, X 12 is S.

[0375] In some embodiments, X 13 is not D. In some embodiments, X 13 is D or R. In some embodiments, X 13 is D. In some embodiments, X 13 is R.

[0376] In some embodiments, X 14 is not C. In some embodiments, X 14 is C, A, S, or Y. In some embodiments, X 14 is A, S, or Y. In some embodiments, X 14 is C. In some embodiments, X 14 is A. In some embodiments, X 14 is S. In some embodiments, X 14 is Y.

[0377] In some embodiments, X 15 is not N. In some embodiments, X 15 is N or R. In some embodiments, X 15 is N. In some embodiments, X 15 is R.

[0378] In some embodiments, X 16 is not S. In some embodiments, X 16 is S or D. In some embodiments, X 16 is S. In some embodiments, X 16 is D.

[0379] In some embodiments, X 17 is not L. In some embodiments, X 17 is L or S. In some embodiments, X 17 is L. In some embodiments, X 17 is S.

[0380] In some embodiments, X 18 is not S. In some embodiments, X 18 is S or F. In some embodiments, X 18 is S. In some embodiments, X 18 is F.

[0381] In some embodiments, X 19 is not G. In some embodiments, X 19 is G or D. In some embodiments, X 19 is G. In some embodiments, X 19 is D.

[0382] In some embodiments, X 20 is not N. In some embodiments, X 20 is N or H. In some embodiments, X 20 is N. In some embodiments, X 20 is H.

[0383] In some embodiments, a) X1 is G, X2 is Y, X3 is D, X4 is N, X5 is L, X6 is F, X7 is A, X8 is H, X9 is P, X 10is D, X 11 is F, X 12 is S, X 13 is D, X 14 is C,X 15 is R, X 16 is D, X 17 is S, X 18 is S, X 19 is G, X 20 is H, or a combination thereof (AB-1a), b) X1 is G, X2 is Y, X3 is D, X4 is N, X5 is L, X6 is F, X7 is A, X8 is H, X9 is P, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is A, X 15 is R, X 16 is D, X 17 is S, X 18 is S, X 19 is G, X 20 is H, or a combination thereof (AB-1b), c) X1 is G, X2 is Y, X3 is D, X4 is N, X5 is L, X6 is F, X7 is A, X8 is H, X9 is P, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is S, X 15 is R, X 16 is D, X 17 is S, X 18 is S, X 19 is G, X 20 is H, or a combination thereof (AB-1c), d) X1 is G, X2 is Y, X3 is D, X4 is N, X5 is L, X6 is F, X7 is A, X8 is H, X9 is P, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is Y, X 15 is R, X 16 is D, X 17 is S, X 18 is S, X 19 is G, X 20 is H, or a combination thereof (AB-1d), e) X1 is D, X2 is T, X3 is S, X4 is D, X5 is L, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is R, X 14 is C,X 15 is R, X 16 is S, X 17 is L, X 18 is F, X 19 is D, X 20 is H, or a combination thereof (AB-2a), f) X1 is D, X2 is T, X3 is S, X4 is D, X5 is L, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is R, X 14 is A, X 15 is R, X 16 is S, X 17 is L, X 18 is F, X 19 is D, X 20is H, or a combination thereof (AB-2b), g) X1 is D, X2 is T, X3 is S, X4 is D, X5 is L, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is R, X 14 is S, X 15 is R, X 16 is S, X 17 is L, X 18 is F, X 19 is D, X 20 is H, or a combination thereof (AB-2c), h) X1 is D, X2 is T, X3 is S, X4 is D, X5 is L, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is R, X 14 is Y, X 15 is R, X 16 is S, X 17 is L, X 18 is F, X 19 is D, X 20 is H, or a combination thereof (AB-2d), i) X1 is D, X2 is T, X3 is S, X4 is D, X5 is M, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is C,X 15 is R, X 16 is S, X 17 is L, X 18is S, X 19 is D, X 20 is H, or a combination thereof (AB-3a), j) X1 is D, X2 is T, X3 is S, X4 is D, X5 is M, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is A, X 15 is R, X 16 is S, X 17 is L, X 18 is S, X 19 is D, X 20 is H, or a combination thereof (AB-3b), k) X1 is D, X2 is T, X3 is S, X4 is D, X5 is M, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is S, X 15 is R, X 16 is S, X 17 is L, X 18 is S, X 19 is D, X 20 is H, or a combination thereof (AB-3c), or l) X1 is D, X2 is T, X3 is S, X4 is D, X5 is M, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is D, X 14 is Y, X 15 is R, X16 is S, X 17 is L, X 18 is S, X 19 is D, X 20 is H, or a combination thereof (AB-3d).

[0384] In some embodiments, X1 is D, X2 is T, X3 is S, X4 is D, X5 is L, X6 is S, X7 is Y, X8 is N, X9 is G, X 10 is D, X 11 is F, X 12 is S, X 13 is R, X 14 is A, X 15 is R, X 16 is S, X 17 is L, X 18 is F, X 19 is D, X 20 is H, or a combination thereof (AB-2b).

[0385] Stationary Domain In some embodiments, the polypeptide (e.g., an antibody or antigen-binding fragment thereof) a) antibody heavy chain constant domain sequences; b) an antibody light chain constant domain sequence, or c) Contains both an antibody heavy chain constant domain sequence and an antibody light chain constant domain sequence.

[0386] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence, hi some embodiments, the 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.

[0387] In some embodiments, the 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).

[0388] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 576).

[0389] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 576. For example, the polypeptide may comprise an antibody heavy chain constant domain sequence having 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, the polypeptide comprises an antibody heavy chain constant domain sequence having at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:576.

[0390] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence comprising 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 to 20, 1 to 19, 2 to 19, 2 to 18, 2 to 17, 3 to 17, 3 to 16, 4 to 16, 4 to 15, 5 to 15, 5 to 14, 6 to 14, 6 to 13, 7 to 13, 7 to 12, 8 to 12, 8 to 11, or 9 to 11. In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence comprising about 1 to 10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 576.

[0391] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:576.

[0392] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 50).

[0393] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 50. For example, the polypeptide may comprise an antibody heavy chain constant domain sequence having 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, the polypeptide comprises an antibody heavy chain constant domain sequence having at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:50.

[0394] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence comprising 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 to 20, 1 to 19, 2 to 19, 2 to 18, 2 to 17, 3 to 17, 3 to 16, 4 to 16, 4 to 15, 5 to 15, 5 to 14, 6 to 14, 6 to 13, 7 to 13, 7 to 12, 8 to 12, 8 to 11, or 9 to 11. In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence comprising about 1 to 10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 50.

[0395] In some embodiments, the polypeptide comprises an antibody heavy chain constant domain sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:50.

[0396] In some embodiments, the polypeptide comprises an Fc polypeptide or Fc domain (e.g., an IgG1 domain, an IgG2 domain, or an IgG4 domain). In some embodiments, the Fc domain comprises one or more mutations that, for example, reduce (e.g., inhibit, eliminate) an effector function of the Fc domain, increase the half-life of an antibody or antibody fragment comprising 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 herein by reference in their entirety). In some embodiments, the Fc domain comprises LS modifications (i.e., M428L / N434S substitutions according to the numbering determined by Kabat) or YTE modifications (i.e., M252Y / S254T / T256E substitutions according to the numbering determined by Kabat). In some embodiments, the Fc domain comprises an LS modification.

[0397] In some embodiments, the polypeptide (eg, an antibody or antigen-binding fragment thereof) comprises an antibody light chain constant domain sequence.

[0398] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence that is a lambda constant domain (eg, SEQ ID NO:577 or SEQ ID NO:52).

[0399] GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 577).

[0400] GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 52).

[0401] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 557 or SEQ ID NO: 52. For example, the polypeptide may comprise an antibody light chain constant domain sequence having 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, the polypeptide comprises an antibody light chain constant domain sequence having at least about 70% or at least about 80% sequence identity to SEQ ID NO:557 or SEQ ID NO:52.

[0402] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence comprising 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, the polypeptide comprises an antibody light chain constant domain sequence comprising 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, at least one amino acid substitution is a conservative substitution. In some embodiments, at least one amino acid substitution is a highly conservative substitution.

[0403] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:557 or SEQ ID NO:52.

[0404] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 557. For example, the polypeptide may comprise an antibody light chain constant domain sequence having 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, the polypeptide comprises an antibody light chain constant domain sequence having at least about 70% or at least about 80% sequence identity to SEQ ID NO:557.

[0405] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence comprising 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, the polypeptide comprises an antibody light chain constant domain sequence comprising about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 557. In some embodiments, at least one amino acid substitution is a conservative substitution. In some embodiments, at least one amino acid substitution is a highly conservative substitution.

[0406] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:557.

[0407] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence that is a kappa constant domain (eg, SEQ ID NO: 51).

[0408] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 51).

[0409] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence having 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, the polypeptide may comprise an antibody light chain constant domain sequence having 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, the polypeptide comprises an antibody light chain constant domain sequence having 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.

[0410] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence comprising 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 to 20, 1 to 19, 2 to 19, 2 to 18, 2 to 17, 3 to 17, 3 to 16, 4 to 16, 4 to 15, 5 to 15, 5 to 14, 6 to 14, 6 to 13, 7 to 13, 7 to 12, 8 to 12, 8 to 11, or 9 to 11. In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence comprising about 1 to 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, at least one amino acid substitution is a conservative substitution. In some embodiments, at least one amino acid substitution is a highly conservative substitution.

[0411] In some embodiments, the polypeptide comprises an antibody light chain constant domain sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:557, SEQ ID NO:52, or SEQ ID NO:51.

[0412] In some embodiments, the polypeptide is a) an antibody heavy chain constant domain sequence, and b) Contains an antibody light chain constant domain sequence.

[0413] In some embodiments, the 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 lambda constant domain (e.g., SEQ ID NO: 577 or SEQ ID NO: 52).

[0414] In some embodiments, the polypeptide is 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 includes both a) and b).

[0415] In some embodiments, the polypeptide is a) an antibody heavy chain constant domain comprising SEQ ID NO: 576, and b) comprises an antibody light chain constant domain comprising SEQ ID NO: 577.

[0416] In some embodiments, the polypeptide is 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 includes both a) and b).

[0417] In some embodiments, the polypeptide is a) an antibody heavy chain constant domain comprising SEQ ID NO: 50, and

[0418] The antibody light chain constant domain comprises SEQ ID NO:577.

[0419] In some embodiments, the polypeptide is 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 includes both a) and b).

[0420] In some embodiments, the polypeptide is a) an antibody heavy chain constant domain comprising SEQ ID NO: 576, and b) comprises an antibody light chain constant domain comprising SEQ ID NO: 52.

[0421] Antibodies and antigen-binding fragments In some embodiments, the polypeptide specifically binds to a spike receptor binding domain (RBD) class 4 epitope of the spike glycoprotein of a betacoronavirus (SARS-CoV-2-spike).

[0422] In some embodiments, the polypeptide is an immunoglobulin molecule, such as an antibody (eg, a whole antibody, an intact antibody) or an antigen-binding fragment of an antibody.

[0423] In some embodiments, the polypeptide is an antibody. As used herein, the term "antibody" refers to an immunoglobulin molecule that can specifically bind to a target such as a carbohydrate, polynucleotide, lipid, or polypeptide 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.

[0424] In some embodiments, the polypeptide is an antibody or a multimer thereof (e.g., IgM) comprising two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. 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). The VH and VL regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), which are interspersed within framework regions (FRs). Each VH and VL 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. The antibody can be of any species, such as a murine antibody, a human antibody, or a humanized antibody.

[0425] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs: 578-591. For example, the polypeptide may comprise a heavy chain amino acid sequence having 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, the polypeptide comprises a heavy chain amino acid sequence having 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.

[0426] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 578).

[0427] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLPGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNRDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 579).

[0428] QVQLVQSGAEVKKPGSSVKVSCKASGDTEDTYTISWVRQAPGQGLEWMGRIILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 580).

[0429] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYGNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 581).

[0430] QVQLVQSGAEVKKPGSSVKVSCKASGDYSDVYTISWVRQAPGQGLEWMGRIILLLGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 582).

[0431] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 583).

[0432] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYSNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 584).

[0433] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 585).

[0434] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSDYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 586).

[0435] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNEDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 587).

[0436] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDIYTISWVRQAPGQGLEWMGRIILLSGYTNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 588).

[0437] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYVNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNPDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 589).

[0438] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYANYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNYDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 590).

[0439] QVQLVQSGAEVKKPGSSVKVSCKASGDTSDTYTISWVRQAPGQGLEWMGRIILLSGYGNYAQKIQGRVTITADKSTSTAYMELTSLRSDDTAVYYCARGFNGDYYGWGDDDAFDFW GQGTLVTVYSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 591).

[0440] In some embodiments, the polypeptide comprises 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. 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 polypeptide comprises 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.

[0441] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence having 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 578-591.

[0442] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 578. For example, the polypeptide may comprise a heavy chain amino acid sequence having 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, the polypeptide comprises a heavy chain amino acid sequence having at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:578.

[0443] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence comprising 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, the polypeptide comprises a heavy chain amino acid sequence comprising about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 578.

[0444] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:578.

[0445] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 579. For example, the polypeptide may comprise a heavy chain amino acid sequence having 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, the polypeptide comprises a heavy chain amino acid sequence having at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:579.

[0446] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence comprising 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, the polypeptide comprises a heavy chain amino acid sequence comprising about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 579.

[0447] In some embodiments, the polypeptide comprises a heavy chain amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:579.

[0448] In some embodiments, the polypeptide comprises a light chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs: 592-603. For example, the polypeptide may comprise a light chain amino acid sequence having 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, the polypeptide comprises a light chain amino acid sequence having 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.

[0449] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYRVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 592).

[0450] QTVLTQPPSVSGAPGQRVTISCTGSESNIGAGYRVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 593).

[0451] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYYVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 594).

[0452] QTVLTQPPSVSGAPGQRVTISCTGSESNIGAGYDVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 595).

[0453] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSYFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 596).

[0454] QTVLTQPPSVSGAPGQRVTISCTGSVSNIGAGYDVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 597).

[0455] QTVLTQPPSVSGAPGQRVTISCTGSPSNIGAGYRVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 598).

[0456] QTVLTQPPSVSGAPGQRVTISCTGSVSNIGAGYRVHWYQQLPGTAPKLLIAGSSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 599).

[0457] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSSFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 600).

[0458] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYRVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSYFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 601).

[0459] QTVLTQPPSVSGAPGQRVTISCTGSVSNIGAGYRVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 602).

[0460] QTVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 603).

[0461] QTVLTQPPSVSGAPGQRVTISCTGSESNIGAGYRVHWYQQLPGTAPKLLIAGRSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDSSLFDPHWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 603).

[0462] In some embodiments, the polypeptide comprises 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. 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 polypeptide comprises 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.

[0463] In some embodiments, the polypeptide comprises a light chain amino acid sequence having 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 592-603.

[0464] In some embodiments, the polypeptide comprises a light chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 592. For example, the polypeptide may comprise a light chain amino acid sequence having 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, the polypeptide comprises a light chain amino acid sequence having at least about 70% or at least about 80% sequence identity to the amino acid sequence of SEQ ID NO:592.

[0465] In some embodiments, the polypeptide comprises a light chain amino acid sequence comprising 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, the polypeptide comprises a light chain amino acid sequence comprising about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 592.

[0466] In some embodiments, the polypeptide comprises a light chain amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO:592.

[0467] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence having at least about 60% sequence identity to any one or more amino acid sequences of SEQ ID NOs: 578 to 591; or b) a light chain amino acid sequence having at least about 60% sequence identity to any one or more amino acid sequences of SEQ ID NOs: 592 to 603; or Includes both a) and b).

[0468] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence having at least about 60% sequence identity to any one or more amino acid sequences of SEQ ID NOs: 578 to 591; and b) A light chain amino acid sequence having at least about 60% sequence identity to any one or more amino acid sequences of SEQ ID NOs: 592 to 603.

[0469] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence containing at least one amino acid substitution relative to any one or more amino acid sequences of SEQ ID NOs: 578 to 591; or b) a light chain amino acid sequence comprising at least one amino acid substitution relative to any one or more amino acid sequences of SEQ ID NOs: 592 to 603; or Includes both a) and b).

[0470] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence containing at least one amino acid substitution with respect to any one or more amino acid sequences of SEQ ID NOs: 578 to 591; and b) A light chain amino acid sequence containing at least one amino acid substitution with respect to any one or more amino acid sequences of SEQ ID NOs: 592 to 603.

[0471] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence comprising about 1 to 10 amino acid substitutions relative to any one or more amino acid sequences of SEQ ID NOs: 578 to 591; or b) a light chain amino acid sequence comprising about 1 to 10 amino acid substitutions relative to any one or more amino acid sequences of SEQ ID NOs: 592 to 603; or Includes both a) and b).

[0472] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence comprising about 1 to 10 amino acid substitutions relative to any one or more amino acid sequences of SEQ ID NOs: 578 to 591; and b) A light chain amino acid sequence comprising approximately 1 to 10 amino acid substitutions relative to any one or more amino acid sequences of SEQ ID NOs: 592 to 603.

[0473] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence having 100% sequence identity to any one of the amino acid sequences of SEQ ID NOs: 578 to 591; or b) a light chain amino acid sequence having 100% sequence identity to any one of the amino acid sequences of SEQ ID NOs: 592 to 603; or Includes both a) and b).

[0474] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence having 100% sequence identity to any one of the amino acid sequences of SEQ ID NOs: 578 to 591; and b) A light chain amino acid sequence having 100% sequence identity to any one of the amino acid sequences of SEQ ID NOs: 592 to 603.

[0475] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 578, or b) a light chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 592; or Includes both a) and b).

[0476] In some embodiments, the polypeptide is a) a heavy chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 578, and b) comprises a light chain amino acid sequence having at least about 60% sequence identity to the amino acid sequence of SEQ ID NO: 592.

[0477] In some embodiments, the polypeptide is 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 to 10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 592; or Includes both a) and b).

[0478] In some embodiments, the polypeptide is 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 to 10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 592.

[0479] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 578, and b) A light chain (AB-2b) comprising the amino acid sequence of SEQ ID NO: 592.

[0480] In some embodiments, the polypeptide is 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.

[0481] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 580, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 593.

[0482] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 581, and b) A light chain comprising the amino acid sequence of SEQ ID NO: 592.

[0483] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 582, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 594.

[0484] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 583, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 594.

[0485] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 584, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 595.

[0486] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 585, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 594.

[0487] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 586, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 593.

[0488] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 585, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 593.

[0489] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 578, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 596.

[0490] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 587, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 597.

[0491] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 585, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 598.

[0492] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 588, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 597.

[0493] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 583, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 595.

[0494] In some embodiments, the polypeptide is a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 585, and b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 599.

[0495] In some embodiments, the polypeptide is 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.

[0496] In some embodiments, the polypeptide is 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.

[0497] In some embodiments, the polypeptide is 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.

[0498] In some embodiments, the polypeptide is 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.

[0499] In some embodiments, the polypeptide is 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.

[0500] In some embodiments, the 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 that consists of a single monomeric variable antibody domain and can specifically bind to a target. Single domain antibodies can be of any species, such as mouse antibodies, human antibodies, or humanized single domain antibodies.

[0501] In some embodiments, V H Domains and V L The domains are linked together via a linker (e.g., a synthetic linker) to form a V H / V L Domains are intramolecular or V H and V L When the domains are expressed by separate chains, they can pair intermolecularly to form a monovalent antigen-binding site, creating various types of single-chain antibody designs.

[0502] In some embodiments, the polypeptide is a heavy chain antibody, or an antigen-binding fragment thereof, that comprises two or more heavy chains but lacks light chains. Non-limiting examples of heavy chain antibodies include camelid Vhh (also referred to as VHH or VHH) antibodies. Camelid antibodies are antibodies from the camelid family of mammals, including llamas, camels, and alpacas.

[0503] In some embodiments, the polypeptide is an antibody mimetic. The term "antibody mimetic" refers to a polypeptide that can mimic the ability of an antibody to bind to an antigen but that is structurally different from the natural antibody structure. Non-limiting examples of antibody mimics include adnectins, affibodies, affilins, affimers, affitins, alphabodies, anticalins, avimers, DARPins, finomers, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMPs, and versabodies.

[0504] In some embodiments, the polypeptide is an antigen-binding fragment of an antibody. The term "antigen-binding fragment" refers to a portion of an immunoglobulin molecule (e.g., an antibody) that retains the antigen-binding properties of a full-length reference antibody. Non-limiting examples of antigen-binding fragments include VH regions, VL regions, Fab fragments, F(ab')2 fragments, Fd fragments, Fv fragments, and domain antibodies (dAbs) consisting of one VH domain or one VL domain. The VH and VL domains can 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 when the VH and VL domains are expressed as separate chains, to form a monovalent antigen-binding site, e.g., a single-chain Fv (scFv) or diabody. In some embodiments, the polypeptide disclosed herein is an antigen-binding fragment selected from a Fab, F(ab')2, Fab', scFv, or Fv. In some embodiments, the polypeptide is an scFv.

[0505] In some embodiments, the polypeptide (e.g., an antibody or antigen-binding fragment) is incorporated into a cell-based therapy. In some embodiments, the polypeptide is an engineered T cell receptor. In some embodiments, the polypeptide is a chimeric antigen receptor (CAR) (e.g., expressed on a T (CAR-T) cell, a natural killer (CAR-NK) cell, or a macrophage (CAR-M) cell). In some embodiments, the CAR comprises a transmembrane domain and an antigen recognition moiety, which binds to SARS-CoV-2 (e.g., an epitope within the RBD, such as an RBD class 4 epitope).

[0506] In some embodiments, the polypeptide is an antibody mimetic.

[0507] In some embodiments, the polypeptide competes with a comparator antibody for binding to wild-type SARS-CoV-2 spike, a SARS-CoV-2 spike variant, or a combination thereof, and the reference antibody specifically binds to wild-type SARS-CoV-2 spike (e.g., RBD). The terms "specifically binding" or "specifically binds" refer to a preferential interaction, i.e., a significantly higher binding affinity, between an antibody or antigen-binding fragment thereof and its epitope compared to other antigens or amino acid sequences.

[0508] In some embodiments, the polypeptide is an isolated polypeptide. In some embodiments, the polypeptide (e.g., the isolated polypeptide) is recombinantly produced. In some embodiments, the polypeptide (e.g., the isolated polypeptide) is synthetically produced.

[0509] In some embodiments, the polypeptide is linked to a second polypeptide. The term "linked" means attached via a covalent bond or a non-covalent interaction. Conjugation can be performed using a suitable linking agent. Non-limiting examples include peptide linkers, compound linkers, and chemical crosslinkers. In some embodiments, the linker is a disulfide bond.

[0510] In some embodiments, the polypeptide is conjugated to a heterologous moiety. The term "conjugated" refers to attachment via a covalent bond or a non-covalent interaction. Conjugation can use any one or more suitable linking agents. Non-limiting examples include peptide linkers, compound linkers, and chemical cross-linkers.

[0511] In some embodiments, the heterologous moiety comprises a therapeutic agent, a diagnostic agent, or both. In some embodiments, the heterologous moiety is selected from polyethylene glycol (PEG), hexadecanoic acid, a hydrogel, a nanoparticle, a multimerization domain, and a carrier peptide.

[0512] In some embodiments, the nanoparticles are lipid nanoparticles. In some embodiments, the nanoparticles are polymeric nanoparticles. In some embodiments, the polymer is an amphiphilic polymer. In some embodiments, the polymer is a hydrophobic or hydrophilic polymer. Non-limiting examples of polymers include poly(lactic acid)-poly(ethylene glycol), poly(lactic acid-co-glycolic acid)-poly(ethylene glycol), poly(lactic acid-co-glycolic acid) (PLGA), poly(lactic acid-co-glycolic acid)-d-α-tocopheryl polyethylene glycol succinate, poly(lactic acid-co-glycolic acid)-ethylene oxide fumarate, poly(glycolic acid)-poly(ethylene glycol), polycaprolactone-poly(ethylene glycol), or any salt thereof. In some embodiments, the polymeric nanoparticles comprise poly(lactic acid-co-glycolic acid) (PLGA).

[0513] In some embodiments, the carrier polypeptide is albumin or an Fc polypeptide.

[0514] In some embodiments, the polypeptide is a) capable of binding to an epitope within the RBD of SARS-CoV-2-Spike, b) a K of 10 μM or less for SARS-CoV-1 and / or SARS-CoV-2 D Combine with c) neutralizing SARS-CoV-1 and / or SARS-CoV-2 infection of human host cells; d) has weaker non-specific binding than the reference antibody; e) has weaker self-association than the reference antibody; or any combination of the foregoing.

[0515] In some embodiments, the polypeptide can bind to one or more epitope residues within the RBD of the SARS-CoV-2 spike, e.g., residues 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of the RBD. In some embodiments, the polypeptide can bind to one or more epitope residues of SEQ ID NO:1 (e.g., residues 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all 16 of the residues).

[0516] In some embodiments, the polypeptide has a binding constant (K D ) and binds to the SARS-CoV-2 spike.

[0517] In some embodiments, the polypeptides include the SARS-CoV-1-spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-spike (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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. , 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, BA5, BA5.2.6, 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 fragments thereof (e.g., the RBD of SARS-CoV-2-spike) with a K of 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. DIn some embodiments, the polypeptide binds to the SARS-CoV-1 spike (e.g., of CoV-1 and / or WIV1) and / or the SARS-CoV-2 spike (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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, BA2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA4, BA4 / 5, BA.4 / 5+K444T, BA.4.6, BA5, BA5.2.6, 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 fragments thereof (e.g., the RBD of SARS-CoV-2-spike) with a K of 100 nM or less. D Combine with.

[0518] In some embodiments, the polypeptides include the SARS-CoV-1-spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2-spike (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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, BA5, BA5.2.6, 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 the SARS-CoV-2 spike), -10 ~10 -5 M, 10 -10 ~5×10 -6 M, 2 x 10 -10 ~5×10 -6 M, 2 x 10 -10 ~2×10 -6 M, 5 x 10 -10 ~2×10 -6 M, 5 x 10 -10 ~10 -7 M, 10 -9 ~10 -7 M, 10 -9 ~5×10 -8 M, 2 x 10 -9 ~5×10 -8 M, 2 x 10 -9 ~2×10 -8 M, 5 x 10 -9 ~2×10 -8 M, or 5 x 10 -9 ~10 -8 K of M D Combine with.

[0519] In some embodiments, the polypeptide (e.g., a full-length IgG1 antibody) is a SARS-CoV-1 spike (e.g., of CoV-1 and / or WIV1) and / or SARS-CoV-2 spike (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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.1.625, B.1.725, B.1.825, B.1.925, B.1.102, B.1.11, B.1.129, B.1.132, B.1.142, B.1.152, B.1.162, B.1.173, B.1.182, B.1.192, B.1.202, B.1.211, B.1.225, B.1.231, B.1.242, B.1.251, B.1.262, B.1.272, B.1.282, B.1.293, B.1.294, B.1.295, B.1.296, B.1.297, B.1.298, B.1.29 ... .1.526, B.1.617.1, B.1.617.2, B.1.621, BA.1, BA.1.1, BA2, BA.2.12.1, BA.2.75, BA.2.75.2, BA.3, BA4, BA4 / 5, BA.4 / 5+K444T, BA.4.6, BA5, BA5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ1.1, C.37, D.2, GA.5, GR / 484A, P.1, P.3, and / or XBB), or fragments thereof (e.g., the RBD of the SARS-CoV-2 spike), -6 K below M D , for example, 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 -6 M, 10 -10 ~5×10 -7 M, 2 x 10 -10 ~5×10 -7 M, 2 x 10 -10 ~2×10 -7 M, 5 x 10 -10 ~2×10 -7 M, 5 x 10 -10 ~10 -7 M, 10 -9 ~10 -7 M, 10 -9 ~5×10 -8 M, 2 x 10 -9 ~5×10 -8 M, 2 x 10 -9 ~2×10 -8 M, 5 x 10 -9 ~2×10 -8 M, or 5 x 10-9 ~10 -8 Join with M.

[0520] In some embodiments, the polypeptide competes with a reference antibody for binding to the SARS-CoV-2 spike (e.g., an RBD, such as an RBD class 4 epitope). Techniques and assays for assessing competition between antibodies are known in the art.

[0521] In some embodiments, the polypeptides are selected from the group consisting of SARS-CoV-1 (e.g., CoV-1 and / or WIV1) and / or SARS-CoV-2 (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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, BA2, 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, BA5, BA5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ1.1, C.37, D.2, GA.5, GR / 484A, P.1, P3, and / or XBB) with an IC of 10 μM or less. 50 Neutralize with.

[0522] In some embodiments, the polypeptide (e.g., a full-length IgG1 antibody) inhibits SARS-CoV-2 (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., B.1, B.1.1, B.1.1.1, B.1.1.529, B.1.1.7, B.1.177, B.1.2, B1.351, B.1.427 / 429, B1.525, B1.526, B.1.61) in human host cells. 7.1, 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, BA5, BA5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P3, and / or XBB) infections at an IC of approximately 25,000 ng / mL or less. 50 , for example, about 20,000ng / mL, 15,000ng / mL, 10,000ng / mL, 5,000ng / mL, 2,500ng / mL, 1,000ng / mL, 750ng / mL, 500ng / mL, 250ng / mL, 100ng / mL, 75ng / mL, 50ng / mL, 25ng / mL, or 10ng / mL or less, for example, about 10 to 25,000ng / mL, 10 to 20,000ng / mL, 2 Neutralize with 5-20,000ng / mL, 25-15,000ng / mL, 50-15,000ng / mL, 50-10,000ng / mL, 75-10,000ng / mL, 75-5,000ng / mL, 100-5,000ng / mL, 100-2,500ng / mL, 250-2,500ng / mL, 250-1,000ng / mL, 500-1,000ng / mL, or 500-750ng / mL.

[0523] In some embodiments, the host cells are selected from the group consisting of pulmonary type II pneumocytes, ileal absorptive enterocytes, nasal goblet secretory cells, and combinations thereof.

[0524] In some embodiments, the polypeptide (e.g., a full-length IgG1 antibody) inhibits SARS-CoV-2 (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., B.1, B.1.1, B.1.1.1, B.1.1.529, B.1.1.7, B.1.177, B.1.2, B1.351, B.1.427 / 429, B1.525, B1.526, B.1.61) in human host cells. 7.1, 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, BA5, BA5.2.6, BF.7, BF.11, BN.1, BQ.1, BQ.1.1, C.37, D.2, GA.5, GR / 484A, P.1, P3, and / or XBB) infections at an IC of approximately 50,000 ng / mL or less. 80 , for example, about 25,000ng / mL, 15,000ng / mL, 10,000ng / mL, 5,000ng / mL, 2,500ng / mL, 1,000ng / mL, 750ng / mL, 500ng / mL, 250ng / mL, 100ng / mL, 75ng / mL, 50ng / mL, 25ng / mL, or 10ng / mL or less, for example, about 10 to 50,000ng / mL, 10 to 25,000ng / mL, 2 Neutralize with 5 to 25,000 ng / mL, 25 to 15,000 ng / mL, 50 to 15,000 ng / mL, 50 to 10,000 ng / mL, 75 to 10,000 ng / mL, 75 to 5,000 ng / mL, 100 to 5,000 ng / mL, 100 to 2,500 ng / mL, 250 to 2,500 ng / mL, 250 to 1,000 ng / mL, 500 to 1,000 ng / mL, or 500 to 750 ng / mL.

[0525] In some embodiments, the polypeptide (e.g., a full-length IgG1 antibody) inhibits SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infection of human host cells with an IC of about 25,000 ng / mL or less. 50, for example, about 20,000ng / mL, 15,000ng / mL, 10,000ng / mL, 5,000ng / mL, 2,500ng / mL, 1,000ng / mL, 750ng / mL, 500ng / mL, 250ng / mL, 100ng / mL, 75ng / mL, 50ng / mL, 25ng / mL, or 10ng / mL or less, for example, about 10 to 25,000ng / mL, 10 to 20,000ng / mL, 2 Neutralize with 5-20,000ng / mL, 25-15,000ng / mL, 50-15,000ng / mL, 50-10,000ng / mL, 75-10,000ng / mL, 75-5,000ng / mL, 100-5,000ng / mL, 100-2,500ng / mL, 250-2,500ng / mL, 250-1,000ng / mL, 500-1,000ng / mL, or 500-750ng / mL.

[0526] In some embodiments, the polypeptide (e.g., a full-length IgG1 antibody) inhibits SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infection of human host cells with an IC of about 50,000 ng / mL or less. 80 , for example, about 25,000ng / mL, 15,000ng / mL, 10,000ng / mL, 5,000ng / mL, 2,500ng / mL, 1,000ng / mL, 750ng / mL, 500ng / mL, 250ng / mL, 100ng / mL, 75ng / mL, 50ng / mL, 25ng / mL, or 10ng / mL or less, for example, about 10 to 50,000ng / mL, 10 to 25,000ng / mL, 2 Neutralize with 5 to 25,000 ng / mL, 25 to 15,000 ng / mL, 50 to 15,000 ng / mL, 50 to 10,000 ng / mL, 75 to 10,000 ng / mL, 75 to 5,000 ng / mL, 100 to 5,000 ng / mL, 100 to 2,500 ng / mL, 250 to 2,500 ng / mL, 250 to 1,000 ng / mL, 500 to 1,000 ng / mL, or 500 to 750 ng / mL.

[0527] In some embodiments, the polypeptide reduces betacoronavirus (e.g., SARS-CoV-2) infectivity of a host cell (e.g., a human host cell). In some embodiments, the polypeptide reduces betacoronavirus (e.g., SARS-CoV-2) infectivity of a host cell (e.g., a human host cell) by at least about 10%, e.g., 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, the polypeptide reduces betacoronavirus (e.g., SARS-CoV-2) infectivity of a human cell by at least about 30%.

[0528] In some embodiments, the polypeptide is capable of inhibiting the replication and development of a betacoronavirus (e.g., SARS-CoV-2 (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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, BA5, BA5.2.6, 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) In some embodiments, the polypeptide is used to inhibit the proliferation of a betacoronavirus (e.g., SARS-CoV-2 (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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, B1.526, B1.617.1, B1.617.2, B1.621, BA.1, BA.11, BA.2, BA.2.12.1, BA.2.12.1, BA.2.12.2, BA.2.12.3, BA.2.12.4, BA.2.12.5, BA.2.12.6, BA.2.12.7, BA.2.12.8, BA.2.12.9, BA.2.13.1, BA.2.13.1, BA.2.13.2, BA.2.13.3, BA.2.13.4, BA.2.13.5, BA.2.13.6, BA.2.13.7, BA.2.13.8, BA.2.13.9, BA.2.14.1, BA.2.14.2, BA.2.14.3, BA.2.14.4, BA.2.14.5, BA.2.14.6, BA.2.14.7, BA.2.14.8, BA.2.14.9, BA.2.14.1, .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)) reinfection is reduced by 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%.In some embodiments, the polypeptide is capable of inhibiting a betacoronavirus (e.g., SARS-CoV-2) in human cells (e.g., alpha, beta, gamma, delta, kappa, epsilon, eta, iota, lambda, mu, and / or omicron, e.g., 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, BA5, 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) reinfection by at least about 30%.

[0529] Infectivity or reinfection can be measured using techniques such as pseudovirus neutralization assays or live virus neutralization assays (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). Kits, such as the GenScript cPass™ SARS-CoV-2 Neutralizing Antibody Detection Kit, can be used according to the manufacturer's protocol.

[0530] In some embodiments, the polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infectivity of a host cell (e.g., a human host cell). In some embodiments, the polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infectivity of a host cell (e.g., a human host cell) by at least about 10%, e.g., 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, the polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) infectivity of a human cell by at least about 30%.

[0531] In some embodiments, the polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) reinfection of host cells (e.g., human host cells). In some embodiments, the polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) reinfection of host cells (e.g., human host cells) by at least about 10%, e.g., 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, the polypeptide reduces SARS-CoV-1 (e.g., CoV-1 and / or WIV1) reinfection of human cells by at least about 30%.

[0532] In some embodiments, the polypeptide has weaker self-association than a reference antibody, as determined, for example, by affinity capture self-interaction nanoparticle spectroscopy (AC-SINS) value. The AC-SINS value is the change in the wavelength of maximum absorbance in the absorption spectrum of the coated nanoparticle compared to the spectrum of the nanoparticle alone. Thus, the greater the change in wavelength of maximum absorbance, the greater the self-interaction of the antibody coated on the nanoparticle. Self-association is an undesirable property that correlates with poor viscosity and poor PK properties. Techniques and assays for assessing protein self-association are known in the art. See, for example, Patro & Przybycien, Biotechnol Bioeng. 52(2):193-203(1996), the contents of which are incorporated herein in their entirety. In some embodiments, the polypeptide has weaker self-association than a reference antibody.

[0533] In some embodiments, the 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 or less. In some embodiments, the polypeptide has an AC-SINS value of about 14 or less. In some embodiments, the polypeptide has an AC-SINS value of about 8 or less. In some embodiments, the 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 or less. In some embodiments, the polypeptide has an AC-SINS value of about 0 to 25, e.g., 0 to 20, 0 to 15, 0 to 10, 0 to 8, 0 to 5, 2 to 20, 2 to 15, 2 to 10, 2 to 8, 2 to 5, 5 to 20, 5 to 15, 5 to 10, 5 to 8, 7 to 8, or 13 to 15. In some embodiments, the polypeptide has an AC-SINS value of about 13 to 14, 13 to 15, 7 to 9, or 7 to 8. In some embodiments, the polypeptide has an AC-SINS value of about 8 or 14.

[0534] In some embodiments, the polypeptide has improved developability (e.g., reduced AC-SINS) compared to a reference antibody. In some embodiments, the self-association of the polypeptide is at least about 10% lower than that of the reference antibody, e.g., 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, the self-association of the polypeptide is at least about 30% lower than that of the reference antibody.

[0535] In some embodiments, the self-association of the polypeptide is less than about 90% of that of the reference antibody, e.g., 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.

[0536] In some embodiments, the self-association of the polypeptide is about 1-90% relative to that of a reference antibody, e.g., 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.

[0537] In some embodiments, the reduction in self-association compared to a reference antibody is at least about 10%, e.g., 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%.

[0538] fusion proteins The present disclosure also provides, inter alia, fusion proteins comprising one or more of the polypeptides disclosed herein.

[0539] The term "fusion protein" refers to a synthetic, semi-synthetic, or recombinant single protein molecule. A fusion protein can contain all or a portion of two or more different proteins and / or polypeptides attached by a covalent bond (e.g., a peptide bond). For example, a fusion protein can contain a full-length polypeptide (e.g., a whole antibody) or a fragment thereof (e.g., an antigen-binding fragment of an antibody) disclosed herein. The heterologous partner can be a full-length protein or a fragment thereof (e.g., a truncated protein).

[0540] The fusion proteins of the present disclosure can be produced recombinantly or synthetically using routine methods and reagents well known in the art. For example, the fusion proteins of the present disclosure can be produced recombinantly in suitable host cells (e.g., bacteria) according to methods known in the art. See, for example, 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 containing a nucleotide sequence encoding a fusion protein described herein can be introduced into a suitable host cell (e.g., E. coli) and expressed, and the expressed fusion protein can be isolated / purified from the host cell (e.g., within inclusion bodies) using routine methods and readily available reagents. For example, DNA fragments encoding different protein sequences (e.g., photoresponsive domains, heterologous peptide components) can be ligated together in frame according to 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 performed using anchor primers that generate complementary overhangs between two consecutive nucleic acid fragments that can then be annealed and reamplified to generate a chimeric nucleic acid sequence (see Ausubel et al., Current Protocols in Molecular Biology, 1992).

[0541] Nucleic acids, vectors, and host cells The present disclosure also provides, inter alia, one or more polynucleotides (e.g., DNA, RNA, or an analog of either, e.g., optionally comprising one or more modified nucleotides; the polynucleotide can be linear or circular, e.g., 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.

[0542] In some embodiments, the polynucleotide comprises a nucleotide sequence that is codon-optimized for a selected host cell.

[0543] The present disclosure also provides, inter alia, vectors (eg, expression vectors, including viral delivery vectors) comprising any one or more of the polynucleotides disclosed herein.

[0544] 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.

[0545] In some embodiments, the 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, the expression control polynucleotide sequence comprises a promoter sequence, an enhancer sequence, or both. In some embodiments, the expression control polynucleotide sequence comprises an inducible promoter sequence. The term "promoter" refers to a region of DNA at which RNA polymerase binds to a gene and initiates transcription of the gene. The term "operably linked" means that the nucleic acid is positioned within a recombinant polynucleotide, e.g., a vector, in a manner that allows expression of the nucleic acid under the 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. The selectable marker element can be a negative or positive selectable marker.

[0546] The present disclosure also provides, inter alia, expression host cells comprising any one or more of the polynucleotides or expression vectors disclosed herein.

[0547] The term "expression host cell" refers to a cell useful for receiving, maintaining, replicating, and / or propagating 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.

[0548] composition The present disclosure also provides, inter alia, a composition comprising any one of the polypeptides, polynucleotides, or fusion proteins disclosed herein. In some embodiments, the composition is a pharmaceutical composition.

[0549] In some embodiments, the composition (e.g., pharmaceutical composition) further comprises a pharmaceutically acceptable carrier, excipient, stabilizer, diluent, or enhancer (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 enhancers 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 counterions (e.g., sodium), metal complexes (e.g., Zn-protein complexes), non-ionic surfactants (e.g., Tween®), PLURONICS®, and polyethylene glycol (PEG).

[0550] In some embodiments, the composition (e.g., 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. In some embodiments, the composition (e.g., pharmaceutical composition) is stored in the form of an aqueous solution or a dried formulation (e.g., lyophilized).

[0551] In some embodiments, the composition is formulated to be administered by injection (e.g., intravenous injection). In other embodiments, the composition is formulated for subcutaneous administration.

[0552] In some embodiments, the composition is provided in a dosage form, such as a pre-filled syringe or an auto-injector.

[0553] In some embodiments, the pharmaceutical composition comprises about 50 mg to about 300 mg, e.g., 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 of a polypeptide or fusion protein disclosed herein. In some embodiments, the pharmaceutical composition comprises about 60 mg to about 300 mg, e.g., about 60 to 280 mg, 80 to 280 mg, 80 to 260 mg, 100 to 260 mg, 100 to 250 mg, 120 to 250 mg, 120 to 240 mg, 140 to 240 mg, 140 to 220 mg, 150 to 250 mg, 150 to 200 mg, 160 to 220 mg, 160 to 200 mg, or 180 to 200 mg of a polypeptide or fusion protein disclosed herein.

[0554] In some embodiments, the pharmaceutical composition comprises about 50 mg / ml to about 200 mg / ml of a polypeptide or fusion protein disclosed herein, e.g., 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, the pharmaceutical composition comprises about 60 mg / ml to about 200 mg / ml, e.g., 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 of a polypeptide or fusion protein disclosed herein.

[0555] In some embodiments, the composition is formulated to be administered with at least one additional therapeutic agent as a combination therapy.

[0556] In some embodiments, the composition further comprises at least one additional therapeutic agent.

[0557] In some embodiments, the at least one additional therapeutic agent comprises any one of the polypeptides described herein (e.g., a reference antibody, a different RBD4-binding agent, an S2-binding agent, or any combination thereof). In some embodiments, the at least one additional therapeutic agent comprises bamlanivimab, etesevimab, casirivimab, imdevimab, silgavimab, tixagevimab, AZD7442 (tixagevimab-silgavimab), regdanvimab, or sotrovimab. In some embodiments, the second therapeutic agent comprises sotrovimab.

[0558] In some embodiments, the at least one additional therapeutic agent is a) an antibody or antigen-binding fragment thereof that specifically binds to SARS-CoV-2 spike; b) a polynucleotide comprising a nucleotide sequence encoding the antibody or antigen-binding fragment thereof of a); c) antiviral agents, d) ACE2 inhibitors, e) antibiotics; f) antimalarials, g) a vaccine, or Any combination of a) to g) is included.

[0559] In some embodiments, a) the antibody or antigen-binding fragment thereof that specifically binds to SARS-CoV-2 spike includes bamlanivimab, etesevimab, bebuterovimab, casirivimab, imdevimab, silgavimab, tixagevimab, AZD7442 (tixagevimab-silgavimab), regdanvimab, sotrovimab, or a combination thereof; b) an antibody or antigen-binding fragment thereof that specifically binds to the SARS-CoV-2 spike binds to the S2 domain of the SARS-CoV-2 spike; c) the antiviral agent includes oseltamivir (Tamiflu), favipiravir, amantadine, remdesivir, rimantadine, pleconaril, antisense RNA against SARS-CoV-2, siRNA against SARS-CoV-2, or a combination thereof; d) the ACE2 inhibitor comprises an RNAi against ACE2, an siRNA against 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 contains azithromycin; f) The antimalarial drug contains chloroquine; g) the vaccine comprises a nucleic acid vaccine and / or an inactivated virus vaccine; Or any combination of a) to g).

[0560] Non-limiting examples of additional therapeutic agents include antibiotics (e.g., azithromycin), antibodies or antigen-binding fragments thereof (e.g., other SARS-CoV-2 binding antibodies or antigen-binding fragments), antimalarials (e.g., chloroquine or hydroxychloroquine), antivirals (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)).

[0561] In some embodiments, the 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, antisense RNA against SARS-CoV-2, siRNA against SARS-CoV-2, an additional anti-SARS-CoV-2 monoclonal antibody, or a combination thereof.

[0562] In some embodiments, the antiviral agent comprises molnupiravir (LAGEVRIO, Merck), PF-07817883 (Pfizer), STI-1558 (Sorrento Therapeutics), PBI-0451 (Pardes Biosciences), EDP-235 (Enanta Pharmaceuticals), or a combination thereof.

[0563] In some embodiments, the anti-SARS-CoV-2 antibody targets the S1 domain of the spike protein of SARS-CoV-2. In some embodiments, the anti-SARS-CoV-2 antibody targets the class 4 region of the S1 domain. In some embodiments, the anti-SARS-CoV-2 monoclonal antibody targets the RBD (e.g., an RBD class 1, 2, or 3 epitope) of the S1 domain of SARS-CoV-2. In some embodiments, the anti-SARS-CoV-2 antibody targets the class 3 region of the S1 domain. In some embodiments, the anti-SARS-CoV-2 antibody targets the N-terminal domain (NTD) non-supersite region of the S1 domain. In some embodiments, the anti-SARS-CoV-2 antibody targets the SD1 region of the S1 domain.

[0564] In some embodiments, the anti-SARS-CoV-2 monoclonal antibody targets (e.g., binds to) the S2 domain of the spike protein of SARS-CoV-2. In some embodiments, the 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), bebuterovimab (LY-CoV1404, LY3853113), casirivimab (REGN10933), imdevimab (REGN10987), silgavimab, tixagevimab, AZD7442 / Evasheld® (tixagevimab-silgavimab), regdanvimab, sotrovimab (Vir Biotechnology, Inc.), ADG20 (Adagio Therapeutics, Inc.), ensovibep (MP0420) (DARPin, Novartis), and P2G3 (Aerium Tx).

[0565] In some embodiments, the at least one additional therapeutic agent comprises an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of the SARS-CoV-2 spike.

[0566] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is 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), 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) H Amino acid sequence and V L V comprising HCDR1, HCDR2, and HCDR3 of an antibody, each comprising the amino acid sequence H domain and V, which contains LCDR1, LCDR2, and LCDR3 L domain.

[0567] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike has the V H Amino acid sequence and V of SEQ ID NO: 75 L The antibody (S2_AB-1) comprises the amino acid sequence HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0568] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is a) HCDR1 comprising GYTFTRYW (SEQ ID NO: 557); b) HCDR2 comprising IYPGDSDV (SEQ ID NO: 558); c) HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO: 559); d) LCDR1 comprising QGISSW (SEQ ID NO: 560); e) LCDR2 containing AAS, and f) LCDR3 comprising QQGHSFPYT (SEQ ID NO: 561).

[0569] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is a) HCDR1 consisting of GYTFTRYW (SEQ ID NO: 557), b) HCDR2 consisting of IYPGDSDV (SEQ ID NO: 558); c) HCDR3 consisting of ARLPQYCSKGVCYRWFDP (SEQ ID NO: 559); d) LCDR1 consisting of QGISSW (SEQ ID NO: 560); e) LCDR2 consisting of AAS, and f) LCDR3 consisting of QQGHSFPYT (sequence number 561).

[0570] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is V comprising the amino acid sequence of SEQ ID NO: 53H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-1), V comprising the amino acid sequence of SEQ ID NO: 57 H V domain and the amino acid sequence of SEQ ID NO: 76 L Domain (S2_AB-2), V comprising the amino acid sequence of SEQ ID NO: 58 H V domain and the amino acid sequence of SEQ ID NO: 77 L Domain (S2_AB-3), V comprising the amino acid sequence of SEQ ID NO: 59 H V domain and the amino acid sequence of SEQ ID NO: 78 L Domain (S2_AB-4), V comprising the amino acid sequence of SEQ ID NO: 60 H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-5), V comprising the amino acid sequence of SEQ ID NO: 61 H V domain and the amino acid sequence of SEQ ID NO: 79 L Domain (S2_AB-6), V comprising the amino acid sequence of SEQ ID NO: 62 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-7), V comprising the amino acid sequence of SEQ ID NO: 63 H V domain and the amino acid sequence of SEQ ID NO: 81 L Domain (S2_AB-8), V comprising the amino acid sequence of SEQ ID NO: 64 H V domain and the amino acid sequence of SEQ ID NO: 82 L Domain (S2_AB-9), V comprising the amino acid sequence of SEQ ID NO: 65 H V domain and the amino acid sequence of SEQ ID NO: 83 L Domain (S2_AB-10), V comprising the amino acid sequence of SEQ ID NO: 66 H V domain and the amino acid sequence of SEQ ID NO: 84 LDomain (S2_AB-11), V comprising the amino acid sequence of SEQ ID NO: 67 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-12), V comprising the amino acid sequence of SEQ ID NO: 68 H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-13), V comprising the amino acid sequence of SEQ ID NO: 62 H V domain and the amino acid sequence of SEQ ID NO: 74 L Domain (S2_AB-14), V comprising the amino acid sequence of SEQ ID NO: 69 H V domain and the amino acid sequence of SEQ ID NO: 85 L Domain (S2_AB-15), V comprising the amino acid sequence of SEQ ID NO: 70 H V domain and the amino acid sequence of SEQ ID NO: 86 L Domain (S2_AB-16), V comprising the amino acid sequence of SEQ ID NO: 58 H V domain and the amino acid sequence of SEQ ID NO: 87 L Domain (S2_AB-17), V comprising the amino acid sequence of SEQ ID NO: 71 H V domain and the amino acid sequence of SEQ ID NO: 88 L Domain (S2_AB-18), V comprising the amino acid sequence of SEQ ID NO: 53 H V domain and the amino acid sequence of SEQ ID NO: 85 L Domain (S2_AB-19), V comprising the amino acid sequence of SEQ ID NO: 72 H V domain and the amino acid sequence of SEQ ID NO: 85 L Domain (S2_AB-20), V comprising the amino acid sequence of SEQ ID NO: 94 H domain and V comprising the amino acid sequence of SEQ ID NO: 113 L Domain (S2_AB-21), V comprising the amino acid sequence of SEQ ID NO: 95H domain and V comprising the amino acid sequence of SEQ ID NO: 114 L Domain (S2_AB-22), V comprising the amino acid sequence of SEQ ID NO: 53 H domain and V comprising the amino acid sequence of SEQ ID NO: 115 L Domain (S2_AB-23), V comprising the amino acid sequence of SEQ ID NO: 96 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-24), V comprising the amino acid sequence of SEQ ID NO: 97 H domain and V comprising the amino acid sequence of SEQ ID NO: 116 L Domain (S2_AB-25), V comprising the amino acid sequence of SEQ ID NO: 98 H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-26), V comprising the amino acid sequence of SEQ ID NO: 99 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-27), V comprising the amino acid sequence of SEQ ID NO: 100 H V domain and the amino acid sequence of SEQ ID NO: 85 L Domain (S2_AB-28), V comprising the amino acid sequence of SEQ ID NO: 101 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-29), V comprising the amino acid sequence of SEQ ID NO: 101 H V domain and the amino acid sequence of SEQ ID NO: 117 L Domain (S2_AB-30), V comprising the amino acid sequence of SEQ ID NO: 102 H V domain and the amino acid sequence of SEQ ID NO: 118 L Domain (S2_AB-31), V comprising the amino acid sequence of SEQ ID NO: 103 H V domain and the amino acid sequence of SEQ ID NO: 119L Domain (S2_AB-32), V comprising the amino acid sequence of SEQ ID NO: 104 H V domain and the amino acid sequence of SEQ ID NO: 120 L Domain (S2_AB-33), V comprising the amino acid sequence of SEQ ID NO: 105 H domain and V comprising the amino acid sequence of SEQ ID NO: 115 L Domain (S2_AB-34), V comprising the amino acid sequence of SEQ ID NO: 106 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-35), V comprising the amino acid sequence of SEQ ID NO: 107 H domain and V comprising the amino acid sequence of SEQ ID NO: 121 L Domain (S2_AB-36), V comprising the amino acid sequence of SEQ ID NO: 108 H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-37), V comprising the amino acid sequence of SEQ ID NO: 109 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-38), V comprising the amino acid sequence of SEQ ID NO: 110 H V domain and the amino acid sequence of SEQ ID NO: 87 L Domain (S2_AB-39), V comprising the amino acid sequence of SEQ ID NO: 111 H V domain and the amino acid sequence of SEQ ID NO: 117 L Domain (S2_AB-40), V comprising the amino acid sequence of SEQ ID NO: 562 H V domain and the amino acid sequence of SEQ ID NO: 573 L Domain (S2_AB-41), V comprising the amino acid sequence of SEQ ID NO: 563 H V domain and the amino acid sequence of SEQ ID NO: 76 L Domain (S2_AB-42), V comprising the amino acid sequence of SEQ ID NO: 564 H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-43), V comprising the amino acid sequence of SEQ ID NO: 565 H V domain and the amino acid sequence of SEQ ID NO: 574 L Domain (S2_AB-44), V comprising the amino acid sequence of SEQ ID NO: 566 H V domain and the amino acid sequence of SEQ ID NO: 80 L Domain (S2_AB-45), V comprising the amino acid sequence of SEQ ID NO: 567 H V domain and the amino acid sequence of SEQ ID NO: 75 L Domain (S2_AB-46), V comprising the amino acid sequence of SEQ ID NO: 568 H V domain and the amino acid sequence of SEQ ID NO: 574 L Domain (S2_AB-47), V comprising the amino acid sequence of SEQ ID NO: 569 H V domain and the amino acid sequence of SEQ ID NO: 77 L Domain (S2_AB-48), V comprising the amino acid sequence of SEQ ID NO: 570 H V domain and the amino acid sequence of SEQ ID NO: 76 L Domain (S2_AB-49), V comprising the amino acid sequence of SEQ ID NO: 571 H V domain and the amino acid sequence of SEQ ID NO: 575 L Domain (S2_AB-50), or V comprising the amino acid sequence of SEQ ID NO: 56 H V domain and the amino acid sequence of SEQ ID NO: 80 L domain (S2_AB-51), including

[0571] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is a) V comprising the amino acid sequence of SEQ ID NO: 53H domain, and b) V comprising the amino acid sequence of SEQ ID NO: 75 L domain, including

[0572] In some embodiments, the composition (e.g., pharmaceutical composition) comprises: a) i. V comprising HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, HCDR2 comprising the amino acid sequence of SEQ ID NO: 28, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 33 H domain, and ii. V comprising LCDR1 comprising the amino acid sequence of SEQ ID NO: 37, LCDR2 comprising the amino acid sequence of SEQ ID NO: 40, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 44 L an antibody or antigen-binding fragment thereof comprising a domain; b) i. V comprising HCDR1 comprising GYTFTRYW (SEQ ID NO: 557), HCDR2 comprising IYPGDSDV (SEQ ID NO: 558), and HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO: 559) H domain, and ii. V comprising an LCDR1 comprising QGISSW (SEQ ID NO: 560), an LCDR2 comprising AAS, and an LCDR3 comprising QQGHSFPYT (SEQ ID NO: 561). L and an antibody or antigen-binding fragment thereof comprising the domain.

[0573] In some embodiments, the composition (e.g., pharmaceutical composition) comprises: a) i. V comprising HCDR1 consisting of the amino acid sequence of SEQ ID NO: 24, HCDR2 consisting of the amino acid sequence of SEQ ID NO: 28, and HCDR3 consisting of the amino acid sequence of SEQ ID NO: 33 H domain, and ii. V comprising LCDR1 consisting of the amino acid sequence of SEQ ID NO: 37, LCDR2 consisting of the amino acid sequence of SEQ ID NO: 40, and LCDR3 consisting of the amino acid sequence of SEQ ID NO: 44 L an antibody or antigen-binding fragment thereof comprising a domain; b) i. V comprising HCDR1 consisting of GYTFTRYW (SEQ ID NO: 557), HCDR2 consisting of IYPGDSDV (SEQ ID NO: 558), and HCDR3 consisting of ARLPQYCSKGVCYRWFDP (SEQ ID NO: 559) H domain, and ii. V 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). L and an antibody or antigen-binding fragment thereof comprising the domain.

[0574] In some embodiments, the composition (e.g., pharmaceutical composition) comprises: a) V comprising the amino acid sequence of SEQ ID NO: 5 H domain and V comprising the amino acid sequence of SEQ ID NO: 14 L an antibody or antigen-binding fragment thereof comprising the domain; b) V comprising the amino acid sequence of SEQ ID NO: 53 H V domain and the amino acid sequence of SEQ ID NO: 75 L an antibody or antigen-binding fragment thereof comprising the domain.

[0575] In some embodiments, the composition (e.g., pharmaceutical composition) comprises: a) an antibody or 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 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.

[0576] S2_AB-1 heavy chain sequence: [ka]

[0577] S2_AB-1 light chain sequence: [ka]

[0578] How to use The present disclosure also provides, inter alia, a method for neutralizing SARS-CoV-2 proteins in a subject comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, any one of the polypeptides, polynucleotides, fusion proteins, or compositions disclosed herein.

[0579] The present disclosure also provides, inter alia, methods of treating a subject in need of treatment comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, any one of the polypeptides, polynucleo...

Claims

1. A polypeptide comprising: a) an immunoglobulin heavy chain variable (V) region comprising heavy chain complementarity determining regions (HCDR) 1, HCDR2, and HCDR3; Ｈ ) domain, wherein the HCDR1, the HCDR2, and the HCDR3 are V as shown in Table 1 or Table 4 herein. Ｈ V, which has 100% sequence identity to HCDR1, HCDR2, and HCDR3 of the domains, respectively. Ｈ The domain and b) an immunoglobulin light chain variable (V) region comprising light chain complementarity determining regions (LCDR) 1, LCDR2, and LCDR3; Ｌ ) domain, wherein the LCDR1, the LCDR2, and the LCDR3 are selected from the group consisting of V and VL domains shown in Table 2 or Table 4 herein. Ｌ V, which has 100% sequence identity to the LCDR1, LCDR2, and LCDR3 of the domain, respectively. Ｌ a domain, A polypeptide that is an antibody or an antigen-binding fragment thereof.

2. a) the V of the polypeptide Ｈ V domain comprising the amino acid sequence of SEQ ID NO:5 Ｈ and comprising HCDR1, HCDR2, and HCDR3 of b) the V Ｌ The V domain comprises the amino acid sequence of SEQ ID NO:

14. Ｌ The polypeptide of claim 1, comprising LCDR1, LCDR2, and LCDR3 of:

3. a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 24; b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 28; c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 33; d) 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 f) LCDR3 comprising the amino acid sequence of SEQ ID NO:

44.

4. a) HCDR1 consisting of the amino acid sequence of SEQ ID NO: 24; b) HCDR2 consisting of the amino acid sequence of SEQ ID NO: 28; c) HCDR3 consisting of the amino acid sequence of SEQ ID NO: 33; d) 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) LCDR3 consisting of the amino acid sequence of SEQ ID NO:

44.

5. a) V that are humanized and / or contain human framework regions Ｈ , b) V that are humanized and / or contain human framework regions Ｌ , Or both of a) and b).

6. a) the V of the polypeptide Ｈ The domain is a V domain shown in Table 1 or Table 4 herein. Ｈ an amino acid sequence having 100% sequence identity to the amino acid sequence of the domain; b) the V of the polypeptide Ｌ The domain is a V domain shown in Table 2 or Table 4 herein. Ｌ an amino acid sequence having 100% sequence identity to the amino acid sequence of the domain; The V Ｈ domain and the V Ｌ The domains are V as shown in Table 5 herein. Ｈ / V Ｌ The polypeptide according to any one of claims 1 to 5, selected from the combinations of:

7. a) V comprising the amino acid sequence of SEQ ID NO: 5 Ｈ , and b) V comprising the amino acid sequence of SEQ ID NO: 14 Ｌ The polypeptide according to any one of claims 1 to 6, comprising:

8. The polypeptide may comprise a single chain variable fragment (scFv), a variable heavy domain of a heavy chain (V ＨＨ ), antigen-binding fragment (Fab), Fab', or F(ab') ２ The polypeptide of any one of claims 1 to 7, which is an antigen-binding fragment comprising:

9. a) an antibody heavy chain constant domain; b) an antibody light chain constant domain; or both of them.

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

11. The polypeptide of any one of claims 1 to 10, comprising an IgG1 antibody heavy chain constant domain.

12. 12. The polypeptide of any one of claims 9 to 11, wherein the antibody heavy chain constant domain comprises at least one mutation that increases the serum half-life of the antibody or antigen-binding fragment thereof in humans.

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

14. 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. a) an antibody HC comprising the amino acid sequence of SEQ ID NO: 576; b) antibody LC comprising the amino acid sequence of SEQ ID NO: 577; Or both a) and b).

16. 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. a) an antibody HC comprising the amino acid sequence of SEQ ID NO: 576; b) antibody LC comprising the amino acid sequence of SEQ ID NO: 52; Or both a) and b).

18. 18. The polypeptide of any one of claims 1 to 17, wherein the polypeptide specifically binds to a spike receptor binding domain (RBD) class 4 epitope of the spike glycoprotein of a betacoronavirus (SARS-CoV-2-spike).

19. The polypeptide of any one of claims 1 to 18, wherein the polypeptide is conjugated to a heterologous moiety.

20. 20. The polypeptide of claim 19, wherein the heterologous moiety is a therapeutic agent, a diagnostic agent, or a combination thereof.

21. 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 polymeric nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA).

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

24. 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 to 24.

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

27. 25. A method for producing a polypeptide according to any one of claims 1 to 24, comprising culturing a host cell comprising a nucleotide sequence encoding said polypeptide under conditions in which said polypeptide is expressed in said host cell.

28. A composition comprising a polypeptide according to any one of claims 1 to 24 or a polynucleotide according to claim 25.

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

30. the at least one additional therapeutic agent is a) an antibody or antigen-binding fragment thereof that specifically binds to the SARS-CoV-2 spike; b) a polynucleotide comprising a nucleotide sequence encoding the antibody or antigen-binding fragment thereof of a); c) antiviral agents; d) ACE2 inhibitors; e) antibiotics; f) antimalarials, g) vaccines; or any combination of a) to g).

31. a) the antibody or antigen-binding fragment thereof that specifically binds to SARS-CoV-2 spike comprises bamlanivimab, etesevimab, bebuterovimab, casirivimab, imdevimab, silgavimab, tixagevimab, AZD7442 (tixagevimab-silgavimab), regdanvimab, sotrovimab, or a combination thereof; b) the antibody or antigen-binding fragment thereof that specifically binds to the SARS-CoV-2 spike binds to the S2 domain of the SARS-CoV-2 spike; c) the antiviral agent comprises oseltamivir (Tamiflu), favipiravir, amantadine, remdesivir, rimantadine, pleconaril, antisense RNA against SARS-CoV-2, siRNA against SARS-CoV-2, or a combination thereof; d) the ACE2 inhibitor comprises an RNAi against ACE2, an siRNA against 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 chloroquine; g) the vaccine comprises a nucleic acid vaccine and / or an inactivated virus vaccine; or any combination of a) to g).

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

33. The antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is 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), 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 V of SEQ ID NO: 56 and SEQ ID NO: 80 (S2_AB-51) Ｈ Amino acid sequence and V Ｌ V comprising HCDR1, HCDR2, and HCDR3 of the antibody, each comprising the amino acid sequence Ｈ domain and a V domain comprising LCDR1, LCDR2, and LCDR3 Ｌ and a domain.

34. The antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is selected from the group consisting of V of SEQ ID NO: 53 Ｈ Amino acid sequence and V of SEQ ID NO: 75 Ｌ The composition of any one of claims 31 to 33, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of an antibody (S2_AB-1) comprising the amino acid sequence.

35. The antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is a) HCDR1 comprising GYTFTRYW (SEQ ID NO: 557); b) HCDR2 comprising IYPGDSDV (SEQ ID NO: 558); c) HCDR3 comprising ARLPQYCSKGVCYRWFDP (SEQ ID NO: 559); d) LCDR1 comprising QGISSW (SEQ ID NO: 560); e) LCDR2 containing an AAS, and f) an LCDR3 comprising QQGHSFPYT (SEQ ID NO: 561).

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

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

38. The antibody or antigen-binding fragment thereof that specifically binds to the S2 domain of SARS-CoV-2 spike is a) V comprising the amino acid sequence of SEQ ID NO: 53 Ｈ , and b) V comprising the amino acid sequence of SEQ ID NO: 75 Ｌ The composition of any one of claims 31 to 37, comprising:

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

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

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

42. 42. The method of claim 40 or 41, wherein the subject is a human.

43. 43. The method of any one of claims 40-42, wherein the subject has, is suspected of having, or is at risk of developing COVID-19.

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

45. a) the cardiac disease comprises congestive heart disease, coronary artery disease, hypertensive heart disease, inflammatory heart disease, pulmonary heart disease, rheumatic heart disease, valvular heart disease, cardiomyopathy, heart failure, or a combination thereof; and optionally i) the heart failure comprises congestive heart failure, and / or ii) the inflammatory heart disease comprises endocarditis, cardiac hypertrophy, myocarditis, or a combination thereof; b) the pulmonary disease comprises acute respiratory distress syndrome, asthma, bronchitis, COPD, emphysema, lung tumor, pleural cavity disease, pulmonary vascular disease, respiratory tract infection, or a combination thereof; and optionally 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 includes embolism, edema, arterial hypertension, and / or hemorrhage, or Is it a combination of these? Alternatively, both a) and b) are the method of claim 44.

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